{
    "train": [
        {
            "context": "Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 698,
                "text": "rabies"
            }
        },
        {
            "context": "Low frequency of the deltaAF508 mutation of the CFTR gene in a highly admixed population in Bahia, Brazil. Cystic fibrosis (CF) is the most common autosomal recessive disease in the European (Caucasian) population, with an incidence of 1:2000 to 1:8000. The deltaF508 mutation (66%) is predominant among more than 1300 different mutations of the CFTR gene. The population of the state of Bahia, in northeastern Brazil, is highly admixed (mainly African and Portuguese descendants), and so far, no study has been carried out to assess the molecular basis of CF in this population. We determined the deltaF508 mutation frequency in 503 individuals from the general population of Salvador, the capital of the state of Bahia, and in 144 CF patients from several cities in Bahia. In the general population samples we found 4 individuals heterozygous for the deltaF508 mutation (allele frequency of 0.4%). This frequency was lower than that found in the state of Rio de Janeiro, in southeastern Brazil, and similar to that reported for the state of Paraná, in the far south. In the CF patients we found 9 heterozygous individuals and 8 homozygous individuals (allele frequency of 8.68%) for the deltaF508 mutation. This frequency is considerably lower than the average frequency of CF in the world population and in the Brazilian CF population of European ancestry (47%). These data could be explained by the intense admixture among the population in Bahia, and they suggest a heterogeneous molecular basis for CF in this area of Brazil.",
            "question": "What is the incidence of cystic fibrosis in the caucasian population?",
            "answers": {
                "answer_start": 236,
                "text": "1:2000"
            }
        },
        {
            "context": "TNF-α: a treatment target or cause of sarcoidosis? Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF-α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF-α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF-α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF-α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF-α in granuloma formation, the therapeutic role of TNF-α inhibition and immunologic abnormalities following treatment with these TNF-α inhibitors including drug-specific alterations involving interferon-γ, lymphotoxin-α, TNF receptor 2 (TNFR2) and T-regulatory cells.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 179,
                "text": "corticosteroids"
            }
        },
        {
            "context": "Coilin, more than a molecular marker of the cajal (coiled) body. The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 445,
                "text": "coilin"
            }
        },
        {
            "context": "The pharmacoepidemiology of antipsychotics for adults with schizophrenia in Canada, 2005 to 2009. OBJECTIVE: To describe the frequency and trends in the use of antipsychotics for adults with schizophrenia in Canada from 2005 to 2009. METHODS: Analyses were performed on IMS Brogan's Canadian Disease and Therapeutic Index (CDTI). The CDTI is a national physician panel study consisting of a representative sample of physicians both geographically and by specialty. Weighting adjustments are made to estimate national drug recommendations. Quarterly, panel physicians record all therapeutic recommendations during a 2-day period, including patient age, sex, and indication. Antipsychotic recommendations were estimated using CDTI data in which schizophrenia was listed as the indication. RESULTS: First-generation antipsychotic (FGA) recommendations for adults with schizophrenia increased by 38% between 2005 and 2009, from 329 380 to 454 960 recommendations. There were notable increases in recommendations for chlorpromazine, loxapine, zuclopenthixol, and flupentixol. Second-generation antipsychotic (SGA) recommendations increased to a much lesser extent (9%), which was mostly attributable to an increase in recommendations for clozapine. Drug recommendations for olanzapine decreased by 9%. CONCLUSION: The rate of increase of FGA use is now greater than that of SGAs. This may be due to data from recent comparative trials, which suggest that clinical efficacy, and the rate of neurological side effects is similar between FGAs and SGAs. The decreasing use of olanzapine may be due to metabolic adverse effects. The increased use of clozapine may be due to data on its superiority in patients who are treatment resistant.",
            "question": "What disease in Loxapine prominently used for?",
            "answers": {
                "answer_start": 865,
                "text": "schizophrenia"
            }
        },
        {
            "context": "\"Mowat-Wilson\" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with \"syndromic Hirschsprung disease\" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations. In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had \"syndromic Hirschsprung disease\" two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the \"Mowat-Wilson syndrome.\"",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 579,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Genetic associations in type I interferon related pathways with autoimmunity. Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFNα activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.",
            "question": "Which is the most common gene signature in Rheumatoid Arthritis patients?",
            "answers": {
                "answer_start": 1247,
                "text": "interferon signature"
            }
        },
        {
            "context": "\"Cherchez La Femme\": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. INTRODUCTION: Selective estrogen receptor modulators (SERMs) have been used off-label in men for more than 50 years. SERMs exert their action on the estrogen receptor agonistically or antagonistically. A fundamental knowledge of the complex molecular action and physiology of SERMs is important in understanding their use and future directions of study in men. AIM: To review the basic science and mechanism of the action of estrogens, the estrogen receptor, and SERMs, and the existing clinical publications on the use of SERMs in men for infertility and hypogonadism with their strengths and weaknesses and to identify the need for future studies. METHODS: After a review of publications on the basic science of estrogen receptors, a chronologic review of published evidence-based studies on the use of SERMs in men for infertility and hypogonadism was undertaken. MAIN OUTCOME MEASURES: Clinical publications were assessed for type of study, inclusion criteria, outcome measurements, and results. Strengths and weaknesses of the publications were assessed and discussed. RESULTS: Few prospective rigorously controlled trials have been undertaken on the use of SERMs in men. Most existing trials are largely retrospective anecdotal studies with inconsistent inclusion and end-point measurements. The SERMs are complex and at times can produce paradoxical results. Their action likely depends on the genetics of the individual, his tissue-specific composition of estrogen receptors, the molecular structure and pharmacodynamics of the SERMs, and their metabolism. CONCLUSION: Rigorously controlled trials of the use of SERMs in men are needed to better identify their clinical benefit and long-term safety in infertile and hypogonadal men. Recent placebo-controlled pharmaceutical industry SERM trials have demonstrated short-term safety and efficacy in men with secondary hypogonadism and eventually might provide an alternative to exogenous testosterone replacement therapy in men with secondary hypogonadism. Helo S, Wynia B, McCullough A. \"Cherchez La Femme\": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. Sex Med Rev 2017;5:365-386.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 150,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 551,
                "text": "CAGEr"
            }
        },
        {
            "context": "Clinical assessment of bortezomib for multiple myeloma in comparison with thalidomide. PURPOSE: We studied the efficacy and safety of bortezomib (BOR) for treatment of multiple myeloma in comparison with thalidomide (THAL) by reference to adverse events, and searched for laboratory markers that could be used for prognostication of patients. METHODS: Biochemical data of patients receiving BOR and THAL for treatment of multiple myeloma at the Japanese Red Cross Narita Hospital were investigated retrospectively, after obtaining Institutional Review Board approval. Judgment of curative effects complied with the effects criteria of the International Myeloma Working Group (IMWG). RESULTS: BOR showed a higher rate of effectiveness than THAL for refractory multiple myeloma, and its effects were rapid. BOR treatment prolonged the survival time of THAL-resistant patients. The efficacy of BOR was unrelated to patient age, the number of previous therapeutic regimens, or the disease period. After medication with BOR, patients in whom it had been effective tended to show an increase of the serum alkaline phosphatase (ALP) level. Thrombocytopenia (86.2%) and leucopenia (69.0%) were observed at high frequencies, but no previously unreported adverse events or fatalities were associated with BOR therapy. CONCLUSION: It is suggested that BOR has therapeutic efficacy for multiple myeloma as a first-line medical treatment and/or for patients with THAL resistance, and can improve prognosis and survival. Since serum ALP elevation was observed in many patients for whom BOR was effective, this may be a predictor of BOR efficacy.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 759,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Assessment of the hemispheric lateralization of grapheme-color synesthesia with Stroop-type tests. Grapheme-color synesthesia, the idiosyncratic, arbitrary association of colors to letters or numbers, develops in childhood once reading is mastered. Because language processing is strongly left-lateralized in most individuals, we hypothesized that grapheme-color synesthesia could be left-lateralized as well. We used synesthetic versions of the Stroop test with colored letters and numbers presented either in the right or the left visual field of thirty-four synesthetes. Interference by synesthetic colors was stronger for stimuli in the right hemifield (first experiment, color naming task). Synesthetes were also faster in the right hemifield when naming the synesthetic color of graphemes (second experiment). Overall, the lateralization effect was 7 ms (the 95% confidence interval was [1.5 12] ms), a delay compatible with an additional callosal transfer for stimuli presented in the left hemifield. Though weak, this effect suggests that the association of synesthetic colors to graphemes may be preferentially processed in the left hemisphere. We speculate that this left-lateralization could be a landmark of synesthetic grapheme-color associations, if not found for color associations learnt by non-synesthete adults.",
            "question": "Which test is used to diagnose colour synesthesia?",
            "answers": {
                "answer_start": 446,
                "text": "Stroop test"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 133,
                "text": "CD38"
            }
        },
        {
            "context": "The role of the ALK receptor in cancer biology. A vast array of oncogenic variants has been identified for anaplastic lymphoma kinase (ALK). Therefore, there is a need to better understand the role of ALK in cancer biology in order to optimise treatment strategies. This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements. A wide variety of ALK fusions, in which the kinase domain of ALK and the amino-terminal portion of various protein partners are fused, occur in cancer, with echinoderm microtubule-associated protein-like 4 (EML4)-ALK being the most prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusion proteins can mediate different signalling outputs, depending on properties such as subcellular localisation and protein stability. The ALK fusions found in tumours lack spatial and temporal regulation, which can also affect dimerisation and substrate specificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and ceritinib, are currently approved in Europe for use in ALK-positive NSCLC and several others are in development. These ALK TKIs bind slightly differently within the ATP-binding pocket of the ALK kinase domain and are associated with the emergence of different resistance mutation patterns during therapy. This emphasises the need to tailor the sequence of ALK TKIs according to the ALK signature of each patient. Research into the oncogenic functions of ALK, and fast paced development of ALK inhibitors, has substantially improved outcomes for patients with ALK-positive NSCLC. Limited data are available surrounding the physiological ligand-stimulated activation of ALK signalling and further research is needed. Understanding the role of ALK in tumour biology is key to further optimising therapeutic strategies for ALK-positive disease.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 413,
                "text": "cancer"
            }
        },
        {
            "context": "Detection of borderline oxacillin-resistant Staphylococcus aureus and differentiation from methicillin-resistant strains. Eighty-eight Staphylococcus aureus clinical isolates meeting criteria for borderline oxacillin resistance (intermediate susceptibility or resistance to oxacillin but susceptibility to amoxicillin/clavulanic acid upon disk diffusion testing) were studied to determine optimal test techniques and conditions for differentiating borderline oxacillin-resistant Staphylococcus aureus (BORSA) from methicillin-resistant Staphylococcus aureus (MRSA). Further testing revealed three distinct resistance patterns: 61 strains (69%) consistently met BORSA criteria and had average beta-lactamase levels five- to six-fold higher than oxacillin-susceptible controls; 11 strains (13%) were markedly heteroresistant MRSA with delayed appearance of resistant colonies leading to spurious susceptibility to amoxicillin/clavulanic acid; 16 strains (18%) appeared to be oxacillin-susceptible on repetitive testing. Under conditions used to elicit intrinsic methicillin resistance in Staphylococcus aureus, a large percentage of BORSA appeared resistant to amoxicillin/clavulanic acid. This clearly shows that BORSA may be misidentified as MRSA while heteroresistant MRSA may appear to be BORSA. It is concluded that amoxicillin/clavulanic acid zone sizes should be measured after a full 24 hours of incubation, that susceptibility testing of Staphylococcus aureus under certain environmental conditions should be interpreted with caution, and that MIC testing is the most reliable technique for differentiating these two resistance patterns in Staphylococcus aureus.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 13,
                "text": "borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Nuclear translocation and activation of the transcription factor NFAT is blocked by herpes simplex virus infection. Transcription factors of the NFAT (nuclear factor of activated T cells) family are expressed in most immune system cells and in a range of other cell types. Signaling through NFAT is implicated in the regulation of transcription for the immune response and other processes, including differentiation and apoptosis. NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation pathway is the regulation of its nuclear import by the Ca(2+)/calmodulin-dependent phosphatase calcineurin. In a cell line stably expressing green fluorescent protein (GFP)-NFAT, this import can be triggered by elevation of intracellular calcium and visualized in live cells. Here we show that the inducible nuclear import of GFP-NFAT is efficiently blocked at early stages of herpes simplex virus (HSV) infection. This is a specific effect, since we observed abundant nuclear accumulation of a test viral protein and no impediment to general nuclear localization signal-dependent nuclear import and retention in infected cells. We show that virus binding at the cell surface is not itself sufficient to inhibit the signaling that induces NFAT nuclear translocation. Since the block occurs following infection in the presence of phosphonoacetic acid but not cycloheximide, we infer that the entry of the virion and early gene transcription are required but the effect is independent of DNA replication or late virus gene expression. A consequence of the block to GFP-NFAT import is a reduction in NFAT-dependent transcriptional activation from the interleukin-2 promoter in infected cells. This HSV-mediated repression of the NFAT pathway may constitute an immune evasion strategy or subversion of other NFAT-dependent cellular processes to promote viral replication.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 606,
                "text": "calcineurin"
            }
        },
        {
            "context": "Long-term control of endemic hospital-wide methicillin-resistant Staphylococcus aureus (MRSA): the impact of targeted active surveillance for MRSA in patients and healthcare workers. OBJECTIVE: To evaluate the long-term impact of successive interventions on rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection and MRSA bacteremia in an endemic hospital-wide situation. DESIGN: Quasi-experimental, interrupted time-series analysis. The impact of the interventions was analyzed by use of segmented regression. Representative MRSA isolates were typed by use of pulsed-field gel electrophoresis. SETTING: A 950-bed teaching hospital in Seville, Spain. PATIENTS: All patients admitted to the hospital during the period from 1995 through 2008. METHODS: Three successive interventions were studied: (1) contact precautions, with no active surveillance for MRSA; (2) targeted active surveillance for MRSA in patients and healthcare workers in specific wards, prioritized according to clinical epidemiology data; and (3) targeted active surveillance for MRSA in patients admitted from other medical centers. RESULTS: Neither the preintervention rate of MRSA colonization or infection (0.56 cases per 1,000 patient-days [95% confidence interval {CI}, 0.49-0.62 cases per 1,000 patient-days]) nor the slope for the rate of MRSA colonization or infection changed significantly after the first intervention. The rate decreased significantly to 0.28 cases per 1,000 patient-days (95% CI, 0.17-0.40 cases per 1,000 patient-days) after the second intervention and to 0.07 cases per 1,000 patient-days (95% CI, 0.06-0.08 cases per 1,000 patient-days) after the third intervention, and the rate remained at a similar level for 8 years. The MRSA bacteremia rate decreased by 80%, whereas the rate of bacteremia due to methicillin-susceptible S. aureus did not change. Eighty-three percent of the MRSA isolates identified were clonally related. All MRSA isolates obtained from healthcare workers were clonally related to those recovered from patients who were in their care. CONCLUSION: Our data indicate that long-term control of endemic MRSA is feasible in tertiary care centers. The use of targeted active surveillance for MRSA in patients and healthcare workers in specific wards (identified by means of analysis of clinical epidemiology data) and the use of decolonization were key to the success of the program.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 88,
                "text": "MRSA"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 1242,
                "text": "IgG4"
            }
        },
        {
            "context": "Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis. The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 232,
                "text": "MC1R"
            }
        },
        {
            "context": "Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1708,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 66,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "α-Synuclein membrane association is regulated by the Rab3a recycling machinery and presynaptic activity. α-Synuclein is an abundant presynaptic protein and a primary component of Lewy bodies in Parkinson disease. Although its pathogenic role remains unclear, in healthy nerve terminals α-synuclein undergoes a cycle of membrane binding and dissociation. An α-synuclein binding assay was used to screen for vesicle proteins involved in α-synuclein membrane interactions and showed that antibodies directed to the Ras-related GTPase Rab3a and its chaperone RabGDI abrogated α-synuclein membrane binding. Biochemical analyses, including density gradient sedimentation and co-immunoprecipitation, suggested that α-synuclein interacts with membrane-associated GTP-bound Rab3a but not to cytosolic GDP-Rab3a. Accumulation of membrane-bound α-synuclein was induced by the expression of a GTPase-deficient Rab3a mutant, by a dominant-negative GDP dissociation inhibitor mutant unable to recycle Rab3a off membranes, and by Hsp90 inhibitors, radicicol and geldanamycin, which are known to inhibit Rab3a dissociation from membranes. Thus, all treatments that inhibited Rab3a recycling also increased α-synuclein sequestration on intracellular membranes. Our results suggest that membrane-bound GTP-Rab3a stabilizes α-synuclein on synaptic vesicles and that the GDP dissociation inhibitor·Hsp90 complex that controls Rab3a membrane dissociation also regulates α-synuclein dissociation during synaptic activity.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 105,
                "text": "α-Synuclein"
            }
        },
        {
            "context": "Preliminary Evaluation of the Effect of Investigational Ebola Virus Disease Treatments on Viral Genome Sequences. BACKGROUND: Several patients with Ebola virus disease (EVD) managed in the United States have received ZMapp monoclonal antibodies, TKM-Ebola small interfering RNA, brincidofovir, and/or convalescent plasma as investigational therapeutics. METHODS: To investigate whether treatment selected for Ebola virus (EBOV) mutations conferring resistance, viral sequencing was performed on RNA extracted from clinical blood specimens from patients with EVD following treatment, and putative viral targets were analyzed. RESULTS: We observed no major or minor EBOV mutations within regions targeted by therapeutics. CONCLUSIONS: This small subset of patients and clinical specimens suggests that evolution of resistance is not a direct consequence of antiviral treatment. As EVD antiviral treatments are introduced into wider use, it is essential that continuous viral full-genome surveillance is performed, to monitor for the emergence of escape mutations.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 148,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "Color blindness defect and medical laboratory technologists: unnoticed problems and the care for screening. Color-blindness is the inability to perceive differences between some color that other people can distinguish. Using a literature search, the results indicate the prevalence of color vision deficiency in the medical profession and its on medical skills. Medical laboratory technicians and technologists employees should also screen for color blindness. This research aimed to study color blindness prevalence among Hospitals' Clinical Laboratories' Employees and Students in Tehran University of Medical Sciences (TUMS). A cross-sectional descriptive and analytical study was conducted among 633 TUMS Clinical Laboratory Sciences' Students and Hospitals' Clinical Laboratories' Employees to detect color-blindness problems by Ishihara Test. The tests were first screened with certain pictures, then compared to the Ishihara criteria to be possible color defective were tested further with other plates to determine color - blindness defects. The data was saved using with SPSS software and analyzed by statistical methods. This is the first study to determine the prevalence of color - blindness in Clinical Laboratory Sciences' Students and Employees. 2.4% of TUMS Medical Laboratory Sciences Students and Hospitals' Clinical Laboratories' Employees are color-blind. There is significant correlation between color-blindness and sex and age. But the results showed that there is not significant correlation between color-blindness defect and exposure to chemical agents, type of job, trauma and surgery history, history of familial defect and race. It would be a wide range of difficulties by color blinded students and employees in their practice of laboratory diagnosis and techniques with a potentially of errors. We suggest color blindness as a medical conditions should restrict employment choices for medical laboratory technicians and technologists job in Iran.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 834,
                "text": "Ishihara Test"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 10,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization. OBJECTIVES: The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. METHODS: Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). RESULTS: Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. CONCLUSIONS: These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 641,
                "text": "HIV"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 535,
                "text": "CD38"
            }
        },
        {
            "context": "Cognitive abilities of Alzheimer's disease transgenic mice are modulated by social context and circadian rhythm. In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer's disease mouse model.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 1173,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Extrachromosomal element capture and the evolution of multiple replication origins in archaeal chromosomes. In all three domains of life, DNA replication begins at specialized loci termed replication origins. In bacteria, replication initiates from a single, clearly defined site. In contrast, eukaryotic organisms exploit a multitude of replication origins, dividing their genomes into an array of short contiguous units. Recently, the multiple replication origin paradigm has also been demonstrated within the archaeal domain of life, with the discovery that the hyperthermophilic archaeon Sulfolobus has three replication origins. However, the evolutionary mechanism driving the progression from single to multiple origin usage remains unclear. Here, we demonstrate that Aeropyrum pernix, a distant relative of Sulfolobus, has two origins. Comparison with the Sulfolobus origins provides evidence for evolution of replicon complexity by capture of extrachromosomal genetic elements. We additionally identify a previously unrecognized candidate archaeal initiator protein that is distantly related to eukaryotic Cdt1. Our data thus provide evidence that horizontal gene transfer, in addition to its well-established role in contributing to the information content of chromosomes, may fundamentally alter the manner in which the host chromosome is replicated.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 437,
                "text": "multiple"
            }
        },
        {
            "context": "FOXP2 gene deletion and infant feeding difficulties: a case report. Forkhead box protein P2 (FOXP2) is a well-studied gene known to play an essential role in normal speech development. Deletions in the gene have been shown to result in developmental speech disorders and regulatory disruption of downstream gene targets associated with common forms of language impairments. Despite similarities in motor planning and execution between speech development and oral feeding competence, there have been no reports to date linking deletions within the FOXP2 gene to oral feeding impairments in the newborn. The patient was a nondysmorphic, appropriately and symmetrically grown male infant born at 35-wk gestational age. He had a prolonged neonatal intensive care unit stay because of persistent oral feeding incoordination requiring gastrostomy tube placement. Cardiac and neurological imagings were within normal limits. A microarray analysis found an ∼9-kb loss within chromosome band 7q3.1 that contains exon 2 of FOXP2, demonstrating a single copy of this region instead of the normal two copies per diploid gene. This case study expands our current understanding of the role FOXP2 exerts on motor planning and coordination necessary for both oral feeding success and speech-language development. This case report has important consequences for future diagnosis and treatment for infants with FOXP2 deletions, mutations, and varying levels of gene expression.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 547,
                "text": "FOXP2"
            }
        },
        {
            "context": "Comparison of the BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay and the BD GeneOhm MRSA achromopeptidase assay with direct- and enriched-culture techniques using clinical specimens for detection of MRSA. We evaluated the new, fully automated molecular BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay for detection of methicillin-resistant S. aureus in a low-prevalence (4.1%) setting. Sensitivity, specificity, and positive and negative predictive values were 93.9%, 99.2%, 83.8%, and 99.7%, respectively. The assay reported fewer unresolved results than the BD GeneOhm MRSA ACP assay.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 216,
                "text": "MRSA"
            }
        },
        {
            "context": "A Study to Determine if Addition of Palatal Petechiae to Centor Criteria Adds More Significance to Clinical Diagnosis of Acute Strep Pharyngitis in Children. Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 2142,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Does the linear Sry transcript function as a ceRNA for miR-138? The sense of antisense. Recently, the sex determining region Y ( Sry) and the cerebellar degeneration-related protein 1 ( CDR1as) RNA transcripts have been described to function as a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7, respectively. A special feature of the Sry gene is its ability to generate linear and circular transcripts, both transcribed in the sense orientation. Here we remark that both sense (e.g. Sry RNA) and antisense (e.g. CDR1as) transcripts could circularize and behave as miRNAs sponges, and importantly, that also protein-coding segments of mRNAs could also assume this role. Thus, it is reasonable to think that the linear Sry sense transcript could additionally act as a miRNA sponge, or as an endogenous competing RNA for miR-138.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 914,
                "text": "miR-138"
            }
        },
        {
            "context": "Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease? The clinical features of two children of a family with rapidly progressive extrapyramidal-pyramidal-dementia complex have been described. Inheritance seems most likely to be autosomal recessive. Magnetic resonance imaging results of brain were negative. Even so, the authors argued in favor of a diagnosis of Hallervorden-Spatz disease because the cases fulfilled the clinical criteria for diagnosis of this disease. Apart from the negative magnetic resonance findings, the other unusual feature was the early development of levodopa-induced dyskinesia. Few conditions need to be considered in the differential diagnosis of a childhood-onset rapidly progressive extrapyramidal syndrome. Such conditions include Wilson's disease, Hallervorden-Spatz disease (HSD), juvenile form of Huntington's disease, juvenile neuronal ceroid lipofuscinosis, early-onset Machado-Joseph disease neuroacanthocytosis, storage disorders, and variant form of dopa-response dystonias (DRD). Rarer conditions are Leigh's disease, Lafora body disease, and dentato-rubro-pallido-luysian atrophy. HSD is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence. The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20. Recently, a mutation in the pantothenate kinase (PANK2) gene on band 20pl3 has been described in patients with typical HSD. HSD produces typical magnetic resonance imaging (MRI) changes in brain, aiding in antemortem diagnosis. The typical finding is of bilaterally symmetrical hyperintense signal changes in the external segment of globus pallidus, with surrounding hypointensity on T(2)-weighted image. These imaging features are fairly diagnostic and have been termed the \"eye-of-the tiger sign\". The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is caused by loss of signal secondary to iron deposition. Described herein are the clinical aspects of a family with autosomal recessive inheritance with rapidly progressive extrapyramidal-pyramidal-dementia complex but with negative brain MRI results. The diagnosis should be considered a variant form of HSD.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 272,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 41,
                "text": "TYR"
            }
        },
        {
            "context": "Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks. Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 339,
                "text": "telomerase"
            }
        },
        {
            "context": "Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 131,
                "text": "Facioscapulohumeral dystrophy"
            }
        },
        {
            "context": "Ackee (Blighia sapida) hypoglycin A toxicity: dose response assessment in laboratory rats. Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome. Hypoglycin A toxicity in this study was determined by feeding male and female Sprague-Dawley rats a control diet and ackee diets that contained 4-3840 ppm of hypoglycin. The fixed dose method was used to quantify the acute toxic dose of hypoglycin A and was determined by feeding a diet consisting of the lowest hypoglycin A concentration; this was increased to the next highest dose after 24h until toxicity was observed. The maximum tolerated dose (MTD) of hypoglycin A was determined by feeding rats the ackee and control diets over a 30-day period. The acute toxic dose for male and female rats was 231.19+/-62.5 5mg hypoglycinA/kgBW and 215.99+/-63.33 mg hypoglycinA/kgBW, respectively. This was considerably greater than the dose of 100 mg hypoglycin/kgBW reported in a previous study when aqueous hypoglycin was administered orally. The MTD of hypoglycin A in both male and female rats was 1.50+/-0.07 mg hypoglycinA/kgBW/day. These findings suggest that the form in which hypoglycin in ackee is administered could affect the toxicological properties it exhibits. Therefore, for the purpose of a hazard assessment, it may be best administered within the matrix of the fruit, which is the form that humans consume it.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 128,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Characterisation of sensory abnormalities observed in an animal model of multiple sclerosis: a behavioural and pharmacological study. Multiple sclerosis is a chronic inflammatory demyelinating disease, associated, in 50-80% of patients, with persistent pain. While the type of pain that affects these patients is being more documented, the mechanisms underlying this pathology are still poorly understood and animal models of such chronic pain associated with MS are required. The aim of our study was to characterize the sensory abnormalities and in particular the clinical signs linked to persistent pain in two models of Experimental Autoimmune Encephalomyelitis (EAE) in the rat. This behavioural characterization tested several sensory modalities such as mechanical and thermal (heat/cold) hyperalgesia or allodynia and explored some of these modalities on two different extremities: the hindpaws and the tail. Our study showed that while one of the model produced more robust motor impairment, animals of both models suffer from mechanical hyperalgesia and thermal allodynia to cold, both at the level of the tail and the hindpaws. While the time-course changes of some of these modalities are shifted in the time between the two models, they represent good models of the sensory abnormalities experienced by MS patients. The second part of our study aimed at characterizing from a pharmacological point of view the most robust model (\"EAE+Cyclosporine\") and showed that Gabapentin, Duloxetine and Tramadol partially relieved some of the clinical signs. Our results suggest that the model \"EAE+Cyclosporine\" in the rat is a good model of chronic sensory abnormalities observed in MS patients both from a behavioural and pharmacological point of view.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 624,
                "text": "Experimental Autoimmune Encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials ( < 104 weeks' duration; typically 24 weeks' duration) and extension studies (typically  > 76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 52,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial. OBJECTIVE: To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX). METHODS: Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined. RESULTS: At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were -31.3 (2.45) versus -17.8 (2.45), p < 0.001 for pain; -29.1 (2.26) versus -16.7 (2.42), p < 0.001 for PtGA; -0.647 (0.064) versus -0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function. CONCLUSION: Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 40,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Targeting alpha-synuclein for the treatment of Parkinson's disease. Parkinson's disease (PD) is characterized as a neurodegenerative movement disorder presenting with rigidity, resting tremor, disturbances in balance and slowness in movement. An important pathologic feature of PD is the presence of Lewy bodies. The primary structural component of Lewy bodies are fibrils composed primarily of alpha-synuclein, a highly conserved 140 amino acid protein that is predominantly expressed in neurons and which may play a role in synaptic plasticity and neurotransmission. Numerous studies suggest the aggregation and modification of alpha-synuclein as a key step leading to Lewy body formation and neuronal cell loss associated with PD. Because of the central role of alpha-synuclein in PD, it represents a novel drug target for the possible treatment of this disease. In this review, an overview of the role of alpha-synuclein in PD will be discussed with an emphasis on recent studies utilizing an immunization approach against alpha-synuclein as a possible treatment option for this debilitating disease.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 395,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Role of ABL family kinases in cancer: from leukaemia to solid tumours. The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration and invasion. ABL1 was first identified as an oncogene required for the development of leukaemias initiated by retroviruses or chromosome translocations. The demonstration that small-molecule ABL kinase inhibitors could effectively treat chronic myeloid leukaemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumours. Enhanced ABL expression and activation in some solid tumours, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may be useful for treating selected solid tumours.",
            "question": "What kind of enzyme is encoded by the proto-oncogene ABL1?",
            "answers": {
                "answer_start": 99,
                "text": "nonreceptor tyrosine kinase"
            }
        },
        {
            "context": "Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. The heterogeneity of mutations causing Tay-Sachs disease in non-Jewish populations requires efficient techniques allowing the simultaneous screening for both known and novel mutations. beta-hexosaminidase mRNA isolated from cultured fibroblasts of 19 Tay-Sachs patients (7 with adult or late onset form of the disease and 12 with infantile Tay-Sachs disease) was amplified by cDNA-PCR in two overlapping segments spanning the entire coding sequence. We used chemical mismatch cleavage (CMC), denaturing gradient gel electrophoresis (DGGE) and direct sequencing of amplified fragments displaying a cleaved product or an altered melting behavior to screen the HEX A gene for mutations and to determine their distribution and frequency in the non-Jewish Tay-Sachs patients. These methods allowed us to identify 31 out of 38 alleles studied (82%). In addition to 9 previously described mutations (the 4 bp insertion in exon 11, G to A transitions at codons 170, 269, 482, 499 and 504, C to T transition at codon 499 and 504 and a GT to AT transition at the donor site of intron 9), we have identified 10 novel mutations. These include 1 donor splice site defect in intron 6, 8 missense mutations at non-randomly distributed conserved residues and a 2 bp deletion in exon 4. These results confirm the extreme molecular heterogeneity of mutations causing Tay-Sachs disease in non-Jewish population. The strategy used should be profitable for identifying mutations in large genes and for diagnostic purposes.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 27,
                "text": "HEXA"
            }
        },
        {
            "context": "Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. INTRODUCTION: Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. METHODS: General clinical assessment, sural nerve biopsy, and genetic analysis were performed. RESULTS: Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular-like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. CONCLUSION: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 212,
                "text": "GAN gene"
            }
        },
        {
            "context": "Frontal hypometabolism in elderly breast cancer survivors determined by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET): a pilot study. PURPOSE: The term \"chemobrain\" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. As breast cancer survivors now commonly reach late life, it is not known whether previous exposure to chemotherapy may affect long-term risk for cognitive impairment. To help address this concern, this study tested whether successfully surviving chemotherapy earlier in life was associated with later differences in brain metabolic function as an older adult compared to controls. This question was examined using positron emission tomography measures of brain glucose metabolism in elderly women cancer survivors. METHODS: Breast cancer survivors (N = 10), currently free of recurrent cancer and without a diagnosis of a cognitive disorder, were compared to matched healthy controls (N = 10). All subjects were imaged at rest with [(18)F]fluorodeoxyglucose. Images were analyzed semi-quantitatively using the Alzheimer's Discrimination Tool and a volume of interest-based approach derived from co-registered magnetic resonance imaging. RESULTS: Relative [(18)F]fluorodeoxyglucose uptake (normalized to global) was significantly lower in the survivors compared with control subjects in bilateral orbital frontal regions, consistent with differences between the groups in cognition and executive function (i.e., Trail Making Test, Part B and mini-mental state examination) and despite no significant differences with respect to age, education, intelligence, or working memory. None of the survivors and only one control manifested a global positron emission tomography score consistent with an Alzheimer's disease metabolic pattern. CONCLUSION: Breast cancer survivors treated with chemotherapy may manifest long-term changes in brain glucose metabolism indicative of subtle frontal hypometabolism, a finding consistent with results from neuropsychological testing and other imaging modalities.",
            "question": "What is a \"chemobrain\"?",
            "answers": {
                "answer_start": 164,
                "text": "The term \"chemobrain\" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment."
            }
        },
        {
            "context": "Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend. Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 610,
                "text": "PLN"
            }
        },
        {
            "context": "Expression of mutated glucocerebrosidase alleles in human cells. Gaucher disease is a heterogeneous disease characterized by impaired activity of the lysosomal enzyme glucocerebrosidase. This heterogeneity is attributed to a large number of mutations in the corresponding gene. In order to test the biochemical properties of some mutations prevalent among Israeli populations, the normal human glucocerebrosidase cDNA and cDNAs carrying mutations N370S, L444P, D409H, recTL, recNcil, P415R and 84GG were coupled to the T7 RNA polymerase promoter in a vaccinia virus-derived expression vector (pTM-1). Recombinant viruses were produced and used to infect human tissue culture cells. RNA and protein stability, recognition by anti-glucocerebrosidase monoclonal antibodies and intracellular enzymatic activity were measured. The results demonstrated that the D409H allele directed synthesis of cytoplasmic RNA with decreased stability compared with its normal counterpart or other mutated forms. The D409H and L444P mutated proteins had lower stability than that of their normal counterpart, while the recNcil-mutated protein was more stable. Only glucocerebrosidase forms harboring leucine at position 444 were recognized by the anti-glucocerebrosidase monoclonal antibodies used (8E4 and 2C7). Measurements of enzymatic activity of the recombinant proteins in cells loaded with a fluorescent glucosylceramide demonstrated that the N370S mutated enzyme had activity similar to that of the normal enzyme. The other mutated enzymes exhibited varying degrees of activities, generally corresponding to the phenotypes with which they are associated. The results presented demonstrate the use of the vaccinia virus-derived expression system and of loading living cells with fluorescent substrate as efficient tools for studying mutants in Gaucher disease and in other lysosomal diseases.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 167,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.",
            "question": "Which R / bioconductor package is used for enrichment analysis of genomic regions?",
            "answers": {
                "answer_start": 402,
                "text": "LOLA"
            }
        },
        {
            "context": "Riociguat: first global approval. Riociguat (Adempas(®)), an oral first-in-class soluble guanylate cyclase (sGC) stimulator, is under global development by Bayer Healthcare Pharmaceuticals Inc. for the treatment of adult patients with inoperable or chronic/persistent chronic thromboembolic pulmonary hypertension (CTEPH) and for the treatment of adult patients with pulmonary arterial hypertension (PAH). The drug directly stimulates sGC in a nitric oxide independent manner, thereby increasing the sensitivity of sGC to nitric oxide, leading to increased cyclic guanosine monophosphate generation (a key signalling molecule involved in regulating vascular tone, proliferation, fibrosis and inflammation). Riociguat is the world's first approved pharmacotherapy for CTEPH, with its first global approval in this indication occurring in Canada. It has subsequently been approved in the USA for the treatment of patients with CTEPH and also received its first global approval in patients with PAH in the USA. It is undergoing regulatory review for these indications in Europe and for use in patients with CTEPH in Japan. This article summarizes the milestones in the development of riociguat, leading to its first global approvals in patients with CTEPH and PAH.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 34,
                "text": "Riociguat"
            }
        },
        {
            "context": "Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. STUDY OBJECTIVE: The literature suggests that the d -dimer is useful in patients suspected of having pulmonary embolism and who have a low pretest probability of disease. A previously defined clinical decision rule, the Wells Criteria, may provide a reliable and reproducible means of determining this pretest probability. We evaluate the interrater agreement and external validity of Wells Criteria in determining pretest probability in patients suspected of having pulmonary embolism. METHODS: This was a prospective observational study. Trained research assistants enrolled patients during 120 random 8-hour shifts. Patients who underwent imaging for pulmonary embolism after a medical history, physical examination, and chest radiograph were enrolled. Treating providers and research assistants determined pretest probability according to Wells Criteria in a blinded fashion. Two d -dimer assays were run. Three-month follow-up for the diagnosis of pulmonary embolism was performed. Interrater agreement tables were created. kappa Values, sensitivities, and specificities were determined. RESULTS: Of the 153 eligible patients, 3 patients were missed, 16 patients declined, and 134 (88%) patients were enrolled. Sixteen (12%) patients were diagnosed with pulmonary embolism. The kappa values for Wells Criteria were 0.54 and 0.72 for the trichotomized and dichotomized scorings, respectively. When Wells Criteria were trichotomized into low pretest probability (n=59, 44%), moderate pretest probability (n=61, 46%), or high pretest probability (n=14, 10%), the pulmonary embolism prevalence was 2%, 15%, and 43%, respectively. When Wells Criteria were dichotomized into pulmonary embolism-unlikely (n=88, 66%) or pulmonary embolism-likely (n=46, 34%), the prevalence was 3% and 28%, respectively. The immunoturbidimetric and rapid enzyme-linked immunosorbent assay d -dimer assays had similar sensitivities (94%) and specificities (45% versus 46%). CONCLUSION: Wells Criteria have a moderate to substantial interrater agreement and reliably risk stratify pretest probability in patients with suspected pulmonary embolism.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 1823,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Impact of training for healthcare professionals on how to manage an opioid overdose with naloxone: effective, but dissemination is challenging. BACKGROUND: Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). Training in these skills has been successfully trialled internationally with opioid users themselves. Healthcare professionals working in substance misuse are in a prime position to deliver overdose prevention training to drug users and may themselves witness opioid overdoses. The best method of training dissemination has not been identified. The study assessed post-training change in clinician knowledge for managing an opioid overdose and administering naloxone, evaluated the 'cascade method' for disseminating training, and identified barriers to implementation. METHODS: A repeated-measures design evaluated knowledge pre-and-post training. A sub-set of clinicians were interviewed to identify barriers to implementation. Clinicians from addiction services across England received training. Participants self-completed a structured questionnaire recording overdose knowledge, confidence and barriers to implementation. RESULTS: One hundred clinicians were trained initially, who trained a further 119 clinicians (n=219) and thereafter trained 239 drug users. The mean composite score for opioid overdose risk signs and actions to be taken was 18.3/26 (±3.8) which increased to 21.2/26 (±4.1) after training, demonstrating a significant improvement in knowledge (Z=9.2, p<0.001). The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation. CONCLUSIONS: Training clinicians how to manage an opioid overdose and administer naloxone was effective. However the 'cascade method' was only modestly successful for disseminating training to a large clinician workforce, with a range of clinician and service perceived obstacles. Drug policy changes and improvements to educational programmes for drug services would be important to ensure successful implementation of overdose training internationally.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 1620,
                "text": "naloxone"
            }
        },
        {
            "context": "recount workflow: Accessing over 70,000 human RNA-seq samples with Bioconductor. The recount2 resource is composed of over 70,000 uniformly processed human RNA-seq samples spanning TCGA and SRA, including GTEx. The processed data can be accessed via the recount2 website and the \n            recount\n           Bioconductor package. This workflow explains in detail how to use the \n            recount\n           package and how to integrate it with other Bioconductor packages for several analyses that can be carried out with the recount2 resource. In particular, we describe how the coverage count matrices were computed in recount2 as well as different ways of obtaining public metadata, which can facilitate downstream analyses. Step-by-step directions show how to do a gene-level differential expression analysis, visualize base-level genome coverage data, and perform an analyses at multiple feature levels. This workflow thus provides further information to understand the data in recount2 and a compendium of R code to use the data.",
            "question": "Which workflow in Bioconductor has been developed for accessing human RNA-seq samples?",
            "answers": {
                "answer_start": 85,
                "text": "recount2"
            }
        },
        {
            "context": "An Outbreak of Clostridium difficile Ribotype 027 Associated with Length of Stay in the Intensive Care Unit and Use of Selective Decontamination of the Digestive Tract: A Case Control Study. BACKGROUND: An outbreak of Clostridium difficile ribotype 027 infection (CDI) occurred at an university hospital, involving 19 departments. To determine what hospital-associated factors drove the outbreak of this particular strain we performed a case-control study. METHODS: Cases (n = 79), diagnosed with CDI due to C. difficile ribotype 027 were matched for age and treating medical specialty to four control patients (n = 316). Patients diagnosed with CDI due to other ribotypes were included as a second control group. A random selection of C. difficile ribotype 027 strains (n = 10) was genotyped by Whole Genome Sequencing (WGS). FINDINGS: WGS showed the outbreak was likely caused by a single strain of C. difficile (two or less single-nucleotide variants between isolates). Ninety-five percent of cases had used antibiotics, compared to 56% of controls. Previous admission to the intensive care unit (ICU) (OR: 2.4, 95% CI 1.0-5.6), longer length of stay (LOS), and recent hospital admission were associated with CDI ribotype 027. Cases were less likely to have been admitted to a ward with a known isolated CDI patient (OR: 0.2, 95% CI 0.1-0.6). Analysis of patients who stayed at the ICU (35 cases; 51 controls), indicated that the use of selective decontamination of the digestive tract (SDD) and a longer LOS in the ICU were associated with CDI risk. INTERPRETATION: In this large outbreak, any antibiotic use, including SDD use, appeared as a prerequisite for acquisition of the outbreak strain. The role of use of SDD and prolonged stay on the ICU could not be disentangled, but both factors can play a biologically plausible role in C. difficile acquisition and infection.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 37,
                "text": "Ribotype 027"
            }
        },
        {
            "context": "Crystallization of Ranasmurfin, a blue-coloured protein from Polypedates leucomystax. Ranasmurfin, a previously uncharacterized approximately 13 kDa blue protein found in the nests of the frog Polypedates leucomystax, has been purified and crystallized. The crystals are an intense blue colour and diffract to 1.51 A with P2(1) symmetry and unit-cell parameters a = 40.9, b = 59.9, c = 45.0 A, beta = 93.3 degrees . Self-rotation function analysis indicates the presence of a dimer in the asymmetric unit. Biochemical data suggest that the blue colour of the protein is related to dimer formation. Sequence data for the protein are incomplete, but thus far have identified no model for molecular replacement. A fluorescence scan shows a peak at 9.676 keV, indicating that the protein binds zinc and suggesting a route for structure solution.",
            "question": "What is the color of the protein Ranasmurfin?",
            "answers": {
                "answer_start": 149,
                "text": "blue"
            }
        },
        {
            "context": "Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 874,
                "text": "FSHD"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 99,
                "text": "53BP1"
            }
        },
        {
            "context": "Imatinib-induced immune hepatitis: case report and literature review. Imatinib is one of the most recent medications used for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). It is an orally administered protein-tyrosine kinase inhibitor, an enzyme which is produced by BCR-ABL fusion which results from translocation of 9:22 chromosome (Philadelphia chromosome). Imatinib blocks proliferation and induces apoptosis of BCR-ABL-expression in CML. Many side effects produced by imatinib have been documented but its induction of hepatotoxcity has been rarely reported. Only a few cases so far have been reported in the literature and almost all were in females. We describe another case of hepatotoxicity due to imatinib in a 17-year old female with clinical, laboratory and histopathological changes. The case described here suggests that imatinib may also induce immune hepatitis, in some patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 461,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. OBJECTIVE: The mechanistic link between Janus kinase (JAK) signaling and structural damage to arthritic joints in rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate how selective inhibition of JAK with tofacitinib (CP-690,550) affects osteoclast-mediated bone resorption in a rat adjuvant-induced arthritis (AIA) model, as well as human T lymphocyte RANKL production and human osteoclast differentiation and function. METHODS: Hind paw edema, inflammatory cell infiltration, and osteoclast-mediated bone resorption in rat AIA were assessed using plethysmography, histopathologic analysis, and immunohistochemistry; plasma and hind paw tissue levels of cytokines and chemokines (including RANKL) were also assessed. In vitro RANKL production by activated human T lymphocytes was evaluated by immunoassay, while human osteoclast differentiation and function were assessed via quantitative tartrate-resistant acid phosphatase staining and degradation of human bone collagen, respectively. RESULTS: Edema, inflammation, and osteoclast-mediated bone resorption in rats with AIA were dramatically reduced after 7 days of treatment with the JAK inhibitor, which correlated with reduced numbers of CD68/ED-1+, CD3+, and RANKL+ cells in the paws; interleukin-6 (transcript and protein) levels were rapidly reduced in paw tissue within 4 hours of the first dose, whereas it took 4-7 days of therapy for RANKL levels to decrease. Tofacitinib did not impact human osteoclast differentiation or function, but did decrease human T lymphocyte RANKL production in a concentration-dependent manner. CONCLUSION: These results suggest that the JAK inhibitor tofacitinib suppresses osteoclast-mediated structural damage to arthritic joints, and this effect is secondary to decreased RANKL production.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1790,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica: Bazex syndrome. Bazex syndrome, or acrokeratosis paraneoplastica, is a cutaneous paraneoplastic syndrome characterized by psoriasiform lesions associated with, usually, a squamous cell carcinoma of the upper aerodigestive tract. We present a case of Bazex syndrome associated with metastatic cervical squamous cell carcinoma with an unknown primary. The features of the condition are discussed in the light of current knowledge.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 31,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism. Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 216,
                "text": "TYR"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 391,
                "text": "PD-L1"
            }
        },
        {
            "context": "Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 1419,
                "text": "SLC9A6"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 0,
                "text": "traseR"
            }
        },
        {
            "context": "A role for p53 in the frequency and mechanism of mutation. The tumor suppressor protein, p53, is often referred to as the guardian of the genome. When p53 function is impaired, its ability to preserve genomic integrity is compromised. This may result in an increase in mutation on both a molecular and chromosomal level and contribute to the progression to a malignant phenotype. In order to study the effect of p53 function on the acquisition of mutation, in vitro and in vivo models have been developed in which both the frequency and mechanism of mutation can be analyzed. In human lymphoblastoid cells in which p53 function was impaired, both the spontaneous and induced mutant frequency increased at the autosomal thymidine kinase (TK) locus. The mutant frequency increased to a greater extent in cell lines in which p53 harbored a point mutation than in those lines in which a \"null\" mutation had been introduced by molecular targeting or by viral degradation indicating a possible \"gain-of-function\" associated with the mutant protein. Further, molecular analysis revealed that the loss of p53 function was associated with a greater tendency towards loss-of-heterozygosity (LOH) within the TK gene that was due to non-homologous recombination than that found in wild-type cells. Most data obtained from the in vivo models uses the LacI reporter gene that does not efficiently detect mutation that results in LOH. However, studies that have examined the effect of p53 status on mutation in the adenine phosphoribosyl transferase (APRT) gene in transgenic mice also suggest that loss of p53 function results in an increase in mutation resulting from non-homologous recombination. The results of these studies provide clear and convincing evidence that p53 plays a role in modulating the mutant frequency and the mechanism of mutation. In addition, the types of mutation that occur within the p53 gene are also of importance in determining the mutant frequency and the pathways leading to mutation.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 89,
                "text": "p53"
            }
        },
        {
            "context": "Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. In mammals Dnmt1 is the DNA methyltransferase chiefly responsible for maintaining genomic methylation patterns through DNA replication cycles, but how its maintenance activity is controlled is still not well understood. Interestingly, Uhrf1, a crucial cofactor for maintenance of DNA methylation by Dnmt1, is endowed with E3 ubiquitin ligase activity. Here, we show that both Dnmt1 and Uhrf1 coprecipitate with ubiquitin specific peptidase 7 (Usp7), a de-ubiquitinating enzyme. Overexpression of Uhrf1 and Usp7 resulted in opposite changes in the ubiquitination status and stability of Dnmt1. Our findings suggest that, by balancing Dnmt1 ubiquitination, Usp7 and Uhrf1 fine tune Dnmt1 stability.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 93,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Structure and characterization of the murine p80 coilin gene, Coil. Cajal bodies (coiled bodies, CBs) are nuclear organelles of unknown function and are characterized by a wide variety of components including various basal transcription and cell cycle proteins, the nucleolar proteins fibrillarin and Nopp140, numerous small nuclear ribonucleoproteins, the survival motor neuron protein complex, and the marker protein, p80 coilin. To gain insight into the role of p80 coilin in CBs, we have cloned the murine gene Coil and have mapped it to the distal portion of chromosome band 11D. The approximately 2.6-kb transcript is detectable in all tissues analyzed, with the highest levels in brain and testis. Sequence analysis shows that, like its human counterpart, the mouse coilin gene is composed of seven exons and spans nearly 30 kb of genomic DNA. The predicted amino acid sequence reveals two conserved N- and C-terminal domains, and comparison with the Xenopus SPH-1 protein reveals that these three genes are indeed orthologous. These results should facilitate gene disruption experiments aimed at creating a genetic model system to study CBs.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 424,
                "text": "coilin"
            }
        },
        {
            "context": "A protein binds the selenocysteine insertion element in the 3'-UTR of mammalian selenoprotein mRNAs. Several gene products are involved in co-translational insertion of selenocysteine by the tRNA(Sec). In addition, a stem-loop structure in the mRNAs coding for selenoproteins is essential to mediate the selection of the proper selenocysteine UGA codon. Interestingly, in eukaryotic selenoprotein mRNAs, this stem-loop structure, the selenocysteine insertion sequence (SECIS) element, resides in the 3'-untranslated region, far downstream of the UGA codon. In view of unravelling the underlying complex mechanism, we have attempted to detect RNA-binding proteins with specificity for the SECIS element. Using mobility shift assays, we could show that a protein, present in different types of mammalian cell extracts, possesses the capacity of binding the SECIS element of the selenoprotein glutathione peroxidase (GPx) mRNA. We have termed this protein SBP, for Secis Binding Protein. Competition experiments attested that the binding is highly specific and UV cross-linking indicated that the protein has an apparent molecular weight in the range of 60-65 kDa. Finally, some data suggest that the SECIS elements in the mRNAs of GPx and another selenoprotein, type I iodothyronine 5' deiodinase, recognize the same SBP protein. This constitutes the first report of the existence of a 3' UTR binding protein possibly involved in the eukaryotic selenocysteine insertion mechanism.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 469,
                "text": "SECIS"
            }
        },
        {
            "context": "Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 128,
                "text": "SGLT2"
            }
        },
        {
            "context": "Disruption of long-distance highly conserved noncoding elements in neurocristopathies. One of the key discoveries of vertebrate genome sequencing projects has been the identification of highly conserved noncoding elements (CNEs). Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes. The abnormal development of neural crest cells (NCCs) leads to a broad spectrum of congenital malformation(s), termed neurocristopathies, and/or tumor predisposition. Here we review recent findings that disruptions of CNEs, within or at long distance from the coding sequences of key genes involved in NCC development, result in neurocristopathies via the alteration of tissue- or stage-specific long-distance regulation of gene expression. While most studies on human genetic disorders have focused on protein-coding sequences, these examples suggest that investigation of genomic alterations of CNEs will provide a broader understanding of the molecular etiology of both rare and common human congenital malformations.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 413,
                "text": "development"
            }
        },
        {
            "context": "Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data. BACKGROUND: The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data. METHODS: We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2-10 years (PrP₂₋₁₀), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. FINDINGS: Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP₂₋₁₀ 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP₂₋₁₀ 20%) it was 41% (21 to 57), and at high transmission (PrP₂₋₁₀ 70%) the efficacy was 4% (-10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)--eg, at low transmission (PrP₂₋₁₀ 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (-38 to 38) after 3 years. INTERPRETATION: Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination. FUNDING: Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 148,
                "text": "malaria"
            }
        },
        {
            "context": "Alpha- and beta-synuclein expression in Parkinson disease with and without dementia. Parkinson disease (PD) is the most important movement disorder and about 50% of patients develop dementia over the time. PD belongs to the group of Lewy body disorders. Alpha-synuclein (AS) is the main component of Lewy bodies and its aggregation is a key event in the pathogenesis of PD. Beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo and has been shown to interact directly with AS regulating its functionality and preventing its oligomerization. Recently, we have described a molecular subgroup of DLB characterized by the drastic BS reduction in cortical areas. In this study we have analyzed the expression of two BS transcripts and the main AS transcript SNCA140, in frozen samples of three brain areas, temporal cortex, caudate nucleus and pons, from patients with PD and PDD in comparison with controls. Relative mRNA expression was determined by real-time PCR with SybrGreen, neuron-specific-enolase as housekeeping gene and the deltadeltaCt method. The most important difference in BS and AS mRNA expression between PD and PDD was found in the caudate nucleus, where BS mRNA was overexpressed in PD and AS mRNA diminished in PDD. Our findings provide new insights into the pathogenesis of dementia in PD, indicating that differential BS and AS expression in the caudate nucleus may represent one of the molecular mechanisms involved in these complex diseases.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 254,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Riociguat for the management of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Pulmonary hypertension (PH) is a progressive disease that is accompanied by a poor prognosis. Pulmonary vasoconstriction is facilitated through multiple pathways and results in increased pulmonary vascular pressure leading to cell proliferation, vascular remodeling, right ventricular hypertrophy/failure, and ultimately death. Until recently, just six medications were approved -all for one subclass of PH. On October 8, 2013, riociguat (Adempas®) became the first medication approved for multiple etiologies of PH. Preclinical studies have demonstrated safety and efficacy with significant clinical trials supporting its advancement into phase IV trials. Although long-term safety and efficacy and place in therapy remain to be established, riociguat presents as an exciting new option for the treatment of PH and potentially has additional indications in the near future.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 543,
                "text": "riociguat"
            }
        },
        {
            "context": "Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. UNLABELLED: Thyroid hormones are known to be essential for growth, development, and metabolism. Recently, the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter, and MCT8 mutations have been associated with Allan-Herndon-Dudley syndrome, an X linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. Here we describe in detail the clinical and biochemical features and the response to thyroid hormone (L-thyroxine (LT4)) administration in a boy with an MCT8 mutation (c.1649delA) that truncates the protein in the twelfth transmembrane domain. It is of note that brain magnetic resonance imaging (MRI) revealed delayed myelination from infancy. Endocrine functions other than thyroid hormone regulation and metabolism were intact, resulting in normal hypothalamic/pituitary function tests. While LT4 administration suppressed thyrotropin (TSH) secretion, no significant changes in thyroid hormone values or clinical symptoms were observed. CONCLUSION: the characteristic thyroid hormone function tests and brain MRI findings may allow screening of high-risk populations for a better understanding of MCT8 pathophysiology.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 914,
                "text": "thyroid"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 805,
                "text": "xa"
            }
        },
        {
            "context": "Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons. Mutations of presenilin 1 (PS1) causing Alzheimer's disease selectively increase the secretion of the amyloidogenic betaA4(1-42), whereas knocking out the gene results in decreased production of both betaA4(1-40) and (1-42) amyloid peptides (De Strooper et al. 1998). Therefore, PS1 function is closely linked to the gamma-secretase processing of the amyloid precursor protein (APP). Given the ongoing controversy on the subcellular localization of PS1, it remains unclear at what level of the secretory and endocytic pathways PS1 exerts its activity on APP and on the APP carboxy-terminal fragments that are the direct substrates for gamma-secretase. Therefore, we have reinvestigated the subcellular localization of endogenously expressed PS1 in neurons in vitro and in vivo using confocal microscopy and fine-tuned subcellular fractionation. We show that uncleaved PS1 holoprotein is recovered in the nuclear envelope fraction, whereas the cleaved PS fragments are found mainly in post-ER membranes including the intermediate compartment (IC). PS1 is concentrated in discrete sec23p- and p58/ERGIC-53-positive patches, suggesting its localization in subdomains involved in ER export. PS1 is not found to significant amounts beyond the cis-Golgi. Surprisingly, we found that APP carboxy-terminal fragments also coenrich in the pre-Golgi membrane fractions, consistent with the idea that these fragments are the real substrates for gamma-secretase. Functional evidence that PS1 exerts its effects on gamma-secretase processing of APP in the ER/IC was obtained using a series of APP trafficking mutants. These mutants were investigated in hippocampal neurons derived from transgenic mice expressing PS1wt or PS1 containing clinical mutations (PS1(M146L) and PS1(L286V)) at physiologically relevant levels. We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of betaA4(1-42) relative to betaA4(1-40), indicating that both mutations operate independently. Overall, our data clearly establish that PS1 controls gamma(42)-secretase activity in pre-Golgi compartments. We discuss models that reconcile this conclusion with the effects of PS1 deficiency on the generation of betaA4(1-40) peptide in the late biosynthetic and endocytic pathways.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 1992,
                "text": "ad"
            }
        },
        {
            "context": "A cascade of genes related to Waardenburg syndrome. On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 713,
                "text": "MITF"
            }
        },
        {
            "context": "A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl) tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 (38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid. Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 501,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 623,
                "text": "xa"
            }
        },
        {
            "context": "Simpson grade: an opportunity to reassess the need for complete resection of meningiomas. BACKGROUND: The relevance of the Simpson grading system as a predictor of meningioma progression or recurrence in modern neurosurgical practice has recently been called into question. The aim of our study was to compare the risk of progression/recurrence of tumours that had been treated with different Simpson grade resections in a contemporary population of benign (WHO grade I) meningioma patients. METHOD: One hundred eighty-three patients with histologically confirmed WHO grade I meningioma were retrospectively analysed. All patients underwent first-time craniotomy as their initial therapy between 2004 and 2012. Univariate analysis was performed using log-rank testing and Kaplan-Meier analysis for progression/recurrence-free survival. Multivariate analysis was performed using Cox proportional hazards regression modelling. RESULTS: The three-year progression/recurrence-free survival rates for patients receiving Simpson grade 1, 2 or 4 resections were 95 %, 87 % and 67 %, respectively. Simpson grade 4 resections progressed/recurred at a significantly greater rate than Simpson grade 1 resections (hazard ratio [HR] = 3.26, P = 0.04), whereas Simpson grade 2 resections did not progress/recur at a significantly greater rate than Simpson grade 1 resections (HR = 1.78, P = 0.29). Subtotal resections progressed/recurred at a significantly greater rate than gross-total resections (HR = 2.47, P = 0.03). CONCLUSIONS: Tumours that undergo subtotal resection are at a significantly greater risk of progression/recurrence than tumours that undergo gross-total resection. Gross-total resection should therefore be the aim of surgery. However, given modern access to follow-up imaging and stereotactic radiosurgery, these results should not be used to justify overly 'heroic' tumour resection.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 471,
                "text": "meningioma"
            }
        },
        {
            "context": "Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 326,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 669,
                "text": "early"
            }
        },
        {
            "context": "Tolerance to oats in dermatitis herpetiformis. OBJECTIVES: Recent studies on coeliac disease have shown that oats can be included in a gluten-free diet without adverse effects on the small bowel. The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats. PATIENTS/METHODS: Eleven patients with dermatitis herpetiformis in remission on a gluten-free diet were challenged daily with 50 g oats for six months. Clinical symptoms were recorded, serum samples taken, and skin and small bowel biopsies performed before and after the oat challenge. A control group comprised of 11 patients with dermatitis herpetiformis on a conventional gluten-free diet was also studied. RESULTS: Eight patients challenged with oats remained asymptomatic, two developed a transient rash, and one withdrew because of the appearance of a more persistent but mild rash. Three of the 11 controls also developed a transient rash. IgA endomysial antibodies remained negative in all patients. The small bowel villous architecture, the densities of intraepithelial CD3 and alpha/beta and gamma/delta T cell receptor positive lymphocytes and crypt epithelial cell DR expression remained unaltered during the oat challenge. CONCLUSIONS: The results confirm the absence of oat toxicity on the gluten sensitive small bowel mucosa and suggest that the rash in patients with dermatitis herpetiformis is not activated by eating oats.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 272,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 694,
                "text": "FSHD"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 575,
                "text": "early"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 339,
                "text": "7"
            }
        },
        {
            "context": "A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. Lipoprotein glomerulopathy (LPG) is a rare glomerulopathy caused by lipoprotein thrombi. In almost all cases of LPG, several apolipoprotein (apo) E mutations were reported. Here, we present a case of LPG caused by a novel mutation that we named ApoE2 Kurashiki, which substitutes arginine with proline at apoE codon 158. ApoE2 polymorphism is well known for its relationship to type III hyperlipoproteinemia, and the common apoE2 isoform is encoded by the R158C allele. ApoE2 Kurashiki substitutes at the same codon and cannot be distinguished from common apoE2 by stan-dard apoE genotyping or phenotyping.",
            "question": "Which ApoE isoform is associated with hyperlipoproteinemia?",
            "answers": {
                "answer_start": 511,
                "text": "apoE2 isoform"
            }
        },
        {
            "context": "From animal models to human disease: a genetic approach for personalized medicine in ALS. Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 312,
                "text": "ALS"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 371,
                "text": "xa"
            }
        },
        {
            "context": "Caralluma Fimbriata Supplementation Improves the Appetite Behavior of Children and Adolescents with Prader-Willi Syndrome. BACKGROUND: Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which when left unmanaged, leads to an excessive ingestion of food. To date there is inadequate pharmacological treatment or supplementation for modification of the PWS hyperphagia and/or the associated behaviors. Therefore, the best practice is familial supervision and restriction of diet and environment. AIM: We aimed to determine if the natural supplement of Caralluma fimbriata extract (CFE) could attenuate hyperphagia or the associated appetite behaviors in children and adolescents with PWS over the 4-week pilot trial period. MATERIALS AND METHODS: We conducted a placebo-controlled, double-blind, randomized crossover trial over a 10-week period to investigate the effects of CFE on hunger control, in a cohort of children and adolescents with confirmed PWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). Participants from Australia and New Zealand ingested CFE or a placebo of maltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the crossover to the other treatment. Weekly comparisons in appetite behavior, severity, and drive were recorded by parents, as scaled time-point measures on a hyperphagia questionnaire validated for PWS. RESULTS: CFE administration was found to induce a significant accumulative easing of hyperphagia (P = 0.05), with decreases evident in one-third of the participants. Furthermore due to CFE supplementation, a significant decrease (P < 0.05) was recorded in the category of behavior and a decrease in hyperphagia (n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended adult dose). There were no reported adverse effects at any dose. CONCLUSION: We demonstrate that an extract of the Indian cactus succulent Caralluma fimbriata eases hyperphagic appetite behavior within a cohort of children and adolescents (n = 15) with PWS without notable adverse effects. The outcomes of this study will have a potential positive impact on PWS management.",
            "question": "Angelman syndrome is associated with deletion of a part of Chromosome 15 but if the deletion occurs in the paternally inherited chromosome 15, what is the disease?",
            "answers": {
                "answer_start": 135,
                "text": "Prader-Willi syndrome"
            }
        },
        {
            "context": "A Phase II Randomized Trial (GO27827) of First-Line FOLFOX Plus Bevacizumab with or Without the MET Inhibitor Onartuzumab in Patients with Metastatic Colorectal Cancer. BACKGROUND: Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). MATERIALS AND METHODS: Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. RESULTS: Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. CONCLUSION: Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. \n            The Oncologist\n           2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.",
            "question": "What is inhibited by a drug rilotumumab?",
            "answers": {
                "answer_start": 2492,
                "text": "hepatocyte growth factor"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 445,
                "text": "bicarbonate"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8 times"
            }
        },
        {
            "context": "Wilson disease and idiopathic copper toxicosis. The pathogenic agent of both Wilson disease (WD) and non-Indian childhood cirrhosis (which we term idiopathic copper toxicosis, or ICT) is copper accumulating to excess in the liver. Inheritance of a pair of alleles of an autosomal recessive gene on chromosome 13 is necessary and sufficient to cause such copper accumulation in WD; reducing the dietary intake of copper cannot prevent the development of WD. In contrast, the lethal accumulations of copper in children with ICT have been attributed primarily to an increased dietary intake of copper. However, 64 124 child-year exposures of children under the age of 6 y to drinking water containing a copper concentration of approximately 125.9 micromol/L (8 mg/L) produced no deaths from any form of liver disease. Moreover, the ICT of seven infants was attributed primarily to drinking water containing < 110.2 micromol Cu/L (7 mg/L) despite evidence of the presence of a genetic defect in three of the patients, one of whom was exclusively breast-fed. These data suggest that ICT cannot be caused solely by increased dietary intake of copper and occurs only in children with an identified genetic defect.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 270,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 900,
                "text": "GBshape"
            }
        },
        {
            "context": "Disease progression and treatment responses in a prospective DMARD-naive seropositive early rheumatoid arthritis cohort: does gender matter? OBJECTIVE: To assess gender differences in disease characteristics and treatment responses over time in a disease-modifying antirheumatic drug (DMARD)-naive seropositive early rheumatoid arthritis (RA) cohort. METHODS: Patients with polyarticular disease who were DMARD-naive and had seropositive early RA (< 14 months) were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using chi-squared, Mann-Whitney U, and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation was significantly influenced by gender. RESULTS: At baseline, men (n = 67) and women (n = 225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year followup, as assessed by trends in Disease Activity Score 28/erythrocyte sedimentation rate (DAS28-ESR4), physician global scores, and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28-ESR4 scores (p = 0.009), although not independently associated with disease activity. Self-reported measures (Health Assessment Questionnaire-Disability Index, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission. CONCLUSION: At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 1070,
                "text": "women"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 227,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Remission of ulcerated necrobiosis lipoidica diabeticorum after bariatric surgery. A 32-year-old woman with type 2 diabetes mellitus suffering from morbid obesity with BMI 45,14 kg/m(2) was operated on. Not only the type 2DM but also one of its complication known as necrobiosis lipoidica diabeticorum remitted postoperatively. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals but an epidemic that threatens global well-being. It causes or exacerbates many health problems, and in particular, it is associated with the type 2 diabetes. Necrobiosis lipoidica is a granulomatous skin disease of unknown etiology, associated mainly with diabetes mellitus. We presented in this paper a morbid obese case of necrobiosis lipoidica diabeticorum with dramatic good response to bariatric surgery.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 681,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 191,
                "text": "NCX"
            }
        },
        {
            "context": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib. Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (\"never smokers\"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 210,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report. INTRODUCTION: Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor. CASE PRESENTATION: Our patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight. CONCLUSIONS: The rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 252,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 447,
                "text": "NCX"
            }
        },
        {
            "context": "Paediatric investigation plans for pain: painfully slow! PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.",
            "question": "How many clinical trials for off-label drugs in neonates are cited in the literature.",
            "answers": {
                "answer_start": 456,
                "text": "0"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 1570,
                "text": "stroke"
            }
        },
        {
            "context": "RNAs mediating cotranslational insertion of selenocysteine in eukaryotic selenoproteins. Selenocysteine, a selenium-containing analog of cysteine, is found in the prokaryotic and eukaryotic kingdoms in active sites of enzymes involved in oxidation-reduction reactions. Its biosynthesis and cotranslational insertion into selenoproteins is performed by an outstanding mechanism, implying the participation of several gene products. The tRNA(Sec) is one of these. In eukaryotes, its transcription mode by RNA polymerase III differs from that of classical tRNA genes, both at the level of the promoter elements and transcription factors involved. In addition, enhanced transcription is afforded by a newly characterized zinc finger activator. Not only transcription of the gene, but also the tRNA(Sec) itself is atypical since its 2D and 3D structures exhibit features which set it apart from classical tRNAs. Decoding of eukaryotic selenocysteine UGA codons requires a stem-loop structure in the 3'UTR of mRNAs, the selenocysteine insertion sequence (SECIS) element. Structure probing and sequence comparisons led us to propose a 2D structure model for the SECIS element, containing a novel RNA motif composed of four consecutive non-Watson-Crick base-pairs. A 3D model, rationalizing the accessibility data, was elaborated by computer modeling. It yields indicative or suggestive evidence for the role that could play some conserved residues and/or structural features in SECIS function. These might act as signals for interaction with SBP, the SECIS binding protein that we have characterized.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 1049,
                "text": "SECIS"
            }
        },
        {
            "context": "Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ. These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy result in Danon disease characterized by hypertrophic cardiomyopathy. The ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte excitation-contraction and its dysfunction can lead to cardiac failure. Whether RyR2 is degraded by CMA is unknown. METHODS AND RESULTS: To induce CMA, cultured neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote protein degradation through this pathway. GA increased LAMP-2A levels together with its redistribution and colocalization with Hsc70 in the perinuclear region, changes indicative of CMA activation. The inhibition of lysosomes but not proteasomes prevented the loss of RyR2. The recovery of RyR2 content after incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ motifs which are required for the recognition Hsc70 and its degradation via CMA. Our data suggest that presenilins are involved in RyR2 degradation by CMA. CONCLUSION: These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 84,
                "text": "Chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Effect of foot orthoses as treatment for plantar fasciitis or heel pain. CLINICAL SCENARIO: Plantar fasciitis is a debilitating and painful problem present in the general population. It most often presents with moderate to severe pain in the proximal inferior heel region and is most commonly associated with repeated trauma to the plantar fascia. Plantar fasciitis, itself, is an injury at the site of attachment at the medial tubercle of the calcaneus, often due to excessive and repetitive traction. Plantar fasciitis is the most common cause of heel pain and is estimated to affect 2 million people in the United States alone. FOCUSED CLINICAL QUESTION: For adults suffering from plantar fasciitis, are foot orthoses a viable treatment option to reduce pain?",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 549,
                "text": "heel pain"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. BACKGROUND: MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins. PROCEDURES: MLN4924 was tested against the PPTP in vitro panel using 96-hour exposure time at concentrations ranging from 1.0 nM to 10 µM. It was tested in vivo at a dose of 100 mg/kg [66 mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily × 5 days. Treatment duration was 3 weeks. RESULTS: The median relative IC(50) for MLN4924 against the PPTP cell lines was 143 nM, (range: 15-678 nM) with that for the Ewing panel being significantly lower (31 nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values >2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilm's tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels. CONCLUSIONS: MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 39,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Thyroid function and morphology in patients affected by Williams syndrome. OBJECTIVE: To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of patients with Williams syndrome (WS). METHODS: Serum concentrations of free-T3, free-T4, TSH, thyroperoxidase antibodies (TPOA) and thyroglobulin antibodies (TgA), as well as ultrasonographic data, of 20 patients with WS (12 females and eight males), aged 1.7-34.9 years, were evaluated. RESULTS: Three cases (15%) of subclinical hypothyroidism were identified. Overt hypothyroidism was diagnosed in two cases (10%). Thyroid antibodies were negative in all patients. Fourteen patients (70%) showed thyroid hypoplasia involving the entire gland. In these patients, the left thyroid lobe appeared usually, but not significantly, reduced compared with the right thyroid lobe. One patient (5%) showed thyroid hemiagenesis. Only five patients (25%) showed a thyroid with normal volume, and of these five, one patient showed marked thyroid hypoplasia of the left lobe. In all WS patients with diagnosis of subclinical or overt hypothyroidism, thyroid hypoplasia was detected. No cases of subclinical or overt hypothyroidism were found in WS with normal thyroid volume. CONCLUSIONS: This study confirms the presence of alterations of thyroid function in WS and also suggests the frequent occurrence of abnormalities of thyroid morphology in these patients. Patients with WS should be monitored for thyroid function and a thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1307,
                "text": "thyroid"
            }
        },
        {
            "context": "CEP proteins: the knights of centrosome dynasty. Centrosome forms the backbone of cell cycle progression mechanism. Recent debates have occurred regarding the essentiality of centrosome in cell cycle regulation. CEP family protein is the active component of centrosome and plays a vital role in centriole biogenesis and cell cycle progression control. A total of 31 proteins have been categorized into CEP family protein category and many more are under candidate evaluation. Furthermore, by the recent advancements in genomics and proteomics researches, several new CEP proteins have also been characterized. Here we have summarized the importance of CEP family proteins and their regulation mechanism involved in proper cell cycle progression. Further, we have reviewed the detailed molecular mechanism behind the associated pathological phenotypes and the possible therapeutic approaches. Proteins such as CEP57, CEP63, CEP152, CEP164, and CEP215 have been extensively studied with a detailed description of their molecular mechanisms, which are among the primary targets for drug discovery. Moreover, CEP27, CEP55, CEP70, CEP110, CEP120, CEP135, CEP192, CEP250, CEP290, and CEP350 also seem promising for future drug discovery approaches. Since the overview implicates that the overall researches on CEP proteins are not yet able to present significant details required for effective therapeutics development, thus, it is timely to discuss the importance of future investigations in this field.",
            "question": "Where in the cell do we find the protein Cep135?",
            "answers": {
                "answer_start": 258,
                "text": "centrosome"
            }
        },
        {
            "context": "Co-amplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma. DEAD box proteins are putative RNA helicases that have been implicated in cellular processes involving alteration of RNA secondary structure, such as translation initiation and splicing. These proteins share eight conserved amino acid motifs, including Asp(D)-Glu-(E)-Ala(A)-Asp(D) which is part of a more extended motif. Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines. Here, we show that the DDX1 gene is co-amplified with the MYCN gene in 2 of three neuroblastoma cell lines and that DDX1 RNA levels correlate with DDX1 gene copy number. Since amplification of MYCN is an indicator of poor prognosis in neuroblastoma, it was of interest to determine whether co-amplification with DDX1 occurred in clinical samples of neuroblastoma and whether such a finding carried any additional prognostic significance. We determined the gene copy number of DDX1 in 32 neuroblastoma patient samples (representative of all stages): 13 were MYCN amplified and 19 had normal copy numbers of the MYCN gene. Of the 13 neuroblastomas that were MYCN amplified, seven were also DDX1 amplified. Of the 19 that were not MYCN amplified, none were DDX1 amplified. This is the first example of a gene that is co-amplified with MYCN at a high frequency in neuroblastoma. While there was a trend towards a worse clinical outcome with co-amplification, the numbers were too small to reach significance.",
            "question": "Which is the conserved motif of DEAD box proteins?",
            "answers": {
                "answer_start": 331,
                "text": "Asp(D)-Glu-(E)-Ala(A)-Asp(D)"
            }
        },
        {
            "context": "Ibrutinib in chronic lymphocytic leukemia and B cell malignancies. Recent clinical data suggest remarkable activity of ibrutinib, the first-in-class covalent inhibitor of Bruton's tyrosine kinase (BTK), in chronic lymphocytic leukemia (CLL), as well as excellent activity in other B cell malignancies, including in particular mantle cell lymphoma and Waldenstrom macroglobulinemia. This review evaluates the data from ongoing clinical and correlative studies of ibrutinib in B cell malignancies with a particular focus on CLL, and considers these data in the context of other B cell receptor pathway inhibitors.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 119,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Tall stature and gonadal dysgenesis in a non-mosaic girl 45,X. Turner's syndrome, also known as 'monosomy X', is a genetic disorder that occurs in 1/2,500 female births and is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. While the classic karyotype related to Turner's syndrome is 45,X, the majority of those affected actually have a mosaic chromosomal complement, most often with a second normal cell line (46,XX). The resulting phenotype is variable and related to the underlying chromosomal pattern, but it is characterized by three cardinal features: short stature (around 100%), ovarian failure (>90%) and congenital lymphedema (>80%). In this paper we report a molecular and cytogenetic investigation of a 26-year-old female with non-mosaic 45,X karyotype, who has a stature of 170 cm without GH treatment, and whose only apparent Turner feature is gonadal dysgenesis. The only possible explanation for the absence of Turner phenotype is the hidden mosaicism combined with an untreated gonadal dysgenesis. Our results support the theory that significant ascertainment bias exists in our understanding of Turner's syndrome.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 367,
                "text": "X"
            }
        },
        {
            "context": "Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke: Design of the randomized Gore REDUCE Clinical Study. Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.",
            "question": "Treatment of which disease was studied in the Gore REDUCE Clinical Study?",
            "answers": {
                "answer_start": 523,
                "text": "patent foramen ovale"
            }
        },
        {
            "context": "[Tuberculosis outbreak in a school]. OBJECTIVE: To demonstrate the importance of preventive measures when a case of tuberculosis is detected, identify the causes that favored a tuberculosis outbreak in a school and determine the efficiency of obtaining induced sputum samples. DESIGN: Descriptive, study. SETTING: The Santa Maria de la Providencia school, located in the municipality of Alcala de Henares in Spain. INTERVENTIONS: On April 11, 2005, a case of bacilliform pulmonary tuberculosis was notified in a teacher. Study of contacts in the collective was performed as a programmed intervention. Mantoux skin test and, if positive, chest radiograph were performed in contacts. Treatment of latent or active tuberculosis was recommended according to the result. RESULTS: School exposures were identified and underwent the Mantoux skin test (142 students in years 1, 2, 3, and 4 of compulsory secondary education and 22 teachers). The Mantoux test was positive in 68 students (48 %) and seven teachers (32 %). In seven students with results compatible with active tuberculosis disease, sputum induction was performed and treatment was started. A further two students, identified as contacts, were studied in another center and also started treatment for active tuberculosis disease. Due to the high risk of contagion, study of contacts was extended to the remaining students in compulsory secondary education. In this second phase, 134 students received the Mantoux skin test and seven were Mantoux positive (5.2 %). In all these students, active tuberculosis disease was ruled out. Latent tuberculosis treatment was recommended in all Mantoux-positive contacts.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 1593,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Proliferation failure and gamma radiation sensitivity of Fen1 null mutant mice at the blastocyst stage. Flap endonuclease 1 (FEN1) has been shown to remove 5' overhanging flap intermediates during base excision repair and to process the 5' ends of Okazaki fragments during lagging-strand DNA replication in vitro. To assess the in vivo role of the mammalian enzyme in repair and replication, we used a gene-targeting approach to generate mice lacking a functional Fen1 gene. Heterozygote animals appear normal, whereas complete depletion of FEN1 causes early embryonic lethality. Fen1(-/-) blastocysts fail to form inner cell mass during cellular outgrowth, and a complete inactivation of DNA synthesis in giant cells of blastocyst outgrowth was observed. Exposure of Fen1(-/-) blastocysts to gamma radiation caused extensive apoptosis, implying an essential role for FEN1 in the repair of radiation-induced DNA damage in vivo. Our data thus provide in vivo evidence for an essential function of FEN1 in DNA repair, as well as in DNA replication.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 288,
                "text": "DNA replication"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 262,
                "text": "naloxone"
            }
        },
        {
            "context": "Gene looping is conferred by activator-dependent interaction of transcription initiation and termination machineries. Gene looping juxtaposes the promoter and terminator regions of RNA polymerase II-transcribed genes in yeast and mammalian cells. Here we report an activator-dependent interaction of transcription initiation and termination factors during gene looping in budding yeast. Chromatin analysis revealed that MET16, INO1, and GAL1p-BUD3 are in a stable looped configuration during activated transcription. Looping was nearly abolished in the absence of transcription activators Met28, Ino2, and Gal4 of MET16, INO1, and GAL1p-BUD3 genes, respectively. The activator-independent increase in transcription was not accompanied by loop formation, thereby suggesting an essential role for activators in gene looping. The activators did not facilitate loop formation directly because they did not exhibit an interaction with the 3' end of the genes. Instead, activators physically interacted with the general transcription factor TFIIB when the genes were activated and in a looped configuration. TFIIB cross-linked to both the promoter and the terminator regions during the transcriptionally activated state of a gene. The presence of TFIIB on the terminator was dependent on the Rna15 component of CF1 3' end processing complex. Coimmunoprecipitation revealed a physical interaction of Rna15 with TFIIB. We propose that the activators facilitate gene looping through their interaction with TFIIB during transcriptional activation of genes.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1035,
                "text": "TFIIB"
            }
        },
        {
            "context": "A novel DNMT3B splice variant expressed in tumor and pluripotent cells modulates genomic DNA methylation patterns and displays altered DNA binding. DNA methylation is an epigenetic mark essential for mammalian development, genomic stability, and imprinting. DNA methylation patterns are established and maintained by three DNA methyltransferases: DNMT1, DNMT3A, and DNMT3B. Interestingly, all three DNMTs make use of alternative splicing. DNMT3B has nearly 40 known splice variants expressed in a tissue- and disease-specific manner, but very little is known about the role of these splice variants in modulating DNMT3B function. We describe here the identification and characterization of a novel alternatively spliced form of DNMT3B lacking exon 5 within the NH(2)-terminal regulatory domain. This variant, which we term DNMT3B3Delta5 because it is closely related in structure to the ubiquitously expressed DNMT3B3 isoform, is highly expressed in pluripotent cells and brain tissue, is downregulated during differentiation, and is conserved in the mouse. Creation of pluripotent iPS cells from fibroblasts results in marked induction of DNMT3B3Delta5. DNMT3B3Delta5 expression is also altered in human disease, with tumor cell lines displaying elevated or reduced expression depending on their tissue of origin. We then compared the DNA binding and subcellular localization of DNMT3B3Delta5 versus DNMT3B3, revealing that DNMT3B3Delta5 possessed significantly enhanced DNA binding affinity and displayed an altered nuclear distribution. Finally, ectopic overexpression of DNMT3B3Delta5 resulted in repetitive element hypomethylation and enhanced cell growth in a colony formation assay. Taken together, these results show that DNMT3B3Delta5 may play an important role in stem cell maintenance or differentiation and suggest that sequences encoded by exon 5 influence the functional properties of DNMT3B.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 347,
                "text": "DNMT1"
            }
        },
        {
            "context": "DNA methyltransferase 1 (Dnmt1) mutation affects Snrpn imprinting in the mouse male germ line. DNA methylation and DNA methyltransferases are essential for spermatogenesis. Mutations in the DNA methyltransferase Dnmt1 gene exert a paternal effect on epigenetic states and phenotypes of offspring, suggesting that DNMT1 is important for the epigenetic remodeling of the genome that takes place during spermatogenesis. However, the specific role of DNMT1 in spermatogenesis and the establishment of genomic imprints in the male germ line remains elusive. To further characterize the effect of DNMT1 deficiency on the resetting of methylation imprints during spermatogenesis, we analyzed the methylation profiles of imprinted regions in the spermatozoa of mice that were heterozygous for a Dnmt1 loss-of-function mutation. The mutation did not affect the H19 or IG differentially methylated regions (DMRs) that are usually highly methylated but led to a partial hypermethylation of the Snrpn DMR, a region that should normally be unmethylated in mature spermatozoa. This defect does not appear in mouse models with mutations in Dnmt3a and Mthfr genes and, therefore, it is specific for the Dnmt1 gene and is suggestive of a role of DNMT1 in imprint resetting or maintenance in the male germ line.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1187,
                "text": "Dnmt1"
            }
        },
        {
            "context": "S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. UNLABELLED: We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 680,
                "text": "SAM"
            }
        },
        {
            "context": "Control of Panama disease of banana by rotating and intercropping with Chinese chive (Allium tuberosum Rottler): role of plant volatiles. Intercropping and rotating banana (Musa spp.) with Chinese chive (Allium tuberosum Rottler) has been used as an effective method to control Panama disease (Fusarium wilt) of banana in South China. However, the underlying mechanism is unknown. In this study, we used aqueous leachates and volatiles from Chinese chive to evaluate their antimicrobial activity on Fusarium oxysporum f. sp. cubense race 4 (FOC), the causal agent of Panama disease in banana, and identified the antifungal compounds. Both leaf and root leachates of Chinese chive displayed strong inhibition against FOC, but the concentrated leachates showed lower inhibition than the original leachates. In a sealed system volatiles emitted from the leaves and roots of Chinese chive inhibited mycelial growth of FOC. Volatile compounds emitted from the intact growing roots mimicking natural environment inhibited spore germination of FOC. We identified five volatiles including 2-methyl-2-pentenal and four organosulfur compounds (dimethyl trisulfide, dimethyl disulfide, dipropyl disulfide, and dipropyl trisulfide) from the leaves and roots of Chinese chive. All these compounds exhibited inhibitory effects on FOC, but 2-methyl-2-pentenal and dimethyl trisulfide showed stronger inhibition than the other three compounds. 2-Methyl-2-pentenal at 50-100 μl/l completely inhibited the mycelial growth of FOC. Our results demonstrate that antifungal volatiles released from Chinese chive help control Panama disease in banana. We conclude that intercropping and rotating banana with Chinese chive can control Panama disease and increase cropland biodiversity.",
            "question": "What is the causative agent of the \"Panama disease\" affecting bananas?",
            "answers": {
                "answer_start": 499,
                "text": "Fusarium oxysporum f. sp. cubense"
            }
        },
        {
            "context": "Avascular necrosis of the femoral head among children and adolescents with sickle cell disease in Greece. Hemoglobinopathies are very common in Greece, the incidence of beta-thalassemia trait being 8% and that of sickle cell trait ranging from 1 to 32% in various districts. In Greek populations, sickle cell disease (SCD) is mainly represented by S-beta thalassemia.",
            "question": "What is the incidence of beta-thalassemia in Greek population?",
            "answers": {
                "answer_start": 198,
                "text": "8%"
            }
        },
        {
            "context": "Deeply conserved chordate noncoding sequences preserve genome synteny but do not drive gene duplicate retention. Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. Researchers have proposed that the strong conservation of these sequences may affect the evolution of the surrounding genome, both by repressing rearrangement, and possibly by promoting duplicate gene retention. Conflicting data, however, have made the validity of these propositions unclear. Here, we use a new computational method to identify phylogenetically conserved noncoding elements (PCNEs) in a manner that is not biased by rearrangement and duplication. This method is powerful enough to identify more than a thousand PCNEs that have been conserved between vertebrates and the basal chordate amphioxus. We test 42 of our PCNEs in transgenic zebrafish assays--including examples from vertebrates and amphioxus--and find that the majority are functional enhancers. We find that PCNEs are enriched around genes with ancient synteny conservation, and that this association is strongest for extragenic PCNEs, suggesting that cis-regulatory interdigitation plays a key role in repressing genome rearrangement. Next, we classify mouse and zebrafish genes according to association with PCNEs, synteny conservation, duplication history, and presence in bidirectional promoter pairs, and use these data to cluster gene functions into a series of distinct evolutionary patterns. These results demonstrate that subfunctionalization of conserved cis-regulation has not been the primary determinate of gene duplicate retention in vertebrates. Instead, the data support the gene balance hypothesis, which proposes that duplicate retention has been driven by selection against dosage imbalances in genes with many protein connections.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 242,
                "text": "development"
            }
        },
        {
            "context": "Self-methylation of the M.BspRI methyltransferase. In the absence of DNA substrate, the DNA methyltransferase (MTase) M.BspRI can methylate itself using the methyl donor S-adenosyl-L-methionine (AdoMet). The methyl group is transferred to two Cys residues of the MTase.",
            "question": "What is the methyl donor of DNA (cytosine-5)-methyltransferases?",
            "answers": {
                "answer_start": 170,
                "text": "S-adenosyl-L-methionine"
            }
        },
        {
            "context": "Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice. BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). It plays an important role in the feedback regulation of HO-1 expression, which protects cells from various insults including oxidative stress and inflammatory cytokines. However, the role of Bach1 in intestinal inflammation remains unclear. In this study, the role of Bach1 in intestinal mucosal injury was elucidated using 8-week-old female C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice. Intestinal mucosal injuries induced by a single subcutaneous administration of indomethacin were evaluated macroscopically, histologically, and biochemically. Mucosal protein content and chemokine mRNA levels were determined by real-time PCR. Our results showed that the indomethacin-induced intestinal injury was remarkably improved in Bach1-deficient mice. Histological examination showed that the area of injured lesion was decreased in Bach1-deficient mice compared to wild-type mice. Administration of indomethacin induced expression of inflammatory chemokines such as KC, MIP1alpha and MCP1, which was suppressed in Bach1-deficient mice. Myeloperoxidase activity in the intestinal mucosa was also significantly decreased in Bach1-deficient mice. Additionally, Bach1 deficiency enhanced immunopositivity of HO-1 in the intestinal mucosa after indomethacin administration. Disruption of the Bach1 gene thus caused inhibition of mucosal injury, indicating that inhibition of Bach1 may be a novel therapeutic strategy for treating indomethacin-induced intestinal injury.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 131,
                "text": "repressor"
            }
        },
        {
            "context": "Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. The aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 185,
                "text": "FBN1"
            }
        },
        {
            "context": "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.",
            "question": "Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?",
            "answers": {
                "answer_start": 805,
                "text": "TBC1D7"
            }
        },
        {
            "context": "Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 1587,
                "text": "XIST"
            }
        },
        {
            "context": "Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function. Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity. To identify additional proteins that may interact with PLN, we used the yeast-two-hybrid system to screen an adult human cardiac cDNA library. HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding partner. The minimal binding regions were mapped to amino acid residues 203-245 for HAX-1 and residues 16-22 for PLN. The interaction between the two proteins was confirmed using GST-HAX-1, bound to the glutathione-matrix, which specifically adsorbed native PLN from human or mouse cardiac homogenates, while in reciprocal binding studies, recombinant His-HAX-1 bound GST-PLN. Kinetic studies using surface plasmon resonance yielded a K(D) of approximately 1 muM as the binding affinity for the PLN/HAX-1 complex. Phosphorylation of PLN by cAMP-dependent protein kinase reduced binding to HAX-1, while increasing concentrations of Ca(2+) diminished the PLN/HAX-1 interaction in a dose-dependent manner. HAX-1 concentrated to mitochondria, but upon transient co-transfection of HEK 293 cells with PLN, HAX-1 redistributed and co-localized with PLN at the endoplasmic reticulum. Analysis of the anti-apoptotic function of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects from hypoxia/reoxygenation-induced cell death. These findings suggest a possible link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival mediated by the PLN/HAX-1 interaction.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 521,
                "text": "(HAX-1)"
            }
        },
        {
            "context": "Diagnosis and characterization of presymptomatic patients with Wilson's disease and the use of molecular genetics to aid in the diagnosis. Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. Although fatal if untreated, the condition can be treated effectively. Autosomal recessive inheritance indicates that siblings of affected patients are at 25% risk of having the disease. If they are diagnosed prior to becoming symptomatic, affected siblings can be kept free of symptoms by prophylactic therapy. In this paper we have examined the utility of copper-related variables, along with other clinical and molecular findings, in identifying those siblings of affected patients who should be further evaluated with a liver biopsy. Data are presented on a series of 13 presymptomatic patients in whom we have made the diagnosis of WD based on liver biopsy findings. Signs of liver disease were present in 12 out of 13 cases. The classic, noninvasive, screening approaches that we evaluated were not adequate to identify all cases of WD in this group of patients. These included positive Kayser-Fleischer (KF) rings, elevated liver serum alanine transferase, elevated urine copper, or elevated plasma nonceruloplasmin copper. We have introduced the use of molecular genetics for screening siblings of affected patients for WD. We show that a probe from the linked retinoblastoma (RB) gene can be very helpful in problem cases. However, at this time, the quantitative determination of liver copper concentration remains as the definitive diagnostic criterion.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 167,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Case-control study of SUDEP. OBJECTIVE: To examine the influence of various factors on the risk of sudden unexpected death in epilepsy (SUDEP). METHODS: The authors investigated 154 cases in which a postmortem examination was performed. Each case had four controls with epilepsy from the community, matched for age and geographic location. Backward stepwise conditional logistic regression analysis was performed and odds ratios for risk and protection were determined. RESULTS: The risk of SUDEP was increased with a history of generalized tonic-clonic seizures in the previous 3 months (odds ratio [OR]: 13.8, 95% CI: 6.6 to 29.1). The presence of supervision at night was found to be protective (OR: 0.4, 95% CI: 0.2 to 0.8) when a supervising individual shared the same bedroom or when special precautions such as a listening device were employed (OR: 0.1, 95% CI: 0.0 to 0.3). CONCLUSION: This work lends support to the view that SUDEP is a seizure-related phenomenon and that control of tonic-clonic seizures is important in its prevention. Nocturnal supervision seems to protect against SUDEP.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 99,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of c-Jun pro-apoptotic activity in cerebellar granule neurons. Cerebellar granule cell (CGC) apoptosis by trophic/potassium (TK) deprivation is a model of election to study the interplay of pro-apoptotic and pro-survival signaling pathways in neuronal cell death. In this model, the c-Jun N-terminal kinase (JNK) induces pro-apoptotic genes through the c-Jun/activator protein 1 (AP-1) transcription factor. On the other side, a survival pathway initiated by lithium leads to repression of pro-apoptotic c-Jun/AP-1 target genes without interfering with JNK activity. Yet, the mechanism by which lithium inhibits c-Jun activity remains to be elucidated. Here, we used this model system to study the regulation and function of site-specific c-Jun phosphorylation at the S63 and T91/T93 JNK sites in neuronal cell death. We found that TK-deprivation led to c-Jun multiphosphorylation at all three JNK sites. However, immunofluorescence analysis of c-Jun phosphorylation at single cell level revealed that the S63 site was phosphorylated in all c-Jun-expressing cells, whereas the response of T91/T93 phosphorylation was more sensitive, mirroring the switch-like apoptotic response of CGCs. Conversely, lithium prevented T91T93 phosphorylation and cell death without affecting the S63 site, suggesting that T91T93 phosphorylation triggers c-Jun pro-apoptotic activity. Accordingly, a c-Jun mutant lacking the T95 priming site for T91/93 phosphorylation protected CGCs from apoptosis, whereas it was able to induce neurite outgrowth in PC12 cells. Vice versa, a c-Jun mutant bearing aspartate substitution of T95 overwhelmed lithium-mediate protection of CGCs from TK-deprivation, validating that inhibition of T91/T93/T95 phosphorylation underlies the effect of lithium on cell death. Mass spectrometry analysis confirmed multiphosphorylation of c-Jun at T91/T93/T95 in cells. Moreover, JNK phosphorylated recombinant c-Jun at T91/T93 in a T95-dependent manner. On the basis of our results, we propose that T91/T93/T95 multiphosphorylation of c-Jun functions as a sensitivity amplifier of the JNK cascade, setting the threshold for c-Jun pro-apoptotic activity in neuronal cells.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1959,
                "text": "JNK"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1550,
                "text": "Nox1"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 673,
                "text": "Malaria"
            }
        },
        {
            "context": "Orteronel for the treatment of prostate cancer. Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Preclinical studies demonstrate that orteronel treatment suppresses androgen levels and causes shrinkage of androgen-dependent organs, such as the prostate gland. Early reports of clinical studies demonstrate that orteronel treatment leads to reduced prostate-specific antigen levels, a marker of prostate cancer tumor burden, and more complete suppression of androgen synthesis than conventional androgen deprivation therapies that act in the testes alone. Treatment with single-agent orteronel has been well tolerated with fatigue as the most common adverse event, while febrile neutropenia was the dose-limiting toxicity in a combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III clinical trial in patients with advanced-stage prostate cancer who had received prior docetaxel was unblinded as the overall survival primary end point was not achieved. However, additional Phase III orteronel trials are ongoing in men with earlier stages of prostate cancer.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 235,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. OBJECTIVE: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. METHODS: In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Treatment with tofacitinib at a dose of > 3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P < 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). CONCLUSION: Tofacitinib monotherapy at > 3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 316,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 240,
                "text": "IgG4"
            }
        },
        {
            "context": "Emerging interest in the kallikrein gene family for understanding and diagnosing cancer. Kallikreins are proteolytic enzymes that constitute a subfamily of serine proteases. Novel kallikrein genes were cloned recently, and it was shown that the human kallikrein family contains 15 genes tandemly aligned on chromosomal locus 19q13.3-q13.4. Based on their altered expression in tumor cells, kallikreins may be involved in the pathogenesis and/or progression of cancer. Evidence is presented that certain kallikreins may be exploited as diagnostic cancer biomarkers. Although the function(s) of novel kallikreins is currently unknown, increasing evidence suggests that kallikreins may participate in regulatory enzymatic cascade(s). Elucidation of the function of novel kallikreins largely depends on the availability of active recombinant proteins. Here, the zymogen for kallikrein 13 was overexpressed in Pichia pastoris and biochemically characterized. It was shown that the kallikrein 13 zymogen displays intrinsic catalytic activity leading to autoactivation. A clipped form of kallikrein 13 was identified, indicating autocatalytic cleavage at the internal bond R114-S115. Mature kallikrein 13 displays trypsin-like activity with restricted specificity on synthetic and protein substrates. Combinatorial P1-Lys libraries of tetrapeptide fluorogenic substrates were synthesized and used for the profiling of the P2 specificity of selected kallikreins. Interestingly, it was shown that human kallikrein 13, similarly to PSA, could specifically cleave human plasminogen to generate angiostatin-like fragments, suggesting that specific kallikreins may have antiangiogenic actions. An understanding of the physiology of human kallikreins is emerging with potential clinical applications.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 278,
                "text": "15"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 817,
                "text": "MethPed"
            }
        },
        {
            "context": "Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 179,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "The S-methylmethionine cycle in angiosperms: ubiquity, antiquity and activity. Angiosperms synthesize S-methylmethionine (SMM) from methionine (Met) and S-adenosylmethionine (AdoMet) in a unique reaction catalyzed by Met S-methyltransferase (MMT). SMM serves as methyl donor for Met synthesis from homocysteine, catalyzed by homocysteine S-methyltransferase (HMT). MMT and HMT together have been proposed to constitute a futile SMM cycle that stops the free Met pool from being depleted by an overshoot in AdoMet synthesis. Arabidopsis and maize have one MMT gene, and at least three HMT genes that belong to two anciently diverged classes and encode enzymes with distinct properties and expression patterns. SMM, and presumably its cycle, must therefore have originated before dicot and monocot lineages separated. Arabidopsis leaves, roots and developing seeds all express MMT and HMTs, and can metabolize [35S]Met to [35S]SMM and vice versa. The SMM cycle therefore operates throughout the plant. This appears to be a general feature of angiosperms, as digital gene expression profiles show that MMT and HMT are co-expressed in leaves, roots and reproductive tissues of maize and other species. An in silico model of the SMM cycle in mature Arabidopsis leaves was developed from radiotracer kinetic measurements and pool size data. This model indicates that the SMM cycle consumes half the AdoMet produced, and suggests that the cycle serves to stop accumulation of AdoMet, rather than to prevent depletion of free Met. Because plants lack the negative feedback loops that regulate AdoMet pool size in other eukaryotes, the SMM cycle may be the main mechanism whereby plants achieve short-term control of AdoMet level.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 155,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "Arabidopsis homologs of components of the SWR1 complex regulate flowering and plant development. The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes. We compared the phenotype of mutants in the homologs of SWR1C components in Arabidopsis thaliana. Mutations in Arabidopsis SWC6 (AtSWC6), SUPPRESSOR OF FRIGIDA 3 (SUF3) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1), homologs of SWC6, ARP6 and SWR1, respectively, caused similar developmental defects, including leaf serration, weak apical dominance, flowers with extra petals and early flowering by reduction in expression of FLOWERING LOCUS C (FLC), a strong floral repressor. Chromatin immunoprecipitation assays showed that AtSWC6 and SUF3 bind to the proximal region of the FLC promoter, and protoplast transfection assays showed that AtSWC6 colocalizes with SUF3. Protein interaction analyses suggested the formation of a complex between PIE1, SUF3, AtSWC6 and AtSWC2. In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2. Finally, knockdown of the H2AZ genes by RNA interference or artificial microRNA caused a phenotype similar to that of atswc6 or suf3. Our results strongly support the presence of an SWR1C-like complex in Arabidopsis that ensures proper development, including floral repression through full activation of FLC.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 1065,
                "text": "SWR1"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1170,
                "text": "Nox1"
            }
        },
        {
            "context": "Lack of action of exogenously administered T3 on the fetal rat brain despite expression of the monocarboxylate transporter 8. Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 332,
                "text": "thyroid"
            }
        },
        {
            "context": "Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. BACKGROUND: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS: In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. FINDINGS: Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. INTERPRETATION: Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. FUNDING: AstraZeneca.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 129,
                "text": "poly(ADP-ribose) polymerase"
            }
        },
        {
            "context": "Demographics of the UK cystic fibrosis population: implications for neonatal screening. The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.",
            "question": "Which is the most common CFTR mutation in Caucasians?",
            "answers": {
                "answer_start": 1042,
                "text": "deltaF508"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 35,
                "text": "XK"
            }
        },
        {
            "context": "SERCA2a: a prime target for modulation of cardiac contractility during heart failure. Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca(2+) cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/ endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a) mediates Ca(2+) reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca(2+) uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 1049,
                "text": "phospholamban"
            }
        },
        {
            "context": "Resveratrol and the pharmacology of aging: a new vertebrate model to validate an old molecule. The natural phytoalexin resveratrol, found in grapes and red wine, recently rose to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the \"pufferfishes\" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.",
            "question": "What can Nothobranchius furzeri be used as a model system for?",
            "answers": {
                "answer_start": 1314,
                "text": "aging research"
            }
        },
        {
            "context": "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia. BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic. METHODOLOGY AND PRINCIPLE FINDINGS: In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006. The severity of the core clinical picture with predominant sensory ataxia, gait apraxia, lower limb spasticity, cognitive impairment and bladder dysfunction correlated with the degree of MRI findings showing enlargement of inner ventricular spaces as in communicating hydrocephalus. Laboratory studies revealed transient eosinophilia during the preceding acute meningitis-like phase, but no ongoing inflammatory process in the CSF. We found immune reactions against Toxocara canis in the majority of chronic VE patients but rarely in controls (P = 0.025; Fisher's exact test). Histological analysis of subacute to subchronic VE brain samples showed eosinophilic infiltrations with no signs of persistent Toxocara canis infection. CONCLUSIONS AND SIGNIFICANCE: Our data showed that pressure by the communicating hydrocephalus as a mechanical factor is the major pathogenic mechanism in chronic VE, most likely triggered by eosinophilic meningitis. There are no signs for an ongoing inflammatory process in chronic VE. The past eosinophilic reaction in VE might be caused by Toxocara ssp. infection and might therefore represent the first hint for an initial cause leading to the development of chronic VE. Our data provide a framework for future studies and potential therapeutic interventions for this enigmatic epidemic neurological disease potentially spreading in Sakha Republic.",
            "question": "Viliuisk encephalomyelitis is diagnosed in which geographical area?",
            "answers": {
                "answer_start": 222,
                "text": "Northeast Siberia"
            }
        },
        {
            "context": "Overview of clinicopathologic features of ALK-rearranged lung adenocarcinoma and current diagnostic testing for ALK rearrangement. Patients with non-small cell lung cancer (NSCLC) who harbor anaplastic lymphoma kinase (ALK) gene rearrangements can derive significant clinical benefit from ALK tyrosine kinase inhibitor. Accurate patient identification is absolutely crucial for successful using ALK inhibitor treatment. However, lung cancer patients with ALK gene rearrangement after ALK inhibitor therapy eventually develop acquired resistance to treatment. In this review, the authors summarize the clinicopathologic features of ALK-rearranged NSCLC and the pros and cons of current diagnostic testing. In addition, we discuss the current diagnostic flow of ALK testing and consideration of rebiopsy sample during disease progression in patients treated by ALK inhibitors.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 165,
                "text": "cancer"
            }
        },
        {
            "context": "The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein. A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 435,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease. Krabbe disease is a lethal, demyelinating condition caused by genetic deficiency of galactocerebrosidase (GALC) and resultant accumulation of its cytotoxic substrate, psychosine (galactosylsphingosine), primarily in oligodendrocytes (OLs). Psychosine is generated by galactosylation of sphingosine by UDP-galactose:ceramide galactosyltransferase (CGT), a galactosylceramide synthesizing enzyme which is primarily expressed in OLs. The expression of CGT and the synthesis of galactosyl-sphingolipids are associated with the terminal differentiation of OL, but little is known about the participation of endogenous psychosine accumulation in OL differentiation under GALC deficient conditions. In this study, we report that accumulation of endogenous psychosine under GALC deficient Krabbe conditions impedes OL differentiation process both by decreasing the expression of myelin lipids and protein and by inducing the cell death of maturating OLs. The psychosine pathology under GALC deficient conditions involves participation of secretory phospholipase A2 (sPLA2) activation and increase in its metabolites, as evidenced by attenuation of psychosine-induced pathology by treatment with pharmacological inhibitor of sPLA2 7,7-dimethyleicosadienoic acid (DEDA). These observations suggest for potential therapeutic efficacy of sPLA2 inhibitor in Krabbe disease.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 208,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 247,
                "text": "MC1R"
            }
        },
        {
            "context": "The Subviral RNA Database: a toolbox for viroids, the hepatitis delta virus and satellite RNAs research. BACKGROUND: Viroids, satellite RNAs, satellites viruses and the human hepatitis delta virus form the 'brotherhood' of the smallest known infectious RNA agents, known as the subviral RNAs. For most of these species, it is generally accepted that characteristics such as cell movement, replication, host specificity and pathogenicity are encoded in their RNA sequences and their resulting RNA structures. Although many sequences are indexed in publicly available databases, these sequence annotation databases do not provide the advanced searches and data manipulation capability for identifying and characterizing subviral RNA motifs. DESCRIPTION: The Subviral RNA database is a web-based environment that facilitates the research and analysis of viroids, satellite RNAs, satellites viruses, the human hepatitis delta virus, and related RNA sequences. It integrates a large number of Subviral RNA sequences, their respective RNA motifs, analysis tools, related publication links and additional pertinent information (ex. links, conferences, announcements), allowing users to efficiently retrieve and analyze relevant information about these small RNA agents. CONCLUSION: With its design, the Subviral RNA Database could be considered as a fundamental building block for the study of these related RNAs. It is freely available via a web browser at the URL: http://subviral.med.uottawa.ca.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 117,
                "text": "Viroids"
            }
        },
        {
            "context": "WRAP53 is essential for Cajal body formation and for targeting the survival of motor neuron complex to Cajal bodies. The WRAP53 gene gives rise to a p53 antisense transcript that regulates p53. This gene also encodes a protein that directs small Cajal body-specific RNAs to Cajal bodies. Cajal bodies are nuclear organelles involved in diverse functions such as processing ribonucleoproteins important for splicing. Here we identify the WRAP53 protein as an essential factor for Cajal body maintenance and for directing the survival of motor neuron (SMN) complex to Cajal bodies. By RNA interference and immunofluorescence we show that Cajal bodies collapse without WRAP53 and that new Cajal bodies cannot be formed. By immunoprecipitation we find that WRAP53 associates with the Cajal body marker coilin, the splicing regulatory protein SMN, and the nuclear import receptor importinβ, and that WRAP53 is essential for complex formation between SMN-coilin and SMN-importinβ. Furthermore, depletion of WRAP53 leads to accumulation of SMN in the cytoplasm and prevents the SMN complex from reaching Cajal bodies. Thus, WRAP53 mediates the interaction between SMN and associated proteins, which is important for nuclear targeting of SMN and the subsequent localization of the SMN complex to Cajal bodies. Moreover, we detect reduced WRAP53-SMN binding in patients with spinal muscular atrophy, which is the leading genetic cause of infant mortality worldwide, caused by mutations in SMN1. This suggests that loss of WRAP53-mediated SMN trafficking contributes to spinal muscular atrophy.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 798,
                "text": "coilin"
            }
        },
        {
            "context": "Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme. Celldex Therapeutics is developing rindopepimut (CDX-110), a 14-mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme (GBM). Rindopepimut specifically targets a novel junctional epitope of the EGFR deletion mutant EGFRvIII, which is a constitutively active receptor that is expressed in approximately 60 to 70% of patients with GBM. EGFRvIII expression is correlated with worse prognosis and reduced overall survival. Importantly, EGFRvIII is not expressed in normal brain tissue, making it an excellent therapeutic target. Preclinical studies demonstrated lasting tumor regression and increased survival times, as well as efficient generation of EGFRvIII-specific humoral and cellular immune responses, in animals expressing EGFRvIII and vaccinated with rindopepimut. Phase I and II clinical trials in patients with GBM demonstrated significantly increased median time to progression and overall survival time in those vaccinated with rindopepimut compared with matched historical controls. Only limited side effects have been observed in patients. Given these results, rindopepimut is an extremely promising therapy for patients with GBM. Phase I and II clinical trials in patients with GBM were ongoing at the time of publication. In the future, it may be beneficial to combine rindopepimut with other treatment modalities to further prolong survival.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 369,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 414,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 489,
                "text": "xa"
            }
        },
        {
            "context": "Current research on pharmacologic and regenerative therapies for osteoarthritis. Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 808,
                "text": "nerve growth factor"
            }
        },
        {
            "context": "LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.",
            "question": "Which R / bioconductor package is used for enrichment analysis of genomic regions?",
            "answers": {
                "answer_start": 0,
                "text": "LOLA"
            }
        },
        {
            "context": "Recent advances in antiarrhythmic drug treatment of atrial fibrillation. Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in clinical practice associated with significant morbidity and mortality. With the growing number of the affected individuals, the development of safe and effective treatment options for AF has become a worldwide priority. Currently available antiarrhythmic medications for the restoration and maintenance of sinus rhythm have limitations due to the modest efficacy and a potential for adverseeffects. Although substantial progress has been made in AF-ablation techniques, broad application of these nonpharmacological treatment modalities is limited and antiarrhythmic drug treatment is still the cornerstone and the first-line therapy for the majority of AF patients. Improvements in the understanding of the principal pathophysiological mechanisms of AF obtained in the last several years have provided promising treatment opportunities. New therapeutic options are based on the more selective targeting of ion channels and intercellular connection proteins predominantly expressed in the atria, the restoration of intracellular Ca(2+) homeostasis and the prevention of AF-associated electrical and structural remodeling. In this review, we provide a highlight of the most important pathophysiological mechanisms in AF with a relation to the potential therapeutic interventions, and discuss novel findings regarding the current and future pharmacological AF management and recent patents.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 94,
                "text": "AF"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 467,
                "text": "Aurora A"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 837,
                "text": "MethPed"
            }
        },
        {
            "context": "Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3(+)CD56(+) lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide.",
            "question": "Name monoclonal antibody against SLAMF7.",
            "answers": {
                "answer_start": 177,
                "text": "signaling lymphocytic activation molecule-F7"
            }
        },
        {
            "context": "A large deletion together with a point mutation in the GALC gene is a common mutant allele in patients with infantile Krabbe disease. Galactocerebrosidase (GALC) activity is deficient in all patients with globoid cell leukodystrophy (GLD). While most patients have the severe infantile form of this autosomal recessive disorder (Krabbe disease), patients up to 50 years of age have been diagnosed in this laboratory. With the cloning of the GALC cDNA and availability of information regarding the gene organization, patients can be evaluated for their disease-causing mutations. We now report that a large deletion, together with a polymorphic C to T transition at position 502 of cDNA (counting from the A of the initiation codon), is responsible for a large number of disease-causing alleles in patients with Krabbe disease. Of 48 patients evaluated, 10 were found to be homozygous for the 502/del allele, five patients were heterozygous for this allele, 21 patients were heterozygous for the 502 mutation (presence of the deletion could not be confirmed), and one infantile patient was homozygous for the 502 mutation but at least one allele was not deleted. No patient was found to have the deletion without the 502 polymorphism. The delineation of mutations causing infantile Krabbe disease will provide new information regarding structure-function relationships in this multi-subunit enzyme and will improve the identification of patients and carriers in some families.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 134,
                "text": "Galactocerebrosidase"
            }
        },
        {
            "context": "Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria. Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 1040,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 109,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "Detection of post-transcriptional RNA editing events. The advent of deep sequencing technologies has greatly improved the study of complex eukaryotic genomes and transcriptomes, providing the unique opportunity to investigate posttranscriptional molecular mechanisms as alternative splicing and RNA editing at single base-pair resolution. RNA editing by adenosine deamination (A-to-I) is widespread in humans and can lead to a variety of biological effects depending on the RNA type or the RNA region involved in the editing modification. Hereafter, we describe an easy and reproducible computational protocol for the identification of candidate RNA editing sites in human using deep transcriptome (RNA-Seq) and genome (DNA-Seq) sequencing data.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 377,
                "text": "A-to-I"
            }
        },
        {
            "context": "Clostridium difficile infection. Clostridium difficile infection (CDI) is the main cause of nosocomial diarrhea in industrialized countries and the source of a growing number of cases of diarrhea in the community. The outbreak of the hypervirulent strain belonging to ribotype 027 has increased the incidence and severity of CDI in some countries. Although CDI usually courses as a mild diarrhea it can lead to severe forms such as toxic megacolon or septic shock. One of every 2 episodes of CDI is not diagnosed in Spanish hospitals due to a lack of clinical suspicion or the use of insensitive diagnostic methods. The diagnostic techniques of choice are algorithms based on the detection of glutamate dehydrogenase and molecular detection of the genes of the toxins with or without the direct detection of the toxins. The recommended treatment for CDI depends on the type of infection and the characteristics of the patient.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 268,
                "text": "ribotype 027"
            }
        },
        {
            "context": "Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease. Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 84,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "[Evaluation of the work-related disability in people affected by Ehlers-Danlos syndrome]. The Ehlers-Danlos syndrome (EDS), inherited disorder of connective tissue, frequently leads to impairment of various functional areas, including employment. In 35 subjects with classic type EDS, 14 hypermobile, 3 vascular was administered 7 visual analogical scales (pain, stiffness, activities of daily living, instrumental activities of daily living, work, social relations). An impairment of particular significance in total score and in individual areas emerges is in the hypermobile group, followed by classic, less for the vasculature. Overall there is a significant alteration of the quality of life that deserves proper evaluation to facilitate the definition of fitness and the improvement of job insertion in patients with EDS.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 146,
                "text": "connective tissue"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2853,
                "text": "CYP17A1"
            }
        },
        {
            "context": "HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. BACKGROUND: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. METHODOLOGY/PRINCIPAL FINDINGS: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. CONCLUSIONS/SIGNIFICANCE: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 211,
                "text": "frataxin"
            }
        },
        {
            "context": "Familial Mediterranean fever--a review. Familial Mediterranean fever is inherited in an autosomal recessive manner. There are two phenotypes: types 1 and 2. Familial Mediterranean fever type 1 is characterized by recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication. Familial Mediterranean fever type 2 is characterized by amyloidosis as the first clinical manifestation of familial Mediterranean fever in an otherwise asymptomatic individual. Routine treatment of end-stage renal disease, including renal transplantation, is advised. Lifelong treatment with colchicine is required for homozygotes for the p.Met694Val mutation or compound heterozygotes for p.Met694Val and another disease-causing allele; this prevents the inflammatory attacks and the deposition of amyloid. Individuals who do not have the p.Met694Val mutation and who are only mildly affected should be either treated with colchicine or monitored every 6 months for the presence of proteinuria. Molecular genetic testing of the MEFV gene, the only gene currently known to be associated with familial Mediterranean fever, can be offered to family members, especially when the p.Met694Val allele is present, because renal amyloidosis can be prevented by colchicine.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 1264,
                "text": "MEFV gene"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. INTRODUCTION: To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile. RESULTS: Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2 h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related. CONCLUSIONS: In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 286,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Transcription-coupled repair: a complex affair. Transcription-coupled repair (TCR) is generally observed as more rapid or more efficient removal of certain types of DNA damage from the transcribed strands of expressed genes compared with the nontranscribed strands. It has been clearly demonstrated to be a subpathway of nucleotide excision repair (NER) in E. coli, yeast and mammalian cells. Genetic and biochemical studies indicate that it is a highly complex process and requires the participation of the NER pathway, the RNA polymerase complex and additional factors. An early event in TCR is likely the blocking of RNA polymerase complex elongation by damage present in the transcribed strands of expressed genes. Whether TCR is involved in base excision repair pathways or the repair of common forms of oxidative damage is less clear. This review is focused on the description of possible mechanisms of TCR in E. coli and mammalian cells.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 181,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Syncope and sudden arrhythmic death complicating pregnancy. A case report of Romano-Ward syndrome. Romano-Ward syndrome is a subtype of prolonged QT syndrome with autosomal dominant inheritance. Stress-induced syncope and sudden death are secondary to ventricular tachydysrhythmias. A case report of Romano-Ward syndrome complicating pregnancy is presented. Successful therapy with propranolol for life-threatening dysrhythmias was achieved. An excellent neonatal outcome occurred.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 163,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Expression level of phosphorylated-4E-binding protein 1 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with mammalian target of rapamycin inhibitors. The objective of this study was to analyze the expression levels of multiple components in the mammalian target of rapamycin (mTOR) signaling pathway in radical nephrectomy specimens from patients with metastatic renal-cell carcinoma (RCC) treated with mTOR inhibitors in order to identify factors predicting susceptibility to these agents. This study retrospectively included a total of 48 consecutive patients undergoing radical nephrectomy, who were diagnosed with metastatic RCC and subsequently treated with an mTOR inhibitor (everolimus or temsirolimus) as either first- or second-line systemic therapy. Expression levels of 5 molecular markers involved in the signaling pathway associated with mTOR, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, and p-4E-binding protein 1 (4E-BP1), were measured by immunohistochemical staining of primary RCC specimens. Of several factors examined, bone metastasis, liver metastasis, and the expression level of p-4E-BP1 were shown to have significant impacts on the response to the mTOR inhibitors. Progression-free survival (PFS) was significantly correlated with the expression levels of PTEN and p-4E-BP1 in addition to the presence of bone metastasis on univariate analysis. Of these significant factors, p-4E-BP1 expression and bone metastasis appeared to be independently associated with PFS on multivariate analysis. These findings suggest that it would be useful to consider the expression levels of potential molecular markers in the mTOR signaling pathway, particularly p-4E-BP1, as well as conventional clinical parameters when selecting patients with metastatic RCC who are likely to benefit from treatment with mTOR inhibitors.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 314,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. Mitochondria display different morphologies, depending on cell type and physiological situation. In many senescent cell types, an extensive elongation of mitochondria occurs, implying that the increase of mitochondrial length in senescence could have a functional role. To test this hypothesis, human endothelial cells (HUVECs) were aged in vitro. Young HUVECs had tubular mitochondria, whereas senescent cells were characterized by long interconnected mitochondria. The change in mitochondrial morphology was caused by downregulation of the expression of Fis1 and Drp1, two proteins regulating mitochondrial fission. Targeted photodamage of mitochondria induced the formation of reactive oxygen species (ROS), which triggered mitochondrial fragmentation and loss of membrane potential in young cells, whereas senescent cells proved to be resistant. Alterations of the Fis1 and Drp1 expression levels also influenced the expression of the putative serine-threonine kinase PINK1, which is associated with the PARK6 variant of Parkinson's disease. Downregulation of PINK1 or overexpression of a PINK1 mutant (G309D) increased the sensitivity against ROS in young cells. These results indicate that there is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells, which, when compromised, could contribute to the age-related progression of Parkinson's disease and arteriosclerosis.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 745,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 822,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Neurofibromatosis type 1 (NF1) is a common familial tumour syndrome with multiple clinical features such as neurofibromas, café-au-lait spots (CLS), iris Lisch nodules, axillary freckling, optic glioma, specific bone lesions and an increased risk of malignant tumours. It is caused by a wide spectrum of mutations affecting the NF1 gene. Most mutations result in the loss of one allele at the DNA, mRNA or protein level and thus in the loss of any function of the gene product neurofibromin. The idea of the simultaneous loss of several different neurofibromin functions has been postulated to explain the pleiotropic effects of its loss. However, we have identified a novel missense mutation in a family with a classical multi-symptomatic NF1 phenotype, including a malignant schwannoma, that specifically abolishes the Ras-GTPase-activating function of neurofibromin. In this family, Arg1276 had mutated into proline. Based on complex biochemical studies as well as the analysis of the crystal structure of the GTPase-activating protein (GAP) domain of p120GAP in the presence of Ras, we unequivocally identified this amino acid as the arginine finger of the neurofibromin GAP-related domain (GRD)-the most essential catalytic element for RasGAP activity. Here, we present data demonstrating that the mutation R1276P, unlike previously reported missense mutations of the GRD region, does not impair the secondary and tertiary protein structure. It neither reduces the level of cellular neurofibromin nor influences its binding to Ras substantially, but it does completely disable GAP activity. Our findings provide direct evidence that failure of neurofibromin GAP activity is the critical element of NF1 pathogenesis. Thus, therapeutic approaches aimed at the reduction of Ras.GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 411,
                "text": "NF1"
            }
        },
        {
            "context": "Autosomal XX sex reversal caused by duplication of SOX9. SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We report here evidence supporting that SOX9 duplication can cause XX sex reversal. A newborn infant was referred for genetic evaluation because of abnormal male external genitalia. The infant had severe penile/scrotal hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY was ruled out by FISH with a probe containing the SRY gene and polymerase chain reaction with SRY-specific primers. Microsatellite analysis with 13 markers on 17q23-24 determined that the duplication is maternal in origin and defined the boundary of the duplication to be approximately 12 centimorgans (cM) proximal and 4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for the sex reversal in this case because it plays an important role in male sex determination and differentiation. This study suggests that extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. Other SRY-negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene.",
            "question": "Which is the main abnormality that arises with Sox9 locus duplication?",
            "answers": {
                "answer_start": 0,
                "text": "Autosomal XX sex reversal"
            }
        },
        {
            "context": "Antigenotoxic effects of p53 on spontaneous and ultraviolet light B--induced deletions in the epidermis of gpt delta transgenic mice. Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as \"the guardian of the genome.\" To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(+/+) mice. However, no increase of such large deletions was observed in irradiated p53(-/-) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 398,
                "text": "p53"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 339,
                "text": "53BP1"
            }
        },
        {
            "context": "Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model? Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3.1.2.45, gene symbol GBA). In type I GD, the CNS is not involved (nonneuronopathic), whereas in type II GD (acute neuronopathic) CNS involvement is early and rapidly progressive, while in type III GD (subacute neuronopathic) CNS involvement occurs later and is slowly progressive. The T6433C (L444P) substitution is prevalent in type GD II. It may occur alone as a single base-pair mutation but often is found as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H). This complex allele is presumed to have formed by recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences. Two complex alleles have never been demonstrated to coexist in any individual. We devised a selective PCR method for the specific amplification of the normal and/or fusion gene. Using this procedure we demonstrated the fusion gene in homozygous form for the first time, in a Macedonian/Ashkenazi Jewish GD type II fetus. Both parents were carriers of the recombination. This was confirmed by direct sequence analysis. A previous conceptus in this family was stillborn at 36 weeks, with features of severe type II GD. Neonates showing a severe clinical phenotype, analogous to the early neonatal lethal disease occurring in mice homozygous for a null allele produced by targeted disruption of GBA, have been described elsewhere, but the specific mutations in these cases have not yet been characterized.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 219,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Linagliptin and newer DPP-4 inhibitors: newer uses and newer indications. The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. These agents may be used either as monotherapy for the treatment of type-2 diabetes or in combination with other anti-diabetic drugs. The present review highlights the use of linagliptin and other new (DPP-4) inhibitors in the management of type-2 diabetes. The review also highlights advantages, comparative pharmacokinetic, safety profile and other potential uses including potential newer indications of DPP-4 inhibitors and relevant patents. The other potential uses that are not restricted to diabetes include obesity, cardiovascular disease, neurological disease, hepatobiliary disease, wound healing, and other inflammatory illnesses.",
            "question": "What are 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin'?",
            "answers": {
                "answer_start": 78,
                "text": "dipeptidyl peptidase-4 (DPP-4) inhibitors"
            }
        },
        {
            "context": "Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region. BACKGROUND: Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). FINDINGS: We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. CONCLUSIONS: Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 403,
                "text": "FOXP2"
            }
        },
        {
            "context": "Determinants of Dropout and Nonadherence in a Dementia Prevention Randomized Controlled Trial: The Prevention of Dementia by Intensive Vascular Care Trial. OBJECTIVES: To explore and compare sociodemographic, clinical, and neuropsychiatric determinants of dropout and nonadherence in older people participating in an open-label cluster-randomized controlled trial-the Prevention of Dementia by Intensive Vascular care (preDIVA) trial-over 6 years. DESIGN: Secondary analysis. SETTING: One hundred sixteen general practices in the Netherlands. PARTICIPANTS: Community-dwelling individuals aged 70 to 78 (N = 2,994). INTERVENTION: Nurse-led multidomain intervention targeting cardiovascular risk factors to prevent dementia. MEASUREMENTS: The associations between participant baseline sociodemographic (age, sex, education), clinical (medical history, disability, cardiovascular risk), neuropsychiatric (depressive symptoms (Geriatric Depression Scale-15), and cognitive (Mini-Mental State Examination)) characteristics and dropout from the trial and nonadherence to the trial intervention were explored using multilevel logistic regression models. RESULTS: Older age, poorer cognitive function, more symptoms of depression, and greater disability were the most important determinants of dropout of older people. The presence of cardiovascular risk factors was not associated with dropout but was associated with nonadherence. Being overweight was a risk factor for nonadherence, whereas people with high blood pressure or a low level of physical exercise adhered better to the intervention. The association between poorer cognitive function and symptoms of depression and dropout was stronger in the control group than in the intervention group, and vice versa for increased disability. CONCLUSION: In a large dementia prevention trial with 6-year follow-up, dropout was associated with older age, poorer cognitive function, symptoms of depression, and disability at baseline. These findings can help to guide the design of future dementia prevention trials in older adults. The associations found between cardiovascular risk factors and nonadherence need to be confirmed in other older populations receiving cardiovascular prevention interventions.",
            "question": "What is the preDIVA clinical trial?",
            "answers": {
                "answer_start": 368,
                "text": "Prevention of Dementia by Intensive Vascular care"
            }
        },
        {
            "context": "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 273,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 548,
                "text": "7"
            }
        },
        {
            "context": "Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 136,
                "text": "CD38"
            }
        },
        {
            "context": "K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through mitogen-activated protein kinase signaling pathways. Activating point mutations in the K-Ras oncogene are among the most common genetic alterations in pancreatic cancer, occurring early in the progression of the disease. However, the function of mutant K-Ras activity in tumor angiogenesis remains poorly understood. Using human pancreatic duct epithelial (HPDE) and K-Ras4B(G12V)-transformed HPDE (HPDE-KRas) cells, we show that activated K-Ras significantly enhanced the production of angiogenic factors including CXC chemokines and vascular endothelial growth factor (VEGF). Western blot analysis revealed that K-Ras activation promoted the phosphorylation of Raf/mitogen-activated protein kinase kinase-1/2 (MEK1/2) and expression of c-Jun. MEK1/2 inhibitors, U0126 and PD98059, significantly inhibited the secretion of both CXC chemokines and VEGF, whereas the c-Jun NH(2)-terminal kinase inhibitor SP600125 abrogated only CXC chemokine production. To further elucidate the biological functions of oncogenic K-Ras in promoting angiogenesis, we did in vitro invasion and tube formation assays using human umbilical vein endothelial cells (HUVEC). HUVEC cocultured with HPDE-KRas showed significantly enhanced invasiveness and tube formation as compared with either control (without coculture) or coculture with HPDE. Moreover, SB225002 (a CXCR2 inhibitor) and 2C3 (an anti-VEGF monoclonal antibody) either alone or in a cooperative manner significantly reduced the degree of both Ras-dependent HUVEC invasiveness and tube formation. Similar results were obtained using another pair of immortalized human pancreatic duct-derived cells, E6/E7/st and its oncogenic K-Ras variant, E6/E7/Ras/st. Taken together, our results suggest that angiogenesis is initiated by paracrine epithelial secretion of CXC chemokines and VEGF downstream of activated oncogenic K-Ras, and that this vascular maturation is in part dependent on MEK1/2 and c-Jun signaling.",
            "question": "Which is the molecular mechanism underlying K-ras alterations in carcinomas?",
            "answers": {
                "answer_start": 159,
                "text": "point mutations"
            }
        },
        {
            "context": "Detection of Turner syndrome using high-throughput quantitative genotyping. CONTEXT: Turner syndrome (TS) is the most common genetic problem affecting women and occurs when an X chromosome is completely deleted, portions of an X chromosome are deleted, or chromosomal mosaicism occurs. Girls with TS may also have occult Y chromosome sequences. Whereas some girls with TS are identified in infancy or early childhood, many girls with TS are not detected until after 10 yr of age, resulting in delayed evaluation and treatment. OBJECTIVE: To prevent the delayed recognition and treatment of TS, a quantitative method of genotyping that can be performed as part of newborn screening is needed. DESIGN: To screen for sex chromosome abnormalities, we assembled a panel of informative single nucleotide polymorphism (SNP) markers that span the X chromosome from the dbSNP database. Pyrosequencing assays suitable for quantitative assessment of signal strength from single nucleotides were designed and used to genotype 46,XX; 46,XY; 45,X; and TS mosaics, examining zygosity and signal strength for individual alleles. Pyrosequencing assays were also designed for the detection of Y chromosome material. RESULTS: With just four informative SNP markers for the X chromosome, all TS girls with 45,X, partial X chromosome deletions, or mosaicism were identified with 100% sensitivity. In mosaic individuals, Y chromosomal material was detected with 100% sensitivity. CONCLUSION: These results suggest that inexpensive high-throughput screening is possible for TS and other sex chromosome disorders using quantitative genotyping approaches.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 81,
                "text": "X"
            }
        },
        {
            "context": "Remission in post-traumatic stress disorder (PTSD): effects of sertraline as assessed by the Davidson Trauma Scale, Clinical Global Impressions and the Clinician-Administered PTSD scale. Rates of remission were examined in two controlled 12-week studies of sertraline and placebo for post-traumatic stress disorder (PTSD). The performance of three scales was evaluated: the self-rated Davidson Trauma Scale (DTS), and two interviewer scales: the Clinician Administered PTSD Scale (CAPS) and Clinical Global Impressions (CGI). Sertraline proved significantly superior to placebo with respect to remission on all three ratings. Rates of remission were very similar for all scales, ranging from 23.1-26.3% for sertraline and 13.9-14.9% for placebo. Traditional thresholds for the CAPS and DTS were tested relative to the CGI and to each other. The CAPS and DTS thresholds of < 20 and < 18 were found to be valid.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 13,
                "text": "post-traumatic stress disorder"
            }
        },
        {
            "context": "BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are reduced during imatinib treatment. PURPOSE: Imatinib induces a durable response in most patients with Philadelphia chromosome-positive chronic myeloid leukemia, but it is currently unclear whether imatinib reduces the leukemic stem cell (LSC) burden, which may be an important step toward enabling safe discontinuation of therapy. In this article, we use mathematical models of BCR-ABL levels to make inferences on the dynamics of LSCs. EXPERIMENTAL DESIGN: Patients with at least 1 BCR-ABL transcript measurement on imatinib were included (N = 477). Maximum likelihood methods were used to test 3 potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy: (i) monoexponential, in which there is little, if any, decline in BCR-ABL transcripts; (ii) biexponential, in which patients have a rapid initial decrease in BCR-ABL transcripts followed by a more gradual response; and (iii) triexponential, in which patients first exhibit a biphasic decline but then have a third phase when BCR-ABL transcripts increase rapidly. RESULTS: We found that most patients treated with imatinib exhibit a biphasic decrease in BCR-ABL transcript levels, with a rapid decrease during the first few months of treatment, followed by a more gradual decrease that often continues over many years. CONCLUSIONS: We show that the only hypothesis consistent with current data on progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL levels seen in most patients is that these patients exhibit a continual, gradual reduction of the LSCs. This observation may explain the ability to discontinue imatinib therapy without relapse in some cases.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 458,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1708,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Endoplasmic reticulum-specific BH3-only protein BNIP1 induces mitochondrial fragmentation in a Bcl-2- and Drp1-dependent manner. Bcl-2/adenovirus E1B 19-kDa interacting protein 1 (BNIP1), which is predominantly localized to the endoplasmic reticulum (ER), is a pro-apoptotic Bcl-2 homology domain 3 (BH3)-only protein. Here, we show that the expression of BNIP1 induced not only a highly interconnected ER network but also mitochondrial fragmentation in a BH3 domain-dependent manner. Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission. Both BNIP1-induced mitochondrial fission and the translocation of Drp1 were abrogated by Bcl-2 overexpression. These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 661,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1732,
                "text": "XK"
            }
        },
        {
            "context": "Phase I/II trial of orteronel (TAK-700)--an investigational 17,20-lyase inhibitor--in patients with metastatic castration-resistant prostate cancer. PURPOSE: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones. EXPERIMENTAL DESIGN: We conducted a phase I/II study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer, and serum testosterone <50 ng/dL. In the phase I part, patients received orteronel 100 to 600 mg twice daily or 400 mg twice a day plus prednisone 5 mg twice a day. In phase II, patients received orteronel 300 mg twice a day, 400 mg twice a day plus prednisone, 600 mg twice a day plus prednisone, or 600 mg once a day without prednisone. RESULTS: In phase I (n = 26), no dose-limiting toxicities were observed and 13 of 20 evaluable patients (65%) achieved > 50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase II (n = 97), 45 of 84 evaluable patients (54%) achieved a > 50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (-7.5 ng/dL) and dehydroepiandrosterone-sulfate (-45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase II patients experienced grade > 3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea. CONCLUSIONS: 17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 111,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3(+)CD56(+) lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide.",
            "question": "Name monoclonal antibody against SLAMF7.",
            "answers": {
                "answer_start": 177,
                "text": "signaling lymphocytic activation molecule-F7"
            }
        },
        {
            "context": "The activation of the decapping enzyme DCP2 by DCP1 occurs on the EDC4 scaffold and involves a conserved loop in DCP1. The removal of the 5'-cap structure by the decapping enzyme DCP2 and its coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3' exonucleolytic degradation by XRN1. Although yeast DCP1 and DCP2 directly interact, an additional factor, EDC4, promotes DCP1-DCP2 association in metazoan. Here, we elucidate how the human proteins interact to assemble an active decapping complex and how decapped mRNAs are handed over to XRN1. We show that EDC4 serves as a scaffold for complex assembly, providing binding sites for DCP1, DCP2 and XRN1. DCP2 and XRN1 bind simultaneously to the EDC4 C-terminal domain through short linear motifs (SLiMs). Additionally, DCP1 and DCP2 form direct but weak interactions that are facilitated by EDC4. Mutational and functional studies indicate that the docking of DCP1 and DCP2 on the EDC4 scaffold is a critical step for mRNA decapping in vivo. They also revealed a crucial role for a conserved asparagine-arginine containing loop (the NR-loop) in the DCP1 EVH1 domain in DCP2 activation. Our data indicate that DCP2 activation by DCP1 occurs preferentially on the EDC4 scaffold, which may serve to couple DCP2 activation by DCP1 with 5'-to-3' mRNA degradation by XRN1 in human cells.",
            "question": "Which is the enzyme that degrades decapped mRNAs?",
            "answers": {
                "answer_start": 1327,
                "text": "XRN1"
            }
        },
        {
            "context": "Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study. BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.",
            "question": "Aleglitazar is agonist of which receptor?",
            "answers": {
                "answer_start": 20,
                "text": "peroxisome proliferator-activated receptor-α/γ"
            }
        },
        {
            "context": "Skin layer-specific transcriptional profiles in normal and recessive yellow (Mc1re/Mc1re) mice. The melanocortin 1 receptor (Mc1r) plays a central role in cutaneous biology, but is expressed at very low levels by a small fraction of cells in the skin. In humans, loss-of-function MC1R mutations cause fair skin, freckling, red hair, and increased predisposition to melanoma; in mice, Mc1r loss-of-function is responsible for the recessive yellow mutation, associated with pheomelanic hair and a decreased number of epidermal melanocytes. To better understand how Mc1r signaling affects different cutaneous phenotypes, we examined large-scale patterns of gene expression in different skin components (whole epidermal sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and recessive yellow mice, starting with a 26K mouse cDNA microarray. From c. 17 000 genes whose levels could be accurately measured in neonatal skin, we identified 883, 2097 and 552 genes that were uniquely expressed in the suprabasal epidermis, basal epidermis and dermis, respectively; specific biologic roles could be assigned for each class. Comparison of normal and recessive yellow mice revealed 69 differentially expressed genes, of which the majority had not been previously implicated in Mc1r signaling. Surprisingly, many of the Mc1r-dependent genes are expressed in cells other than melanocytes, even though Mc1r expression in the skin is confined almost exclusively to epidermal melanocytes. These results reveal new targets for Mc1r signaling, and point to a previously unappreciated role for a Mc1r-dependent paracrine effect of melanocytes on other components of the skin.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 384,
                "text": "Mc1r"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 4,
                "text": "xa"
            }
        },
        {
            "context": "Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan anemia. Mutations in the ribosomal protein (RP)S19 gene have been found in about 25% of the cases of Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia that includes variable physical malformations. Various mutations have been identified in the RPS19 gene, but no investigations regarding the effect of these alterations on RPS19 mRNA levels have been performed. It is well established that mutated mRNA containing a premature stop codon (PTC) or lacking a stop codon can be rapidly degraded by specific mechanisms called nonsense mediated decay (NMD) and nonstop decay. To study the involvement of such mechanisms in DBA, we analyzed immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. We found that RPS19 mRNA levels are decreased in the cells with allelic deletion and, to a variable extent, also in all the cell lines with PTC or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA. Our findings indicate that NMD and nonstop decay affect the expression of mutated RPS19 genes; this may help to clarify genotype-phenotype correlations in DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 187,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 794,
                "text": "telomerase"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 0,
                "text": "GBshape"
            }
        },
        {
            "context": "Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series. Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 124,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 1340,
                "text": "CisMapper"
            }
        },
        {
            "context": "Epidermal growth factor receptor-directed monoclonal antibodies in nonsmall cell lung cancer: an update. PURPOSE OF REVIEW: The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies has been studied as a strategy to improve the outcome of first-line chemotherapy in patients with NSCLC. The present review updates the findings from phase III trials. RECENT FINDINGS: Cetuximab improved survival when combined with first-line chemotherapy and this benefit was limited to patients with high EGFR expression in their tumors. A Southwest Oncology Group study currently prospectively evaluates the predictive biomarkers for cetuximab. In the SQUIRE phase III trial, necitumumab added to cisplatin and gemcitabine increased the survival in patients with advanced squamous cell NSCLC. The INSPIRE trial studied chemotherapy with and without necitumumab in patients with nonsquamous NSCLC but was prematurely halted because of increased thromboembolic events with chemotherapy and necitumumab. SUMMARY: EGFR monoclonal antibodies improved the outcome including survival in selected patients with advanced NSCLC. Prospective validation of predictive biomarkers is ongoing.",
            "question": "What is targeted by Palbociclib?",
            "answers": {
                "answer_start": 0,
                "text": "Epidermal growth factor receptor"
            }
        },
        {
            "context": "The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review. INTRODUCTION: Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. AREAS COVERED: SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1506,
                "text": "xa"
            }
        },
        {
            "context": "MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 297,
                "text": "MITF"
            }
        },
        {
            "context": "Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. Mutational activation of BRAF is a frequent event in human malignant melanomas suggesting that BRAF-dependent signaling is conducive to melanoma cell growth and survival. Previously published work reported that melanoma cells exhibit constitutive anti-apoptotic nuclear factor kappaB (NF-kappaB) transcription factor activation triggered by proteolysis of its inhibitor IkappaB. IkappaB degradation is dependent upon its phosphorylation by the IkappaB kinase (IKK) complex and subsequent ubiquitination facilitated by beta-Trcp E3 ubiquitin ligase. Here, we report that melanocytes expressing a conditionally oncogenic form of BRAF(V600E) exhibit enhanced beta-Trcp expression, increased IKK activity and a concomitant increase in the rate of IkappaBalpha degradation. Conversely, inhibition of BRAF signaling using either a broad-spectrum Raf inhibitor (BAY 43-9006) or by selective knock-down of BRAF(V600E) expression by RNA interference in human melanoma cells leads to decreased IKK activity and beta-Trcp expression, stabilization of IkappaB, inhibition of NF-kappaB transcriptional activity and sensitization of these cells to apoptosis. Taken together, these data support a model in which mutational activation of BRAF in human melanomas contributes to constitutive induction of NF-kappaB activity and to increased survival of melanoma cells.",
            "question": "Which is the E3 ubiquitin ligase which ubiquitinates IkB leading to its proteasomal degradation?",
            "answers": {
                "answer_start": 612,
                "text": "beta-Trcp"
            }
        },
        {
            "context": "Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 1640,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1644,
                "text": "Xa"
            }
        },
        {
            "context": "Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 179,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica Bazex syndrome associated with esophageal squamocellular carcinoma. BACKGROUND: Acrokeratosis paraneoplastica Bazex (APB) is a very rare disease in the group of obligate paraneoplastic dermatoses, associated mostly with squamous cell carcinoma of the upper aerodigestive tract and metastatic cervical lymphadenopathy. The disease is characterized by violaceous erythemosquamous changes on the acral regions. This entity was first reported by Bazex in 1965. About 160 cases have been presented so far. CASE REPORT: We presented a patient with a three-month history of violaceous erythema, edema, erosions and scaling on the acral regions, elbows and knees and severe nail dystrophy. When the diagnosis was established, he did not have any symptom of internal malignancy. Esophagogastroscopy revealed ulcerovegetant lesion of the esophagus, while histology showed squamocellular invasive carcinoma. Surgical tumor removal resulted in significant improvement of skin changes in 15 days. Unfortunately, four months later, extensive skin lesions pointed to metastasis of squamous cell carcinoma. CONCLUSION: Skin changes can precede a few years the first manifestations of neoplasia. The course of the disease in our patient proved that APB is a specific marker of underlying malignancy.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 30,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 477,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 274,
                "text": "ret"
            }
        },
        {
            "context": "Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative disorder of childhood, is caused by mutations in a recently identified gene ( CLN3 ) localized to chromosome 16p11.2-12.1. To elucidate the biosynthesis and localization of the CLN3 protein, we expressed CLN3 cDNA in COS-1 and HeLa cell lines. In vitro translation, immunoprecipitation and Western blotting analyses detected an approximately 43 kDa polypeptide. Pulse-chase experiments indicated that the CLN3 protein is synthesized as an N -glycosylated single-chain polypeptide, which was not detected in growth medium. Confocal immunofluorescence microscopy revealed that the CLN3 protein is localized to the lysosomal compartment. These results provide evidence that Batten disease can be classified as a member of lysosomal diseases.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 153,
                "text": "JNCL"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 816,
                "text": "xa"
            }
        },
        {
            "context": "Prognostic factors associated with complete cytogenetic response in patients with chronic myelogenous leukemia on imatinib mesylate therapy. INTRODUCTION: Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has proved to be most effective therapy of Philadelphia chromosome-positive chronic myelogenous leukemia. Imatinib induces complete haematological and cytogenetic response in high percentage of patients. OBJECTIVE: The aim of this study was to identify potential prognostic factors before beginning treatment with imatinib associated with complete cytogenetic response. METHODS: We analyzed 20 patients with newly diagnosed Philadelphia positive chronic myelogenous leukemia treated at our institution from June 2006 until May 2009. These patients were treated with imatinib mesylate in oral dose of 400 to 800 mg daily. Complete blood counts were performed every month, while serum chemistry evaluations and bone marrow evaluations including morphology and cytogenetics were performed every 6 months. RESULTS: Of the 20 patients analyzed in this study, 19 (95%) achieved complete haematologic response within three months. In all patients cytogenetic analyses were done and all have achieved absolute cytogenetic response. The best cytogenetic response rate at any time during study treatment among 20 patients was: complete cytogenetic response in 15, partial cytogenetic response in three and minor cytogenetic response in two patients. Among 11 observed base-line patients' characteristics five were independent predictors of a high rate of complete cytogenetic response; the absence of blasts and basophils in peripheral blood, the presence of less than 5 percent of bone marrow blasts, white blood cell count less than 10 x 10(9)/L and the absence of splenomegaly (p < 0.01). CONCLUSION: Our results showed that some pre-treatment characteristics of patients might be the cause of differences in treatment outcome. On the basis of this analysis, we identified several pre-treatment patients' characteristics to be independent prognostic factors for achievement of complete cytogenetic response.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 186,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Protection conferred by recombinant Yersinia pestis antigens produced by a rapid and highly scalable plant expression system. Plague is still an endemic disease in different regions of the world. Increasing reports of incidence, the discovery of antibiotic resistance strains, and concern about a potential use of the causative bacteria Yersinia pestis as an agent of biological warfare have highlighted the need for a safe, efficacious, and rapidly producible vaccine. The use of F1 and V antigens and the derived protein fusion F1-V has shown great potential as a protective vaccine in animal studies. Plants have been extensively studied for the production of pharmaceutical proteins as an inexpensive and scalable alternative to common expression systems. In the current study the recombinant plague antigens F1, V, and fusion protein F1-V were produced by transient expression in Nicotiana benthamiana by using a deconstructed tobacco mosaic virus-based system that allowed very rapid and extremely high levels of expression. All of the plant-derived purified antigens, administered s.c. to guinea pigs, generated systemic immune responses and provided protection against an aerosol challenge of virulent Y. pestis.",
            "question": "Which bacteria caused plague?",
            "answers": {
                "answer_start": 337,
                "text": "Yersinia pestis"
            }
        },
        {
            "context": "The use of cffDNA in fetal sex determination during the first trimester of pregnancy of female DMD carriers. Chorionic villus sampling (CVS) or amniocentesis for fetal sex determination is generally the first step in the prenatal diagnosis of X-linked genetic disorders such as Duchenne muscular dystrophy (DMD). However, non-invasive prenatal diagnostic (NIPD) techniques such as measurement of cell-free fetal DNA (cffDNA) in maternal plasma are preferable given the procedure-related miscarriage rate of CVS. We determined fetal sex during the first trimester using a quantitative real-time polymerase chain reaction (PCR) assay of cffDNA in pregnant carriers of DMD. The fetal sex was confirmed by amniocentesis karyotype analysis and multiplex ligation-dependent probe amplification (MLPA) at 16 weeks. This procedure may avoid unnecessary CVS or amniocentesis of female fetuses.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 56,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 135,
                "text": "FSHD"
            }
        },
        {
            "context": "Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 16,
                "text": "MITF"
            }
        },
        {
            "context": "MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappaB-dependent lymphomas.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 11,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 590,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.",
            "question": "Inhibition of which transporter is the mechanism of action of drug Canagliflozin?",
            "answers": {
                "answer_start": 263,
                "text": "sodium glucose co-transporter 2"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1924,
                "text": "fungi"
            }
        },
        {
            "context": "SECISearch3 and Seblastian: new tools for prediction of SECIS elements and selenoproteins. Selenoproteins are proteins containing an uncommon amino acid selenocysteine (Sec). Sec is inserted by a specific translational machinery that recognizes a stem-loop structure, the SECIS element, at the 3' UTR of selenoprotein genes and recodes a UGA codon within the coding sequence. As UGA is normally a translational stop signal, selenoproteins are generally misannotated and designated tools have to be developed for this class of proteins. Here, we present two new computational methods for selenoprotein identification and analysis, which we provide publicly through the web servers at http://gladyshevlab.org/SelenoproteinPredictionServer or http://seblastian.crg.es. SECISearch3 replaces its predecessor SECISearch as a tool for prediction of eukaryotic SECIS elements. Seblastian is a new method for selenoprotein gene detection that uses SECISearch3 and then predicts selenoprotein sequences encoded upstream of SECIS elements. Seblastian is able to both identify known selenoproteins and predict new selenoproteins. By applying these tools to diverse eukaryotic genomes, we provide a ranked list of newly predicted selenoproteins together with their annotated cysteine-containing homologues. An analysis of a representative candidate belonging to the AhpC family shows how the use of Sec in this protein evolved in bacterial and eukaryotic lineages.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 272,
                "text": "SECIS"
            }
        },
        {
            "context": "Prognostic impact of central nervous system metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-negative status and leptomeningeal metastases. AIM: The aim of the present study was to investigate the prognostic impact of central nervous system metastases (CNS) after acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We defined CNS-collapse as death due to uncontrolled and progressive CNS metastases. Post-progression survival (PPS) after initial TKI failure and T790M status were retrospectively compared in 92 patients with or without CNS collapse. RESULTS: The median PPS in 32 patients with CNS-collapse (16.7 months) was significantly shorter than that of 60 without (26.8 months) (p=0.0002). T790M was detected in four (12%) out of the 32 CNS-collapse patients and in 26 (43%) out of 60 without (p=0.0026). Median PPS in 39 patients with leptomeningeal metastases (LM) (11.4 months) was significantly shorter versus 53 without (26.8 months) (p=0.0006). The median PPS was 25.1 months in 40 patients with brain metastases and 11.2 months in 52 without (p=0.0387). T790M was detected in 4/5 resected brain tumors (80%) and in 1/26 cerebrospinal fluid (CSF) samples (4%) (p=0.0008). CONCLUSION: CNS-collapse represented poorer prognosis, which was associated with T790M-negative status and LM. Controlling CNS metastases, especially LM, is important to achieve longer survival.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 84,
                "text": "EGFR"
            }
        },
        {
            "context": "[Clinical experience in benzodiazepine antagonist]. Flumazenil, a potent benzodiazepine antagonist, is a newly synthetic imidazo-benzodiazepine, which blocks the neurological effects of benzodiazepines. The purpose of this study was to evaluate the effects of this agent in reversal of benzodiazepine overdose and differentiation of comatous patients with drug overdose. Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration. Three cases with different drug history and variant response after flumazenil treatment were also illustrated and discussed. The dosage of flumazenil used in this study ranged from 0.25 mg to 3 mg (average 0.87 +/- 0.74 mg). We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 473,
                "text": "flumazenil"
            }
        },
        {
            "context": "Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. BACKGROUND: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder resulting in the growth of a variety of tumours, and is inherited in an autosomal dominant pattern. Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that commonly harbour oncogenic mutations in KIT or PDGFRA and are thought to arise from the interstitial cells of Cajal (ICC; the pacemaker cells of the gut). AIM: To characterise two patients with NF1 and GISTs. METHODS: Two patients were genotyped for germline mutations in NF1. GISTs from both patients were genotyped for somatic mutations in KIT and PDGFRA. Loss of heterozygosity (LOH) of NF1 in one GIST was assessed by genotyping seven microsatellite markers spanning 2.39 Mb of the NF1 locus in the tumour and in genomic DNA. The known germline mutation in NF1 was confirmed in GIST DNA by sequencing. The copy number of the mutated NF1 allele was determined by multiplex ligand-dependent probe amplification. RESULTS: GISTs from both patients were of wild type for mutations in KIT and PDGFRA. In the GIST with adequate DNA, all seven markers were informative and showed LOH at the NF1 locus; sequencing of NF1 from that GIST showed no wild-type sequence, suggesting that it was lost in the tumour. Multiplex ligand-dependent probe amplification analysis showed that two copies of all NF1 exons were present. CONCLUSIONS: This is the first evidence of mitotic recombination resulting in a reduction to homozygosity of a germline NF1 mutation in an NF1-associated GIST. We hypothesise that the LOH of NF1 and lack of KIT and PDGFRA mutations are evidence of an alternative pathogenesis in NF1-associated GISTs.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 759,
                "text": "NF1"
            }
        },
        {
            "context": "Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer.",
            "question": "Are most driver gene mutations synonymous or non-synonymous?",
            "answers": {
                "answer_start": 267,
                "text": "non-synonymous"
            }
        },
        {
            "context": "New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors. The treatment of migraine was advanced dramatically with the introduction of triptans in the early 1990s. Despite the substantial improvement in the quality of life that triptans have brought to many migraineurs, a substantial cohort of patients remain highly disabled by attacks and need new therapeutic approaches, which ideally should be quick-acting, have no vasoconstrictor activity, and have a longer duration of action and be better tolerated than current therapies. The calcitonin gene-related peptide (CGRP) receptor antagonists (gepants)-olcegepant (BIBN 4096 BS), telcagepant (MK-0974), MK3207, and BI 44370 TA-are effective in treating acute migraine. They have no vasoconstrictive properties, fewer adverse effects, and may act longer than triptans. Their development has been complicated by liver toxicity issues when used as preventives. Results from studies with BI 44370 TA do not support broad concern about a class effect, and further studies are ongoing in this respect. Many experimental studies and clinical trials suggest that nitric oxide may have a role in the pathophysiology of migraine. Therefore, the inhibition of nitric oxide synthase (NOS) for the acute or prophylactic treatment of migraine offered a feasible approach; as inducible NOS (iNOS) is involved in several pain states, such as inflammatory pain, it appeared to be an attractive target. However, despite high selectivity and potency, the iNOS inhibitor GW274150 was not effective for acute treatment or prophylaxis of migraine, suggesting that iNOS is very unlikely to be a promising target.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 566,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "The mystery of Gustave Flaubert's death: could sudden unexpected death in epilepsy be part of the context? Epilepsy is the most common serious neurological condition and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. More than two decades ago, temporal lobe epilepsy was suggested as having been the ''nervous disease'' of Gustave Flaubert, one of the most important French novelists. In these lines, as the circumstances of his death were the subject of fabulous and mysterious speculations, we postulated in this paper that Flaubert's death could be due SUDEP phenomenon.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 170,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Enzyme replacement and substrate reduction therapy for Gaucher disease. BACKGROUND: Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. OBJECTIVES: To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews.Date of last search: 07 August 2014. SELECTION CRITERIA: All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. MAIN RESULTS: Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy.Treatment-naïve participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose.A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment.There are, as yet, no randomized trials of substrate reduction therapy in treatment-naïve patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat.One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. AUTHORS' CONCLUSIONS: The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety - with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 2684,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 507,
                "text": "IL-1β"
            }
        },
        {
            "context": "Should the annular tendon of the eye be named 'annulus of Zinn' or 'of Valsalva'? The annular tendon is commonly named 'annulus of Zinn', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755). This structure, however, had been previously discovered not by Zinn, but by Antonio Maria Valsalva (1666-1723) some decades before the publication of Zinn, in his Dissertatio anatomica prima and Dissertatio anatomica altera (First and Second Anatomical Dissertations), inside Valsalva's Opera omnia published in 1740. We advance that this structure could be re-named such as 'annulus of Valsalva-Zinn' because Valsalva, even making a mistake in its functional interpretation, first described this anatomical structure. Likewise, Valsalva, with his discovery, advanced a revolutionary idea for that time on the usefulness of anatomy for clinic and pathology.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 33,
                "text": "eye"
            }
        },
        {
            "context": "Dominant alleles identify SET domain residues required for histone methyltransferase of Polycomb repressive complex 2. Polycomb gene silencing requires histone methyltransferase activity of Polycomb repressive complex 2 (PRC2), which methylates lysine 27 of histone H3. Information on how PRC2 works is limited by lack of structural data on the catalytic subunit, Enhancer of zeste (E(Z)), and the paucity of E(z) mutant alleles that alter its SET domain. Here we analyze missense alleles of Drosophila E(z), selected for molecular study because of their dominant genetic effects. Four missense alleles identify key E(Z) SET domain residues, and a fifth is located in the adjacent CXC domain. Analysis of mutant PRC2 complexes in vitro, and H3-K27 methylation in vivo, shows that each SET domain mutation disrupts PRC2 histone methyltransferase. Based on known SET domain structures, the mutations likely affect either the lysine-substrate binding pocket, the binding site for the adenosylmethionine methyl donor, or a critical tyrosine predicted to interact with the substrate lysine epsilon-amino group. In contrast, the CXC mutant retains catalytic activity, Lys-27 specificity, and trimethylation capacity. Deletion analysis also reveals a functional requirement for a conserved E(Z) domain N-terminal to CXC and SET. These results identify critical SET domain residues needed for PRC2 enzyme function, and they also emphasize functional inputs from outside the SET domain.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 981,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ. These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy result in Danon disease characterized by hypertrophic cardiomyopathy. The ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte excitation-contraction and its dysfunction can lead to cardiac failure. Whether RyR2 is degraded by CMA is unknown. METHODS AND RESULTS: To induce CMA, cultured neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote protein degradation through this pathway. GA increased LAMP-2A levels together with its redistribution and colocalization with Hsc70 in the perinuclear region, changes indicative of CMA activation. The inhibition of lysosomes but not proteasomes prevented the loss of RyR2. The recovery of RyR2 content after incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ motifs which are required for the recognition Hsc70 and its degradation via CMA. Our data suggest that presenilins are involved in RyR2 degradation by CMA. CONCLUSION: These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 84,
                "text": "Chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Novel anticoagulants for stroke prevention in atrial fibrillation: current clinical evidence and future developments. Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 690,
                "text": "xa"
            }
        },
        {
            "context": "Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 114,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Bacillus anthracis virulence regulator AtxA: oligomeric state, function and CO(2) -signalling. AtxA, a unique regulatory protein of unknown molecular function, positively controls expression of the major virulence genes of Bacillus anthracis. The 475 amino acid sequence of AtxA reveals DNA binding motifs and regions similar to proteins associated with the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS). We used strains producing native and functional epitope-tagged AtxA proteins to examine protein-protein interactions in cell lysates and in solutions of purified protein. Co-affinity purification, non-denaturing polyacrylamide gel electrophoresis and bis(maleimido)hexane (BMH) cross-linking experiments revealed AtxA homo-multimers. Dimers were the most abundant species. BMH cross-links available cysteines within 13 Å. To localize interaction sites, six AtxA mutants containing distinct Cys→Ser substitutions were tested for multimerization and cross-linking. All mutants multimerized, but one mutation, C402S, prevented cross-linking. Thus, BMH uses C402 to make the inter-molecular bond between AtxA proteins, but C402 is not required for protein-protein interaction. C402 is in a region bearing amino acid similarity to Enzyme IIB proteins of the PTS. The AtxA EIIB motif may function in protein oligomerization. Finally, cultures grown with elevated CO(2) /bicarbonate exhibited increased AtxA dimer/monomer ratios and increased AtxA activity, relative to cultures grown without added CO(2) /bicarbonate, suggesting that this host-associated signal enhances AtxA function by shifting the dimer/monomer equilibrium towards the dimeric state.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1389,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Origin of human chromosome 2: an ancestral telomere-telomere fusion. We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 16,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Protracted course of Krabbe disease in an adult patient bearing a novel mutation. BACKGROUND: Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC) activity. Although most cases are diagnosed in infancy and show a fatal outcome in childhood, adult patients have been identified, showing progressive spastic hemiparesis to tetraparesis, followed by optic atrophy, dementia, and neuropathy. The disease can be diagnosed by detecting the deficiency of GALC activity (less than 5% of normal) in any available tissue sample. The cloning of the human GALC gene allowed the molecular characterization of newly diagnosed patients. More than 75 disease-causing mutations and polymorphisms in this gene have been identified. OBJECTIVE: To describe a 28-year-old woman with Krabbe disease, correlating clinical and biochemical abnormalities to a novel mutation on the GALC gene. METHODS: Clinical investigation was enriched by neurophysiological and neuroimaging data. The activity of GALC was assayed in white blood cells using radiolabeled natural substrate. Genomic DNA was isolated from peripheral blood, and the GALC gene was sequenced. The mutated gene was expressed and GALC activity was measured in transfected COS-1 cells. RESULTS: The patient had progressive and bilateral amaurosis starting at 8 years of age. Although she was experiencing weakness in all her extremities, her intellect remained intact. She was found to be homozygous for a previously unreported missense mutation (T1886G), which leads to low, but not totally deficient, GALC activity. CONCLUSIONS: Expression of this mutation in COS-1 cells using the pcDNA3 expression vector (Invitrogen, Carlsbad, Calif) resulted in low, although not null, GALC activity, which can explain the protracted clinical course in this patient. Patients carrying the mutation described herein might be potential candidates for therapeutic trials, such as bone marrow transplantation or gene therapy.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 205,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. BACKGROUND: Sulfonylureas (SUs) are commonly used in the treatment of type 2 diabetes (T2DM), usually as second-line treatment after the failure of metformin. However, SUs are associated with poor durability, hypoglycemia and weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of T2DM. In Phase II/III trials, empagliflozin reduced hyperglycemia, body weight and blood pressure, with a low incidence of hypoglycemia. The aim of this Phase III study is to compare the effects of empagliflozin and the SU glimepiride as second-line therapy in patients with T2DM inadequately controlled with metformin immediate release (IR) and diet/exercise. METHOD: After a 2-week placebo run-in, patients were randomized to receive empagliflozin 25 mg once daily (qd) or glimepiride 1-4 mg qd double-blind for 2 years, in addition to metformin IR. Patients who participate in the initial 2-year randomization period will be eligible for a 2-year double-blind extension. The primary endpoint is change from baseline in HbA1c. Secondary endpoints are change from baseline in body weight, the incidence of confirmed hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory endpoints include markers of insulin secretion, body composition and responder analyses. Safety endpoints include the incidence of adverse events (AEs) (including macro- and microvascular adverse events) and changes from baseline in clinical laboratory parameters. RESULTS: Between August 2010 and June 2011, 1549 patients were randomized and 1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m², systolic blood pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg. DISCUSSION: This is the largest study to compare the efficacy and safety of an SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on metformin to date. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate effects on beta-cell function, cardiovascular risk factors and markers of renal function/damage. The results will help to inform the choice of second-line treatment in patients with T2DM who have failed on metformin. TRIAL REGISTRATION: Clinicaltrials.gov NCT01167881.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 107,
                "text": "SGLT2"
            }
        },
        {
            "context": "Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae. OBJECTIVE: Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system. APPROACH AND RESULTS: Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, membrane integrity, and morphology are readily seen. Using flow cytometry, we find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress induced by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading as evidenced by blunted lysosomal dysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β, enhanced cholesterol efflux, and decreased polyubiquitinated protein aggregation. CONCLUSIONS: Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 1212,
                "text": "Transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Midazolam and other benzodiazepines. The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 2137,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. BACKGROUND: Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH-) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 1144,
                "text": "PARP"
            }
        },
        {
            "context": "Bazex syndrome (acrokeratosis paraneoplastica): persistence of cutaneous lesions after successful treatment of an associated oropharyngeal neoplasm. Acrokeratosis paraneoplastica is a rare paraneoplastic syndrome commonly affecting males over 40 years of age. There exists a strong association with squamous cell carcinoma (SCC) of the upper aerodigestive tract or cervical metastatic disease originating from an unknown primary. We report a case associated with SCC of the right tonsil with persistent paraneoplastic cutaneous lesions 2 years after successful treatment of the underlying neoplasm.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 0,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Progranulin (PGRN) is known to play a role in the pathogenesis of neurodegenerative diseases. Recently, it has been demonstrated that patients with the homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal function. In the present study, we investigated the possible role of PGRN in the lysosomes of activated microglia in the cerebral cortex after traumatic brain injury (TBI). We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes. PGRN was colocalized with Lamp1, a lysosomal marker, and Lamp1-positive areas in GRN-deficient (KO) mice were significantly expanded compared with wild-type (WT) mice after TBI. Expression of all the lysosome-related genes examined in KO mice was significantly higher than that in WT mice. The number of activated microglia with TFEB localized to the nucleus was also significantly increased in KO as compared with WT mice. Since the TFEB translocation is regulated by the mammalian target of rapamycin complex 1 (mTORC1) activity in the lysosome, we compared ribosomal S6 kinase 1 (S6K1) phosphorylation that reflects mTORC1 activity. S6K1 phosphorylation in KO mice was significantly lower than that in WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive cells around the injury was significantly decreased and increased, respectively, in KO as compared with WT mice. These results suggest that PGRN localized in the lysosome is involved in the activation of mTORC1, and its deficiency leads to increased TFEB nuclear translocation with a resultant increase in lysosomal biogenesis in activated microglia and exacerbated neuronal damage in the cerebral cortex after TBI.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 746,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 825,
                "text": "xa"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 621,
                "text": "SERCA"
            }
        },
        {
            "context": "Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities. Rapid laboratory methods provide optimal support for active surveillance efforts to screen for methicillin-resistant Staphylococcus aureus (MRSA). Most laboratories struggle to determine the optimal use of resources, considering options to balance cost, speed, and diagnostic accuracy. To assess the performance of common methods, the first comparison of MRSASelect agar (MS) and CHROMagar MRSA (CA), with and without broth enrichment followed by a 24-h subculture to MS, was performed. Results were compared to those of the Xpert MRSA assay. For direct culture methods, the agreement between MS and CA was 98.8%. At 18 h, direct MS identified 93% of all positive samples from direct culture and 84% of those identified by the Xpert MRSA. For Trypticase soy broth-enriched MS culture, incubated overnight and then subcultured for an additional 24 h, the agreement with Xpert MRSA was 96%. The agreement between direct MS and Xpert MRSA was 100% when semiquantitative culture revealed a bacterial density of 2+ or greater; however, discrepancies between culture and Xpert MRSA arose for MRSA bacterial densities of 1+ or less, indicating low density as a common cause of false-negative culture results. Since 1+ or less was established as the most common MRSA carrier state, broth enrichment or PCR may be critical for the identification of all MRSA carriers who may be reservoirs for transmission. In this active-surveillance convenience sample, the use of broth enrichment followed by subculture to MS offered a low-cost but sensitive method for MRSA screening, with performance similar to that of Xpert MRSA PCR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 136,
                "text": "MRSA"
            }
        },
        {
            "context": "Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons. We investigated the requirements for selenocysteine insertion at single or multiple UGA codons in eukaryotic selenoproteins. Two functional SECIS elements were identified in the 3' untranslated region of the rat selenoprotein P mRNA, with predicted stem-loops and critical nucleotides similar to those in the SECIS elements in the type I iodothyronine 5' deiodinase (5'DI) and glutathione peroxidase selenoprotein mRNAs. Site-directed mutational analyses of three SECIS elements confirmed that conserved nucleotides in the loop and in unpaired regions of the stem are critical for activity. This indicates that multiple contact sites are required for SECIS function. Stop codon function at any of five out-of-context UGA codons in the 5'DI mRNA was suppressed by SECIS elements from the 5'DI or selenoprotein P genes linked downstream. Thus, the presence of SECIS elements in eukaryotic selenoprotein mRNAs permits complete flexibility in UGA codon position.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 423,
                "text": "SECIS"
            }
        },
        {
            "context": "GATA1 and PU.1 Bind to Ribosomal Protein Genes in Erythroid Cells: Implications for Ribosomopathies. The clear connection between ribosome biogenesis dysfunction and specific hematopoiesis-related disorders prompted us to examine the role of critical lineage-specific transcription factors in the transcriptional regulation of ribosomal protein (RP) genes during terminal erythroid differentiation. By applying EMSA and ChIP methodologies in mouse erythroleukemia cells we show that GATA1 and PU.1 bind in vitro and in vivo the proximal promoter region of the RPS19 gene which is frequently mutated in Diamond-Blackfan Anemia. Moreover, ChIPseq data analysis also demonstrates that several RP genes are enriched as potential GATA1 and PU.1 gene targets in mouse and human erythroid cells, with GATA1 binding showing an association with higher ribosomal protein gene expression levels during terminal erythroid differentiation in human and mouse. Our results suggest that RP gene expression and hence balanced ribosome biosynthesis may be specifically and selectively regulated by lineage specific transcription factors during hematopoiesis, a finding which may be clinically relevant to ribosomopathies.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 602,
                "text": "Diamond-Blackfan Anemia"
            }
        },
        {
            "context": "Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1501,
                "text": "flumazenil"
            }
        },
        {
            "context": "Structural ramification for acetyl-lysine recognition by the bromodomain of human BRG1 protein, a central ATPase of the SWI/SNF remodeling complex. Bromodomains represent an extensive family of evolutionarily conserved domains that are found in many chromatin-associated proteins such as histone acetyltransferases (HAT) and subunits of ATP-dependent chromatin-remodeling complexes. These domains are associated with acetylated lysine residues that bind both in vivo and in vitro; for example, they bind to the N-acetylated lysines of the histone tail of nucleosomes. In this report, we determined the structure of the bromodomain from human brahma-related gene 1 (BRG1) protein, a subunit of an ATP-dependent switching/sucrose nonfermenting (SWI/SNF) remodeling complex, and have also characterized its in vitro interaction with N-acetylated lysine peptides from histones. In addition to a typical all-alpha-helical fold that was observed in the bromodomains, we observed for the first time a small beta-sheet in the ZA loop region of the BRG1 protein. The BRG1 bromodomain exhibited binding, albeit weak, to acetylated peptides that were derived from histones H3 and H4. We have compared the acetyl-lysine binding sites of BRG1 bromodomain with the yGCN5 (general control of amino acid biosynthesis). By modeling the acetylated-lysine peptide into the BRG1 bromodomain structure, we were able to explain the weak binding of acetylated-lysine peptides to this bromodomain.",
            "question": "What is the structural fold of bromodomain proteins?",
            "answers": {
                "answer_start": 899,
                "text": "all-alpha-helical fold"
            }
        },
        {
            "context": "Transgenic rice plants expressing trichothecene 3-O-acetyltransferase show resistance to the Fusarium phytotoxin deoxynivalenol. Fusarium head blight (FHB) is a devastating disease of small grain cereal crops caused by the necrotrophic pathogen Fusarium graminearum and Fusarium culmorum. These fungi produce the trichothecene mycotoxin deoxynivalenol (DON) and its derivatives, which enhance the disease development during their interactions with host plants. For the self-protection, the trichothecene producer Fusarium species have Tri101 encoding trichothecene 3-O-acetyltransferase. Although transgenic expression of Tri101 significantly reduced inhibitory action of DON on tobacco plants, there are several conflicting observations regarding the phytotoxicity of 3-acetyldeoxynivalenol (3-ADON) to cereal plants; 3-ADON was reported to be highly phytotoxic to wheat at low concentrations. To examine whether cereal plants show sufficient resistance to 3-ADON, we generated transgenic rice plants with stable expression and inheritance of Tri101. While root growth of wild-type rice plants was severely inhibited by DON in the medium, this fungal toxin was not phytotoxic to the transgenic lines that showed trichothecene 3-O-acetylation activity. This is the first report demonstrating the DON acetylase activity and DON-resistant phenotype of cereal plants expressing the fungal gene.",
            "question": "The pathogen Fusarium graminearum affects what type of plant species?",
            "answers": {
                "answer_start": 196,
                "text": "cereal crops"
            }
        },
        {
            "context": "Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 163,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.",
            "question": "Which is the cellular localization of the protein Opa1?",
            "answers": {
                "answer_start": 136,
                "text": "mitochondrial intermembrane space"
            }
        },
        {
            "context": "Selective estrogen receptor modulators: from bench to bedside and back. OBJECTIVE: To provide a brief review of the history of the development of selective estrogen receptor modulators (SERMs), the current data assessing the effect of SERMs at the organ level, and the mechanism of action of these agents. METHODS: All the pertinent medical literature was reviewed, and the effects of SERMs on various end-organs were summarized. RESULTS: SERMs have been available for clinical use since the late 1960s. By the late 1980s, several SERMs had become available that influenced clinical practice. Multiorgan effects of these compounds include variable clinical efficacy for treatment of menopausal symptoms involving the central nervous system, variable effects on the genitourinary tract, and, in general, positive effects on serum lipid levels. SERMs seem to affect bone density positively, albeit to variable degrees, depending on the agent being used. The greatest effect of SERMs has been on the breast, and current SERMs seem to have efficacy for prevention of breast cancer as opposed to the controversial effect of estrogen on the breast. Disadvantages of SERMs include exacerbation of menopausal symptoms and, as with estrogen, an increased incidence of venous thrombosis and pulmonary emboli. SERMs act by modifying the configuration of the estrogen receptor. Effects at the gene transcription level seem to be tissue specific, a factor that likely accounts for the variability of clinical action seen. CONCLUSION: SERMs are a viable option for treatment of various problems associated with menopause.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 146,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Early onset HER2-positive breast cancer is associated with germline TP53 mutations. BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 1617,
                "text": "positive"
            }
        },
        {
            "context": "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. BACKGROUND: PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome. Based on previous reports, patients with PLA2G6 mutations could show axonal dystrophy, dystonia, dementia, and cerebellar signs. Recently, PLA2G6 was also reported as the causative gene for early-onset PARK14-linked dystonia-parkinsonism. METHODS: To clarify the role of PLA2G6 mutation in parkinsonism, we conducted mutation analysis in 29 selected patients with very early-onset ( < 30, mean 21.2 ± 8.4 years, ± SD) parkinsonism. These patients had other clinical features (e.g., mental retardation/dementia [14/29], psychosis [15/29], dystonia [11/29], and hyperreflexia [11/29]). RESULTS: Two novel compound heterozygous PLA2G6 mutations were detected (patient A: p.F72L/p.R635Q; patients B1 and B2: p.Q452X/p.R635Q). All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy. Disease progression was relatively rapid. SPECT in patient B1 showed frontotemporal lobar hypoperfusion. MRI in patient A showed iron accumulation in the substantia nigra and striatum. CONCLUSIONS: Although the clinical presentation of PLA2G6-associated neurodegeneration was reported to be homogeneous, our findings suggest patients with PLA2G6 mutation could show heterogeneous phenotype such as dystonia-parkinsonism, dementia, frontotemporal atrophy/hypoperfusion, with or without brain iron accumulation. Based on the clinical heterogeneity, the functional roles of PLA2G6 and the roles of PLA2G6 variants including single heterozygous mutations should be further elucidated in patients with atypical parkinsonism, dementia, or Parkinson disease. PLA2G6 mutations should be considered in patients with early-onset l-dopa-responsive parkinsonism and dementia with frontotemporal lobar atrophy.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 97,
                "text": "PLA2G6"
            }
        },
        {
            "context": "A Tyrosinase missense mutation causes albinism in the Wistar rat. Tyrosinase serves as a key enzyme in the synthesis of melanin. In humans mutations in the TYR gene are associated with type 1 oculocutaneous albinism (OCA1) that leads to reduced or absent pigmentation of skin, hair and eye. Various mutations causing OCA in man, mouse, rabbit and cattle have been identified throughout the Tyrosinase gene including nonsense, missense, frameshift and splice site alterations. Here we report a missense substitution at codon R299H in exon 2 of the Tyr gene in the albino Wistar rat. As this very exchange has already been described in OCA patients, our findings reinforce the significance of this region for normal catalytic activity of tyrosinase protein.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 156,
                "text": "TYR"
            }
        },
        {
            "context": "A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 208,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Janus kinase inhibition with tofacitinib: changing the face of inflammatory bowel disease treatment. The advent of anti-Tumor Necrosis Factor (TNF) therapy has changed the way of treating inflammatory bowel disease (IBD). However, primary and secondary failure are relatively frequent with all anti-TNF agents, which are available only as parenteral agents. Tofacitinib is an oral janus kinase (JAK) inhibitor that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. It first proved its efficacy as an immunosuppressive regimen after renal transplantation, and was recently approved by the FDA for rheumatoid arthritis. First data in IBD are promising, especially in ulcerative colitis. Ongoing clinical trials in both UC and Crohn's disease (CD) are needed to further explore its efficacy in CD and to better assess its safety profile.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 358,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "[Abdominal emergencies in type IV ehlers-Danlos syndrome]. Ehlers-Danlos syndrome denotes a group of inherited connective tissue diseases comprising nine types. Type IV Ehlers-Danlos syndrome is the most life-threatening form. It is characterized by a type III collagen deficiency resulting in arterial fragility and death from vascular rupture or bowel perforation. This disease involves a col 3A1 gene mutation. We report the case of a 44 year-old woman with type IV Ehlers-Danlos syndrome. The medical history of our patient included bowel necrosis and two vascular ruptures. We indicate data required to establish Ehlers-Danlos syndrome diagnosis and guidelines for patient management.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 111,
                "text": "connective tissue"
            }
        },
        {
            "context": "[Intracutaneous tuberculin test using the Mendel-Mantoux technique. Tuberculin reactivity among inpatients in a pneumology department]. Detection of latent tuberculosis infection is an important step in the control of tuberculosis. The tuberculin skin test is the only proven method for identifying tuberculosis infection in patients who do not have tuberculosis disease. The prevalence of tuberculosis infection among hospitalized patients in a pneumological department of an inner-city hospital was evaluated, using the intradermal tuberculin skin test (Mantoux technique). Interpretation of the Mantoux test was based on the size of induration in millimeters and the individual risk profile of the patients, according to the guidelines of the American Thoracic Society and the Centers for Disease Control, revised in 1989. Of 697 tested patients, 252 showed test results consistent with tuberculosis infection (36.2%). 55 of these 697 patients had active tuberculosis disease or a prior history of tuberculosis (7.9%). A positive tuberculin skin test was found in 197 of 642 patients (30.7%) with a diagnosis different from tuberculosis (COPD, pneumonia, cancer and others). In our study, the sensitivity of the tuberculin skin test for active tuberculosis infection was 95%. The present study revealed a high prevalence of tuberculosis infection among hospitalized patients in a pneumological department. Further studies are needed to assess the usefulness of routine tuberculin skin testing in hospitalized populations.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 390,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Adductor laryngeal breathing dystonia in a patient with lubag (X-linked dystonia-Parkinsonism syndrome). We report a patient with Lubag (X-linked dystonia-parkinsonism) who presented with severe respiratory stridor from adductor laryngeal breathing dystonia. Emergency tracheostomy was necessary, and subsequent laryngeal injection with botulinum toxin led to worsening aspiration. Botulinum toxin injection for severe lingual dystonia was successful.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 63,
                "text": "X-linked dystonia-Parkinsonism"
            }
        },
        {
            "context": "Evidence for ADAR-induced hypermutation of the Drosophila sigma virus (Rhabdoviridae). BACKGROUND: ADARs are RNA editing enzymes that target double stranded RNA and convert adenosine to inosine, which is read by translation machinery as if it were guanosine. Aside from their role in generating protein diversity in the central nervous system, ADARs have been implicated in the hypermutation of some RNA viruses, although why this hypermutation occurs is not well understood. RESULTS: Here we describe the hypermutation of adenosines to guanosines in the genome of the sigma virus--a negative sense RNA virus that infects Drosophila melanogaster. The clustering of these mutations and the context in which they occur indicates that they have been caused by ADARs. However, ADAR-editing of viral RNA is either rare or edited viral RNA are rapidly degraded, as we only detected evidence for editing in two of the 104 viral isolates we studied. CONCLUSION: This is the first evidence for ADARs targeting viruses outside of mammals, and it raises the possibility that ADARs could play a role in the antiviral defences of insects.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 344,
                "text": "ADAR"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 324,
                "text": "beta-Trcp"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 827,
                "text": "53BP1"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1341,
                "text": "telomerase"
            }
        },
        {
            "context": "Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Multiple endocrine neoplasia type 2 (MEN2) is an inherited, autosomal-dominant disorder caused by deleterious mutations within the RET protooncogene. MEN2 RET mutations are mainly heterozygous, missense sequence changes found in RET exons 10, 11, and 13-16. Our group has developed the publicly available, searchable MEN2 RET database to aid in genotype/phenotype correlations, using Human Genome Variation Society recommendations for sequence variation nomenclature and database content. The MEN2 RET database catalogs all RET sequence variation relevant to the MEN2 syndromes, with associated clinical information. Each database entry lists a RET sequence variation's location within the RET gene, genotype, pathogenicity classification, MEN2 phenotype, first literature reference, and comments (which may contain information on other clinical features, complex genotypes, and additional literature references). The MEN2 phenotype definitions were derived from the International RET Mutation Consortium guidelines for classification of MEN2 disease phenotypes. Although nearly all of the 132 RET sequence variation entries initially cataloged in the database were from literature reports, novel sequence variation and updated phenotypic information for any existing database entry can be submitted electronically on the database website. The database website also contains links to selected MEN2 literature reviews, gene and protein information, and RET reference sequences. The MEN2 RET database (www.arup.utah.edu/database/MEN2/MEN2_welcome.php) will serve as a repository for MEN2-associated RET sequence variation and reference for RET genotype/MEN2 phenotype correlations.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 323,
                "text": "RET"
            }
        },
        {
            "context": "Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. BACKGROUND: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING: Novartis.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 5,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "The pharmacoepidemiology of antipsychotics for adults with schizophrenia in Canada, 2005 to 2009. OBJECTIVE: To describe the frequency and trends in the use of antipsychotics for adults with schizophrenia in Canada from 2005 to 2009. METHODS: Analyses were performed on IMS Brogan's Canadian Disease and Therapeutic Index (CDTI). The CDTI is a national physician panel study consisting of a representative sample of physicians both geographically and by specialty. Weighting adjustments are made to estimate national drug recommendations. Quarterly, panel physicians record all therapeutic recommendations during a 2-day period, including patient age, sex, and indication. Antipsychotic recommendations were estimated using CDTI data in which schizophrenia was listed as the indication. RESULTS: First-generation antipsychotic (FGA) recommendations for adults with schizophrenia increased by 38% between 2005 and 2009, from 329 380 to 454 960 recommendations. There were notable increases in recommendations for chlorpromazine, loxapine, zuclopenthixol, and flupentixol. Second-generation antipsychotic (SGA) recommendations increased to a much lesser extent (9%), which was mostly attributable to an increase in recommendations for clozapine. Drug recommendations for olanzapine decreased by 9%. CONCLUSION: The rate of increase of FGA use is now greater than that of SGAs. This may be due to data from recent comparative trials, which suggest that clinical efficacy, and the rate of neurological side effects is similar between FGAs and SGAs. The decreasing use of olanzapine may be due to metabolic adverse effects. The increased use of clozapine may be due to data on its superiority in patients who are treatment resistant.",
            "question": "What disease in Loxapine prominently used for?",
            "answers": {
                "answer_start": 743,
                "text": "schizophrenia"
            }
        },
        {
            "context": "Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1899,
                "text": "dabigatran"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 224,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 163,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BACKGROUND: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. METHODS: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. RESULTS: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (-9% and -11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. CONCLUSIONS: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01583543.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 379,
                "text": "PARP"
            }
        },
        {
            "context": "Genetic analysis of melanocortin 1 receptor red hair color variants in a Russian population of Eastern Siberia. The melanocortin 1 receptor is a Gs protein-coupled receptor implicated in melanogenesis regulation. The receptor gene is highly polymorphic, which accounts for the association of several of its single-nucleotide polymorphisms (SNPs) with an increased risk of melanoma. The present study aimed to evaluate the distribution of melanocortin 1 receptor gene variants R151C, R160W, and D294H within the Russian population of Eastern Siberia and its association with melanoma development. Melanoma patients (n=95) admitted to Krasnoyarsk Territorial Oncological Center and healthy controls (n=334) were enrolled in the study. A clinical examination of patients was performed to evaluate the phenotypic features of melanoma patients. SNPs were analyzed by real-time PCR. Clinical examination indicated a more frequent occurrence of fair skin type, blue eyes, blonde and red hair, and more frequent localization of freckles on the neck, trunk, and extremities in the melanoma group of patients. The R151C melanocortin 1 receptor gene variant was found in 18% of melanoma patients and associated with an increased likelihood of melanoma development (odds ratio=6.4; 95% confidence interval: 2.8-14.3; P=0.0001). The two remaining variant alleles of the melanocortin 1 receptor gene occurred with low frequency both in controls and in the melanoma group. The R160W SNP was identified neither in controls nor in melanoma patients. The D294H heterozygous variant was observed in 0.3% of individuals in the control group and in 1.1% of the patients in the melanoma group. Such an asymmetric distribution of the melanocortin 1 receptor within red hair color genotypes in the population under study compared with other populations may be because of Russian genetic homogeneity. Carriers of the mutant R151C allele should exercise caution in terms of exposure to the sun to avoid the risk of melanoma development.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 20,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Catalytic properties and kinetic mechanism of human recombinant Lys-9 histone H3 methyltransferase SUV39H1: participation of the chromodomain in enzymatic catalysis. Histone H3 lysine 9 (H3K9) methylation is a major component of gene regulation and chromatin organization. SUV39H1 methylates H3K9 at the pericentric heterochromatin region and participates in the maintenance of genome stability. In this study, a recombinant purified SUV39H1 is used for substrate specificity and steady-state kinetic analysis with peptides representing the un- or dimethylated lysine 9 histone H3 tail or full-length human recombinant H3 (rH3). Recombinant SUV39H1 methylated its substrate via a nonprocessive mechanism. Binding of either peptide or AdoMet first to the enzyme made a catalytically competent binary complex. Product inhibition studies with SUV39H1 showed that S-adenosyl-l-homocysteine is a competitive inhibitor of S-adenosyl-l-methionine and a mixed inhibitor of substrate peptide. Similarly, the methylated peptide was a competitive inhibitor of the unmethylated peptide and a mixed inhibitor of AdoMet, suggesting a random mechanism in a bi-bi reaction for recombinant SUV39H1 in which either substrate can bind to the enzyme first and either product can release first. The turnover numbers (k(cat)) for the H3 tail peptide and rH3 were comparable (12 and 8 h(-)(1), respectively) compared to the value of 1.5 h(-)(1) for an identical dimethylated lysine 9 H3 tail peptide. The Michaelis constant for the methylated peptide (K(m)(pep)) was 13-fold lower compared to that of the unmethylated peptide. The Michaelis constants for AdoMet (K(m)(AdoMet)) were 12 and 6 microM for the unmethylated peptide substrate and rH3, respectively. A reduction in the level of methylation was observed at high concentrations of rH3, implying substrate inhibition. Deletion of the chromodomain or point mutation of the conserved amino acids, W64A or W67A, of SUV39H1 impaired enzyme activity despite the presence of an intact catalytic SET domain. Thus, SUV39H1 utilizes both the chromodomain and the SET domain for catalysis.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 2023,
                "text": "SET domain"
            }
        },
        {
            "context": "Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single-center study. Our objective was to evaluate the efficacy of influenza and meningococcal vaccinations in healthy subjects exposed to the anti-interleukin-17A (IL-17A) monoclonal antibody (MAb) secukinumab. We used an open-label, parallel-group, randomized single-center study of 50 healthy subjects. Subjects received a single 150-mg dose of secukinumab or no treatment, followed by vaccination with inactivated trivalent subunit influenza virus and conjugate group C meningococcal vaccine (Agrippal and Menjugate, respectively) 2 weeks later. Primary efficacy variables were responses of > 4-fold increases in antibody titer (hemagglutination inhibition [HI; for influenza virus] and serum bactericidal assay [SBA; for Neisseria meningitides]) for meningococcus and influenza (at least two out of three serotypes), both at 4 weeks postvaccination. All subjects randomized to secukinumab (n = 25) or the control (n = 25) completed the study. Antibody responses to vaccinations measured at 4 weeks were comparable in both groups, with > 4-fold increased responses following influenza virus vaccination of 20/25 (80%) for both groups and following meningococcal vaccination of 19/25 (76%) for the secukinumab group and 18/25 (72%) for the control group. Differences between groups were 0% (90% confidence intervals [CI], 19 and 19%) and 4% (90% CI, 16 and 24%) for influenza virus and meningococcal vaccines, respectively. Antibody responses were comparable between the 2 groups at different time points. Headache was the most frequently reported adverse effect. No deaths or serious adverse events were reported. Blockade of IL-17A by secukinumab does not appear to interfere with efficacy of influenza and meningococcal vaccinations, as assessed by the achievement of protective antibody levels. A protective ( > 4-fold) immune response to both vaccinations at 4 weeks was achieved in 80 and 76% of subjects exposed to secukinumab and the control, respectively.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 368,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 84,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Influence of lateral association on forced unfolding of antiparallel spectrin heterodimers. Protein extensibility appears to be based broadly on conformational changes that can in principle be modulated by protein-protein interactions. Spectrin family proteins, with their extensible three-helix folds, enable evaluation of dimerization effects at the single molecule level by atomic force microscopy. Although some spectrin family members function physiologically only as homodimers (e.g. alpha-actinin) or are strictly monomers (e.g. dystrophin), alpha- and beta-spectrins are stable as monomeric forms but occur physiologically as alpha,beta-heterodimers bound laterally lengthwise. For short constructs of alpha- and beta-spectrin, either as monomers or as alpha,beta-dimers, sawtooth patterns in atomic force microscopy-forced extension show that unfolding stochastically extends repeats approximately 4-5-fold greater in length than native conformations. For both dimers and monomers, distributions of unfolding lengths appear bimodal; major unfolding peaks reflect single repeats, and minor unfolding peaks at twice the length reflect tandem repeats. Cooperative unfolding thus propagates through helical linkers between serial repeats (1, 2). With lateral heterodimers, however, the force distribution is broad and shifted to higher forces. The associated chains in a dimer can stay together and unfold simultaneously in addition to unfolding independently. Weak lateral interactions do not inhibit unfolding, but strong lateral interactions facilitate simultaneous unfolding analogous to serial repeat coupling within spectrin family proteins.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 56,
                "text": "antiparallel"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8 times"
            }
        },
        {
            "context": "[Atrial fibrillation in athletes]. Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting up to 1-1.5% of the population. Regular physical activity reduces the risk of cardiovascular diseases, however several studies have shown paradoxically increased incidence of AF in people practicing sport, especially in elite athletes. The results of studies suggest a U-shape relationship between sport and risk of arrhythmia. Minor regular exertion protects from arrhythmia through reduction in AF risk factors, while intense physical activity increases the risk of arrhythmia. The etiopathogenesis of arrhythmia in athletes has not been fully elucidated yet, but it is definitely multifactorial. Arrhythmia's occurrence may be related to adaptative remodeling of a heart, autonomic nervous system alteration as well as may be associated with other factors like inflammation or dyselectrolitaemia. Atrial Fibrillation in athletes should always be considered as an abnormality which requires further investigation as in small percentage of cases arrhythmia may be the first manifestation of a structural heart disease or chanellopathy potentially leading to sudden cardiac death. Taking into account several problems related to pharmacotherapy, AF ablation has become the first line treatment in athletes.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 98,
                "text": "af"
            }
        },
        {
            "context": "Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. BACKGROUND: The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS: We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS: Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 19,
                "text": "ibrutinib"
            }
        },
        {
            "context": "A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia. Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 259,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "[Atrial fibrillation in athletes]. Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting up to 1-1.5% of the population. Regular physical activity reduces the risk of cardiovascular diseases, however several studies have shown paradoxically increased incidence of AF in people practicing sport, especially in elite athletes. The results of studies suggest a U-shape relationship between sport and risk of arrhythmia. Minor regular exertion protects from arrhythmia through reduction in AF risk factors, while intense physical activity increases the risk of arrhythmia. The etiopathogenesis of arrhythmia in athletes has not been fully elucidated yet, but it is definitely multifactorial. Arrhythmia's occurrence may be related to adaptative remodeling of a heart, autonomic nervous system alteration as well as may be associated with other factors like inflammation or dyselectrolitaemia. Atrial Fibrillation in athletes should always be considered as an abnormality which requires further investigation as in small percentage of cases arrhythmia may be the first manifestation of a structural heart disease or chanellopathy potentially leading to sudden cardiac death. Taking into account several problems related to pharmacotherapy, AF ablation has become the first line treatment in athletes.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 56,
                "text": "AF"
            }
        },
        {
            "context": "Familial isolated pituitary adenomas: an emerging clinical entity. Familial pituitary tumors are increasingly recognized. While some of these cases are related to wellknown syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex soma- totroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 435,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients. Bortezomib, a proteasome inhibitor, has been used for patients with refractory and relapsed multiple myeloma, lymphoma and leukemia. We used bortezomib in ten refractory or relapsed patients (seven of multiple myeloma, two of lymphoma and one of acute myeloblastic leukemia). Six out of ten (60%) patients developed varicella herpes zoster after the complete of one cycle of bortezomib. The incidence of varicella herpes zoster was higher than reported in the literature. It may be due to immunosuppression caused by the combination of high-dose dexamethasone or other drugs. We considered that prophylactic antiviral medication could be used in predisposed patients to reduce the incidence of varicella herpes zoster.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 181,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "The arrhythmogenic substrate of the long QT syndrome: genetic basis, pathology, and pathophysiologic mechanisms. The Long QT syndrome (LQTS) is a relatively rare disorder. It has a major clinical impact as affected individuals are prone to syncope and sudden arrhythmogenic cardiac death. The LQTS comprises three groups of patients. The Jervell-Lange-Nielsen syndrome is characterized by an autosomal recessive pattern of inheritance and congenital neural deafness. The Romano-Ward syndrome shows an autosomal dominant pattern of inheritance and normal hearing. Patients with the sporadic form of LQTS have no evidence of familial transmission and have normal hearing. Imbalance of sympathetic cardiac innervation with predominance of the left stellate ganglion and an intrinsic myocardial defect leading to early afterdepolarization are the two pathogenetic mechanisms of LQTS discussed today. More recently a genetic basis for the Romano-Ward LQTS has been reported. The genetic linkage to the Harvey ras-1 gene provides the basis for a new hypothesis that an impairment of guanine nucleotide binding proteins is responsible for symptoms observed in LQTS. This paper discusses the genetic basis, pathology and pathophysiology of LQTS and tries to unify the different theories.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 501,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1001,
                "text": "53BP1"
            }
        },
        {
            "context": "The expression of UCP3 directly correlates to UCP1 abundance in brown adipose tissue. UCP1 and UCP3 are members of the uncoupling protein (UCP) subfamily and are localized in the inner mitochondrial membrane. Whereas UCP1's central role in non-shivering thermogenesis is acknowledged, the function and even tissue expression pattern of UCP3 are still under dispute. Because UCP3 properties regarding transport of protons are qualitatively identical to those of UCP1, its expression in brown adipose tissue (BAT) alongside UCP1 requires justification. In this work, we tested whether any correlation exists between the expression of UCP1 and UCP3 in BAT by quantification of protein amounts in mouse tissues at physiological conditions, in cold-acclimated and UCP1 knockout mice. Quantification using recombinant UCP3 revealed that the UCP3 amount in BAT (0.51ng/(μg total tissue protein)) was nearly one order of magnitude higher than that in muscles and heart. Cold-acclimated mice showed an approximate three-fold increase in UCP3 abundance in BAT in comparison to mice in thermoneutral conditions. Surprisingly, we found a significant decrease of UCP3 in BAT of UCP1 knockout mice, whereas the protein amount in skeletal and heart muscles remained constant. UCP3 abundance decreased even more in cold-acclimated UCP1 knockout mice. Protein quantification in UCP3 knockout mice revealed no compensatory increase in UCP1 or UCP2 expression. Our results do not support the participation of UCP3 in thermogenesis in the absence of UCP1 in BAT, but clearly demonstrate the correlation in abundance between both proteins. The latter is important for understanding UCP3's function in BAT.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 217,
                "text": "UCP1"
            }
        },
        {
            "context": "A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family. Giant axonal neuropathy is a severe autosomal recessive neurodegenerative disorder of childhood that affects both the peripheral and central nervous systems. It is caused by mutations in the GAN gene linked to chromosome 16q24.1 At least 45 distinct disease-causing mutations have been identified throughout the gene in families of various ethnic origins, with different symptomatologies and different clinical courses. To date, no characteristic mutation or phenotype-genotype correlation has been established. We describe a novel missense mutation in four siblings born to consanguineous parents of Arab original with clinical and molecular features compatible with giant axonal neuropathy. The phenotype was characterized by a predominant motor and sensory peripheral neuropathies and severe skeletal deformities.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 24,
                "text": "GAN gene"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 23,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Delamanid for multidrug-resistant pulmonary tuberculosis. BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 149,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 462,
                "text": "Stroke"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 0,
                "text": "libFLASM"
            }
        },
        {
            "context": "Lewy bodies in progressive supranuclear palsy represent an independent disease process. Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies (LBs) are detected in approximately 10% of PSP cases, but there is little information on the relationship of LBs to tau pathology. We determined the frequency of LBs in a large series of autopsy-confirmed cases of PSP and studied the density and distribution of LBs, including Parkinson disease stage, in cases with LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including assessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for alpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple system atrophy in addition to PSP and was excluded from further study along with 2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were compared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, Braak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile plaques were not different among PSP, LBD, and PSP/LBD, but disease duration was longer in LBD. The Parkinson disease stage was similar, but the density of LBs in most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In contrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP and LBD. Double immunostaining demonstrated alpha-synuclein and tau in different neurons with few exceptions. The findings suggest that LBs in PSP are similar in distribution to those in LBD and independent of tau pathology. The greater density of LBs in LBD compared with PSP/LBD may be the result of longer disease duration in LBD, whereas greater neuronal loss in the substantia nigra in PSP/LBD may be the result of vulnerability of this brain region to both disease processes.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 707,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 134,
                "text": "tyr"
            }
        },
        {
            "context": "The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 88,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Teaching Dialectical Behavior Therapy to Psychiatry Residents: The Columbia Psychiatry Residency DBT Curriculum. OBJECTIVE: Dialectical behavior therapy (DBT) is an evidence-based psychosocial treatment with efficacy in reducing self-harm behaviors in borderline personality disorder (BPD). This study describes and evaluates a clinical curriculum to teach DBT to psychiatry residents, developed at a large urban university hospital. The curriculum objectives are to (1) have psychiatry residents achieve basic understanding of DBT theory and clinical skill, (2) increase residents' ability and confidence in treating self-harm behaviors (both suicidal behavior and non-suicidal self-injury), and (3) enhance residents' willingness to treat individuals with BPD. METHODS: In addition to a 6-week didactic course on DBT offered to all residents (n = 62), 25 elected to enroll in a year-long DBT clinical training curriculum over the course of a 5-year period. The DBT clinical training consisted of 15 h of additional didactics, ongoing conduct of individual therapy and group DBT skills training, videotaping of individual therapy sessions, and weekly supervision meetings utilizing videotape to provide feedback. Residents participating in the clinical training program videotaped baseline and later sessions, which were rated for DBT adherence. All 62 graduates of the program were surveyed regarding the impact of the training on their practice of psychiatry. RESULTS: Upon graduation, a high percentage (87 % in the curriculum and 70 % in the didactic course only) reported incorporating DBT into their psychiatry practice, as well as willingness and confidence in treating BPD and self-harm behaviors. Residents participating in the clinical training demonstrated significant improvement in their ability to utilize DBT interventions, particularly in structuring sessions, problem assessment, problem solving, and using validation and dialectical strategies. CONCLUSION: This DBT curriculum was effective in preparing psychiatrists-in-training to incorporate evidence-based practices for effective treatment of BPD and self-harm behaviors and can serve as a model for teaching DBT during psychiatry residency training. Limitations include a small sample size and lack of baseline survey measurement of attitudes for pre- and post-curriculum comparison.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 252,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice. Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the alpha-synuclein (alphaSYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of alphaSYN protein fibrils. Moreover, alphaSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]alphaSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)-[A30P]alphaSYN transgenic mice further developed age-dependent, specific neuritic/terminal alphaSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-[A30P]alphaSYN mice. Thus, alphaSYN becomes phosphorylated in distinct parts of the brain in this alpha-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 223,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "The second generation of BCR-ABL tyrosine kinase inhibitors. Imatinib was developed as the first molecularly targeted therapy to specifically inhibit the BCR-ABL kinase in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Because of the excellent hematologic and cytogenetic responses, imatinib has moved toward first-line treatment for newly diagnosed CML. However, the emergence of resistance to imatinib remains a major problem in the treatment of Ph-positive leukemia. Several mechanisms of imatinib resistance have been identified, including BCR-ABL gene amplification that leads to overexpression of the BCR-ABL protein, point mutations in the BCR-ABL kinase domain that interfere with imatinib binding, and point mutations outside of the kinase domain that allosterically inhibit imatinib binding to BCR-ABL. The need for alternative or additional treatment for imatinib-resistant BCR-ABL-positive leukemia has guided the way to the design of a second generation of targeted therapies, which has resulted mainly in the development of novel small-molecule inhibitors such as AMN107, dasatinib, NS-187, and ON012380. The major goal of these efforts is to create new compounds that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. In this review, we discuss the next generation of BCR-ABL kinase inhibitors for overcoming imatinib resistance.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 154,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Positron emission tomographic findings in Filipino X-linked dystonia-parkinsonism. Regional and global metabolic rates for glucose (rCMRGlc and GMR) were estimated using [18F]fluorodeoxyglucose and positron emission tomography in 3 patients with Filipino X-linked dystonia-parkinsonism (lubag). In all 3 patients a selective reduction in normalized striatal glucose metabolism (rCMRGlc/GMR) was observed compared with 15 normal volunteer subjects. Presynaptic nigrostriatal function was assessed in these patients using [18F]fluorodopa and positron emission tomography. Striatal rate constants for [18F]flurodopa uptake were found to be in the normal range in all 3 patients with lubag. These findings suggest that the extrapyramidal manifestations of lubag are metabolically localized to the striatum and that clinical parkinsonism in these patients may be secondary to extranigral factors.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 255,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Stabilities of folding of clustered, two-repeat fragments of spectrin reveal a potential hinge in the human erythroid spectrin tetramer. The large size of spectrin, the flexible protein promoting reversible deformation of red cells, has been an obstacle to elucidating the molecular mechanism of its function. By studying cloned fragments of the repeating unit domain, we have found a correspondence between positions of selected spectrin repeats in a tetramer with their stabilities of folding. Six fragments consisting of two spectrin repeats were selected for study primarily on the basis of the predicted secondary structures of their linker regions. Fragments with a putatively helical linker were more stable to urea- and heat-induced unfolding than those with a putatively nonhelical linker. Two of the less stably folded fragments, human erythroid alpha-spectrin repeats 13 and 14 (HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), are located opposite each other on antiparallel spectrin dimers. At least partial unfolding of these repeats under physiological conditions indicates that they may serve as a hinge. Also less stably folded, the fragment of human erythroid alpha-spectrin repeats 4 and 5 (HEalpha4,5) lies opposite the site of interaction between the partial repeats at the C- and N-terminal ends of beta- and alpha-spectrin, respectively, on the opposing dimer. More stably folded fragments, human erythroid alpha-spectrin repeats 1 and 2 (HEalpha1,2) and human erythroid alpha-spectrin repeats 2 and 3 (HEalpha2,3), lie nearly opposite each other on antiparallel spectrin dimers of a tetramer. These clusterings along the spectrin tetramer of repeats with similar stabilities of folding may have relevance for spectrin function, particularly for its well known flexibility.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 1002,
                "text": "antiparallel"
            }
        },
        {
            "context": "Human RNA polymerase II-association factor 1 (hPaf1/PD2) regulates histone methylation and chromatin remodeling in pancreatic cancer. Change in gene expression associated with pancreatic cancer could be attributed to the variation in histone posttranslational modifications leading to subsequent remodeling of the chromatin template during transcription. However, the interconnected network of molecules involved in regulating such processes remains elusive. hPaf1/PD2, a subunit of the human PAF-complex, involved in the regulation of transcriptional elongation has oncogenic potential. Our study explores the possibility that regulation of histone methylation by hPaf1 can contribute towards alteration in gene expression by nucleosomal rearrangement. Here, we show that knockdown of hPaf1/PD2 leads to decreased di- and tri-methylation at histone H3 lysine 4 residues in pancreatic cancer cells. Interestingly, hPaf1/PD2 colocalizes with MLL1 (Mixed Lineage Leukemia 1), a histone methyltransferase that methylates H3K4 residues. Also, a reduction in hPaf1 level resulted in reduced MLL1 expression and a corresponding decrease in the level of CHD1 (Chromohelicase DNA-binding protein 1), an ATPase dependent chromatin remodeling enzyme that specifically binds to H3K4 di and trimethyl marks. hPaf1/PD2 was also found to interact and colocalize with CHD1 in both cytoplasmic and nuclear extracts of pancreatic cancer cells. Further, reduced level of CHD1 localization in the nucleus in hPaf1/PD2 Knockdown cells could be rescued by ectopic expression of hPaf1/PD2. Micrococcal nuclease digestion showed an altered chromatin structure in hPaf1/PD2-KD cells. Overall, our results suggest that hPaf1/PD2 in association with MLL1 regulates methylation of H3K4 residues, as well as interacts and regulates nuclear shuttling of chromatin remodeling protein CHD1, facilitating its function in pancreatic cancer cells.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 1018,
                "text": "H3K4"
            }
        },
        {
            "context": "A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia. Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 390,
                "text": "DBA"
            }
        },
        {
            "context": "Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 408,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Methylation of cytosine in DNA plays a crucial role in development through inheritable gene silencing. The DNA methyltransferase Dnmt1 is responsible for the propagation of methylation patterns to the next generation via its preferential methylation of hemimethylated CpG sites in the genome; however, how Dnmt1 maintains methylation patterns is not fully understood. Here we report the crystal structure of the large fragment (291-1620) of mouse Dnmt1 and its complexes with cofactor S-adenosyl-L-methionine and its product S-adenosyl-L-homocystein. Notably, in the absence of DNA, the N-terminal domain responsible for targeting Dnmt1 to replication foci is inserted into the DNA-binding pocket, indicating that this domain must be removed for methylation to occur. Upon binding of S-adenosyl-L-methionine, the catalytic cysteine residue undergoes a conformation transition to a catalytically competent position. For the recognition of hemimethylated DNA, Dnmt1 is expected to utilize a target recognition domain that overhangs the putative DNA-binding pocket. Taking into considerations the recent report of a shorter fragment structure of Dnmt1 that the CXXC motif positions itself in the catalytic pocket and prevents aberrant de novo methylation, we propose that maintenance methylation is a multistep process accompanied by structural changes.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 396,
                "text": "Dnmt1"
            }
        },
        {
            "context": "[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1986,
                "text": "CD38"
            }
        },
        {
            "context": "Current and emerging management options for hereditary angioedema in the US. Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of swelling that may involve multiple anatomical locations. In the majority of patients, it is caused by a functional or quantitative defect in the C1 inhibitor (C1-INH), which is an important regulator of the complement, fibrinolytic, kallikrein-kinin and coagulation systems. Standard treatments used for other types of angioedema are ineffective for HAE. Traditional therapies for HAE, including fresh frozen plasma, epsilon-aminocaproic acid and danazol, may be well tolerated and effective in some patients; however, there are limitations both in their safety and efficacy. Several novel therapies have completed phase III trials in the US, including: (i) plasma-derived C1-INH replacement therapies (Berinert P and Cinryze); (ii) a recombinant C1-INH replacement therapy (conestat alfa; Rhucin); (iii) a kallikrein inhibitor (ecallantide [DX-88]); and (iv) a bradykinin-2-receptor antagonist (icatibant). Both Berinert P and Cinryze are reported to have excellent efficacy and safety data from phase III trials. Currently, only Cinryze has been approved for prophylactic use in the US. US FDA approval for other novel agents to treat HAE and for the use of Cinryze in the treatment of acute attacks is pending.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 991,
                "text": "ecallantide"
            }
        },
        {
            "context": "[Current Therapeutic Approaches to Sarcoidosis]. Sarcoidosis represents a non-caseating, granulomatous disorder of unknown aetiology whose clinical manifestation is heterogeneous and frequently multisystemic. The portion of patients needing systemic treatment varies: though many patients may undergo spontaneous remission, organ-threatening courses demand systemic therapy. Corticosteroids are the first-line treatment option; however, disease´s progression and/or major corticosteroid side effects may require second- and third-line therapeutics. A current stepwise therapeutic algorithm to sarcoidosis that characterizes additive and alternative therapeutic agents is given in the following review.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 375,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "Autoimmune dacryoadenitis of NOD/LtJ mice and its subsequent effects on tear protein composition. Sjögren's syndrome (SjS) is a human autoimmune disease characterized by exocrine dysfunction resulting from chronic autoimmune attack primarily against the lacrimal and/or salivary glands. Although, we previously established a good correlation between SjS in humans and autoimmune exocrinopathy in NOD/LtJ mice an in-depth evaluation of lacrimal gland disease in the NOD/LtJ mouse has remained limited. This leaves a major gap in our understanding of the dacryoadenitis/keratoconjunctivitis sicca in this model. Here we characterize the development of the autoimmune dacryoadenitis in NOD/LtJ and NOD.B10-H2(b) mice in comparison with age- and sex-matched nonautoimmune CD1 mice. We observed a decline in tear production beginning at 8 weeks of age in both NOD/LtJ and NOD.B10-H2(b) mice, continuing throughout the 40 to 46 weeks studied. This correlated with a quantifiable increase in mixed T- and B-lymphocyte infiltrations in the extraorbital lacrimal glands. In addition, temporal differences in tear protein expression between NOD/LtJ and CD1 mice were identified using two-dimensional gel electrophoresis and tandem mass spectrometry. Thus, using this model we can identify potentially important pathophysiological mechanisms of the autoimmune attack and possible diagnostic markers for development of SjS-associated dacryoadenitis.",
            "question": "Which glands are subject to attack by lymphocytes in Sjogren's syndrome?",
            "answers": {
                "answer_start": 250,
                "text": "the lacrimal and/or salivary glands"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 529,
                "text": "INCA"
            }
        },
        {
            "context": "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this \"miracle herb\" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 547,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "New anticoagulants for atrial fibrillation. Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 630,
                "text": "xa"
            }
        },
        {
            "context": "Delayed myelination is not a constant feature of Allan-Herndon-Dudley syndrome: report of a new case and review of the literature. INTRODUCTION: Allan-Herndon-Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. CASE REPORT: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14months, were normal. DISCUSSION: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan-Herndon-Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 407,
                "text": "thyroid"
            }
        },
        {
            "context": "Spontaneously arising red cells with a McLeod-like phenotype in normal donors. Very few human genes can be used to identify spontaneous inactivating somatic mutations. We hypothesized that because the XK gene is X-linked, it would be easy to identify spontaneously arising red cells with a phenotype resembling the McLeod syndrome, which results from inherited XK mutations. Here, by flow cytometry, we detect such phenotypic variants at a median frequency of 9 x 10(-6) in neonatal cord blood samples and 39 x 10(-6) in healthy adults (p=0.004). It may be possible to further investigate the relationship between aging, mutations, and cancer using this approach.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 361,
                "text": "XK"
            }
        },
        {
            "context": "Advances in understanding chromosome silencing by the long non-coding RNA Xist. In female mammals, one of the two X chromosomes becomes genetically silenced to compensate for dosage imbalance of X-linked genes between XX females and XY males. X chromosome inactivation (X-inactivation) is a classical model for epigenetic gene regulation in mammals and has been studied for half a century. In the last two decades, efforts have been focused on the X inactive-specific transcript (Xist) locus, discovered to be the master regulator of X-inactivation. The Xist gene produces a non-coding RNA that functions as the primary switch for X-inactivation, coating the X chromosome from which it is transcribed in cis. Significant progress has been made towards understanding how Xist is regulated at the onset of X-inactivation, but our understanding of the molecular basis of silencing mediated by Xist RNA has progressed more slowly. A picture has, however, begun to emerge, and new tools and resources hold out the promise of further advances to come. Here, we provide an overview of the current state of our knowledge, what is known about Xist RNA and how it may trigger chromosome silencing.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 480,
                "text": "Xist"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 951,
                "text": "xa"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 653,
                "text": "FSHD"
            }
        },
        {
            "context": "iLIR database: A web resource for LIR motif-containing proteins in eukaryotes. Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.",
            "question": "Which web resource for LIR motif-containing proteins in eukaryotes has been developed?",
            "answers": {
                "answer_start": 1491,
                "text": "the iLIR database"
            }
        },
        {
            "context": "The origin of mitochondria in light of a fluid prokaryotic chromosome model. Biologists agree that the ancestor of mitochondria was an alpha-proteobacterium. But there is no consensus as to what constitutes an alpha-proteobacterial gene. Is it a gene found in all or several alpha-proteobacteria, or in only one? Here, we examine the proportion of alpha-proteobacterial genes in alpha-proteobacterial genomes by means of sequence comparisons. We find that each alpha-proteobacterium harbours a particular collection of genes and that, depending upon the lineage examined, between 97 and 33% are alpha-proteobacterial by the nearest-neighbour criterion. Our findings bear upon attempts to reconstruct the mitochondrial ancestor and upon inferences concerning the collection of genes that the mitochondrial ancestor possessed at the time that it became an endosymbiont.",
            "question": "Which species of bacteria did the mitochondria originate from?",
            "answers": {
                "answer_start": 77,
                "text": "Biologists agree that the ancestor of mitochondria was an alpha-proteobacterium."
            }
        },
        {
            "context": "Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex. BACKGROUND: Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear. METHODS: Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki-67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2. RESULTS: In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex. CONCLUSION: EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 1552,
                "text": "H3K4"
            }
        },
        {
            "context": "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 344,
                "text": "Transcription Factor EB (TFEB)"
            }
        },
        {
            "context": "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 613,
                "text": "orexin"
            }
        },
        {
            "context": "Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age > 18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 316,
                "text": "CD38"
            }
        },
        {
            "context": "Identification and characterization of a highly conserved crenarchaeal protein lysine methyltransferase with broad substrate specificity. Protein lysine methylation occurs extensively in the Crenarchaeota, a major kingdom in the Archaea. However, the enzymes responsible for this type of posttranslational modification have not been found. Here we report the identification and characterization of the first crenarchaeal protein lysine methyltransferase, designated aKMT, from the hyperthermophilic crenarchaeon Sulfolobus islandicus. The enzyme was capable of transferring methyl groups to selected lysine residues in a substrate protein using S-adenosyl-l-methionine (SAM) as the methyl donor. aKMT, a non-SET domain protein, is highly conserved among crenarchaea, and distantly related homologs also exist in Bacteria and Eukarya. aKMT was active over a wide range of temperatures, from ~25 to 90 °C, with an optimal temperature at ~60 to 70 °C. Amino acid residues Y9 and T12 at the N terminus appear to be the key residues in the putative active site of aKMT, as indicated by sequence conservation and site-directed mutagenesis. Although aKMT was identified based on its methylating activity on Cren7, the crenarchaeal chromatin protein, it exhibited broad substrate specificity and was capable of methylating a number of recombinant Sulfolobus proteins overproduced in Escherichia coli. The finding of aKMT will help elucidate mechanisms underlining extensive protein lysine methylation and the functional significance of posttranslational protein methylation in crenarchaea.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 670,
                "text": "SAM"
            }
        },
        {
            "context": "Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer. AIM: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies. METHODS: We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells. RESULTS: In a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis. CONCLUSION: Taken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 659,
                "text": "PARP"
            }
        },
        {
            "context": "Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 312,
                "text": "orally"
            }
        },
        {
            "context": "[Successful therapy of ulcerated necrobiosis lipoidica non diabeticorum with cyclosporine A]. Necrobiosis lipoidica is an inflammatory granulomatous skin disease of unknown etiology which is associated with diabetes mellitus in about 60% of the patients. In 15-35% of the affected patients painful ulcerations may occur after minimal trauma which can be extremely refractory to therapy. Because of the unknown pathomechanisms, current therapeutic options are limited. We report on a 68-year-old patient with an 18 year history of ulcerated necrobiosis lipoidica non diabeticorum of both lower limbs, which responded to systemic cyclosporine A. Based on this case, we discuss the role of cyclosporine A in patients with necrobiosis lipoidica in the context of the disease etiology.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 207,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Simpson grade: an opportunity to reassess the need for complete resection of meningiomas. BACKGROUND: The relevance of the Simpson grading system as a predictor of meningioma progression or recurrence in modern neurosurgical practice has recently been called into question. The aim of our study was to compare the risk of progression/recurrence of tumours that had been treated with different Simpson grade resections in a contemporary population of benign (WHO grade I) meningioma patients. METHOD: One hundred eighty-three patients with histologically confirmed WHO grade I meningioma were retrospectively analysed. All patients underwent first-time craniotomy as their initial therapy between 2004 and 2012. Univariate analysis was performed using log-rank testing and Kaplan-Meier analysis for progression/recurrence-free survival. Multivariate analysis was performed using Cox proportional hazards regression modelling. RESULTS: The three-year progression/recurrence-free survival rates for patients receiving Simpson grade 1, 2 or 4 resections were 95 %, 87 % and 67 %, respectively. Simpson grade 4 resections progressed/recurred at a significantly greater rate than Simpson grade 1 resections (hazard ratio [HR] = 3.26, P = 0.04), whereas Simpson grade 2 resections did not progress/recur at a significantly greater rate than Simpson grade 1 resections (HR = 1.78, P = 0.29). Subtotal resections progressed/recurred at a significantly greater rate than gross-total resections (HR = 2.47, P = 0.03). CONCLUSIONS: Tumours that undergo subtotal resection are at a significantly greater risk of progression/recurrence than tumours that undergo gross-total resection. Gross-total resection should therefore be the aim of surgery. However, given modern access to follow-up imaging and stereotactic radiosurgery, these results should not be used to justify overly 'heroic' tumour resection.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 77,
                "text": "meningioma"
            }
        },
        {
            "context": "[SENSITIVITY OF THE NEW SKIN TEST DIASKINTEST® FOR THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN CHILDREN AND ADOLESCENTS]. In Russia, an intradermal Diaskintest® drug has been designed, which is a recombinant tuberculosis allergen based on M. tuberculosis-- specific proteins: ESAT-6 and CFP-10 produced by a genetically modified Escherichia coli culture. Diaskintest® test and Mantoux test with 2TE PPD-L were concurrently carried out in 300 children and adolescents with tuberculosis and followed up in risk groups at a tuberculosis dispensary to determine the sensitivity of the new skin test in active tuberculosis infection. Diaskintest® showed a high sensitivity not only in active tuberculosis, but also in occult, the so-called latent, tuberculosis infection. This is suggested by the following evidence. The high percentage (83.8%) of positive responses to Diaskintest® is noted in children and adolescents with tuberculosis, receiving an intensive course of chemotherapy. Negative tests were observed only in minor forms at the resolution stage. In the children who had completed treatment, positive tests were seen in 78.3%, moreover in those with prior tuberculosis of intrathoracic lymph nodes; negative tests were observed not earlier than 18 months after start of treatment. The highest sensitivity of Diaskintest® was shown in children with early primary tuberculosis infection and through family contact with bacteria-excreting subjects (91.7%). These children may be judged with the highest assurance to have latent tuberculosis infection, the population of which is in an active state at the moment of the study. The children with early primary tuberculosis infection, but in no family contact with bacteria-excreting individuals, showed a lower percentage of positive responses to Diaskintest® both before (37.5%) and after (10%) treatment, which suggests that there must be a lower bacterial burden in the child. A high percentage of positive responses to Diaskintest® (76.2%) were found in subjects with hyperergic reactions to tuberculin. These were in only 16.7% in the group of patients receiving preventive therapy. In children and adolescents with a persistent positive Mantoux test (for more than 3 years), the response to Diaskintest® was negative in most cases since in early infection when mycobacteria propagated, the reaction to the drug was positive, but as 3 years pass the probability of the infection transition to the persistence stage is high--at that time the response to Diaskintest® becomes negative. Diaskintest® induces no delayed hypersensitivity associated with BCG vaccination, suggesting its high specificity. There were no positive reactions in patients with nonspecific lung diseases.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 520,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 225,
                "text": "CCs"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 3289,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 561,
                "text": "orally"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 4,
                "text": "xa"
            }
        },
        {
            "context": "A Novel Deletion Mutation of SLC16A2 Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome. Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 344,
                "text": "thyroid"
            }
        },
        {
            "context": "The physical and genetic map surrounding the Lyst gene on mouse chromosome 13. During the recent cloning of the mouse Lyst gene we developed both a high-resolution genetic map and a complete YAC and BAC contig of the Lyst critical region on mouse Chromosome 13. We also report the mapping of the human homologue of the mouse Lyst gene (LYST) to 1q43. These data are consistent with LYST being the gene for the human Chediak-Higashi Syndrome and strengthen the synteny relationship between MMU13 and human 1q43.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 416,
                "text": "Chediak-Higashi Syndrome"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2778,
                "text": "5-HT2A"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 821,
                "text": "xa"
            }
        },
        {
            "context": "Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1102,
                "text": "thyroid"
            }
        },
        {
            "context": "Valsalva leak point pressure-associated Q-tip angle and simple female stress urinary incontinence symptoms. PURPOSE: To clarify the association between clinically defined simple stress urinary incontinence (SUI) symptoms and urodynamic SUI, we examined the relationship between Valsalva leak point pressure (VLPP) as measured by the Q-tip test and Stamey grade in simple female SUI. METHODS: Two hundred grade I or II female SUI patients with SUI symptom were examined by reviewing medical history; physical examination; urethral mobility as assessed by Q-tip test; stress test; and cystometry, including VLPP measurement. On the basis of the VLPP, patients were classified into urethral hypermobility [UH, subdivided into anatomical incontinence (AI) and equivocal incontinence (EI)] or intrinsic sphincter deficiency groups for analysis of the relationship between VLPP and Stamey grade and Q-tip angle. RESULTS: Seventy-eight patients were included, and the mean patient age was 54 ± 7.5 years, mean SUI symptom duration 2.8 years (range 0.5-6 years), mean VLPP 103.6 ± 18.4 cm H2O, and mean Q-tip angle 28.6° ± 7.2°. Fifty-three patients were categorized as Stamey grade I, 25 as Stamey grade II, 51 as AI, and 27 as EI. VLPP was found to be negatively correlated with Q-tip angle (Rs = -0.798, Y = -0.313X + 60.95, P < 0.001), and classifications of VLPP and Stamey grade have positive correlation (χ (2) = 4.9130, P = 0.0267). CONCLUSIONS: In simple female SUI, VLPP is associated with the Q-tip angle and Stamey grade, which may help to reduce some of urodynamic items.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 178,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 217,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments. Tibolone, selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene, and estrogen (+/-progestogen) treatments prevent bone loss in postmenopausal women. They exert their effects on bone via the estrogen receptor (ER) and the increase in bone mass is due to resorption inhibition. The effect of SERMs on bone mineral density is less than that with the other treatments, but the SERM raloxifene still has a positive effect on vertebral fractures. In contrast to tibolone and estrogens (+/-progestogen), SERMs do not treat climacteric complaints, whilst estrogen plus progestogen treatments cause a high incidence of bleeding. Estrogen plus progestogen combinations have compromising effects on the breast. Tibolone and SERMs do not stimulate the breast or endometrium. Unlike SERMs, tibolone does not possess antagonistic biological effects via the ER in these tissues. Estrogenic stimulation in these tissues is prevented by local metabolism and inhibition of steroid metabolizing enzymes by tibolone and its metabolites. SERMs and estrogen (+/-progestogen) treatments increase the risk of venous thromboembolism (VTE), whilst estrogen (+/-progestogen) combinations have unwanted effects on cardiovascular events. So far, no detrimental effects of tibolone have been observed with respect to VTE or cardiovascular events. The clinical profile of tibolone therefore has advantages over those of other treatment modalities. It is also clear that tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective, tissue estrogenic activity regulators (STEARs).",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 153,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Use of dialectical behavior therapy in inpatient treatment of borderline personality disorder: a systematic review. OBJECTIVE: Dialectical behavior therapy (DBT) is an empirically supported treatment for outpatients with borderline personality disorder. However, the utility of DBT strategies for inpatients with the disorder is unclear. This review summarizes and synthesizes findings from trials of DBT in inpatient settings. METHODS: Multiple research databases were searched for articles published through June 2011 that reported on any implementation of DBT in an inpatient setting to address symptoms related to borderline personality disorder, including suicidal and self-injurious behavior. RESULTS: Eleven studies that reported pre- and posttreatment symptoms related to borderline personality disorder were evaluated. Studies indicated that many variations of standard DBT have been used in inpatient settings, including approaches that do not include phone consultation, that include group therapy only, and that vary in treatment duration (from two weeks to three months). Most studies reported reductions in suicidal ideation, self-injurious behaviors, and symptoms of depression and anxiety, whereas results for reducing anger and violent behaviors were mixed. Follow-up data indicated that symptom reduction was often maintained between one and 21 months posttreatment. On the basis of the evidence, the authors identify essential components of an inpatient DBT package and discuss its potential function as an \"intensive orientation\" to outpatient DBT services. CONCLUSIONS: There is considerable variation in the configuration and duration of DBT implementation for inpatients with borderline personality disorder. However, findings suggest that DBT may be effective in reducing symptoms related to borderline personality disorder in inpatient settings. Future research should standardize and systematically test inpatient DBT. (Psychiatric Services 63:881-888, 2012; doi: 10.1176/appi.ps.201100311).",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 221,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "A comparison of apixaban and dabigatran etexilate for thromboprophylaxis following hip and knee replacement surgery. INTRODUCTION: Patients who have undergone hip or knee replacement surgery are exposed to a high risk of developing a post-operative venous thromboembolus and so have a need for an effective, medication-based, thrombosis prophylaxis. New orally active anticoagulants have been available for a few years now. These specific substances directly block either thrombin (e.g., dabigatran etexilate) or Factor Xa (e.g., apixaban). It is not clear whether there are any efficacy differences between these two substances because there have never been any head-to-head studies carried out. MATERIALS AND METHODS: We have carried out a study comparing two new orally active anticoagulants dabigatran etexilate (Pradaxa) and apixaban (Eliquis) that were each given to two groups of 200 patients respectively, who had undergone elective hip or knee arthroplasty (100 each). Each patient was assessed for pre- and post-operative hemoglobin concentrations, post-operative blood loss, the number of transfused erythrocyte concentrates, the duration of wound secretion, clinical thromboembolic complications (deep vein thrombosis, pulmonary embolism, myocardial infarct), as well as gastrointestinal, intracranial or wound-related bleeding complications. RESULTS: Dabigatran etexilate treatment led to a significant increase in the duration of wound secretion in both arthroplasty groups when compared to apixaban: wound secretion lasted 1.2 days longer on average in the dabigatran etexilate group than in the apixaban group (4.1 ± 2.1 vs. 2.9 ± 1.8 days). There were no significant differences observed between the two anticoagulant groups when comparing pre- and post-operative Hb values, post-operative blood loss and the other clinical parameters. CONCLUSIONS: Thus, it appears that the direct thrombin inhibitor, dabigatran etexilate, is associated with a longer period of wound secretion following the implantation of hip and knee endoprostheses than that associated with the Factor Xa inhibitor, apixaban.",
            "question": "What is the drug target for Eliquis (Apixaban)?",
            "answers": {
                "answer_start": 513,
                "text": "Factor Xa"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 272,
                "text": "methylKit"
            }
        },
        {
            "context": "Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region. BACKGROUND: Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). FINDINGS: We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. CONCLUSIONS: Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 403,
                "text": "FOXP2"
            }
        },
        {
            "context": "Efficacy and limitations of transarterial acrylic glue embolization for intracranial dural arteriovenous fistulas. The efficacy and limitations of transarterial acrylic glue embolization for the treatment of intracranial dural arteriovenous fistulas (DAVFs) were investigated. Thirty-four DAVFs treated by transarterial embolization using n-butyl cyanoacrylate were retrospectively reviewed. The locations of DAVFs were the transverse-sigmoid sinus in 11, tentorium in 10, cranial vault in 9, and superior sagittal sinus, jugular bulb, foramen magnum, and middle cranial fossa in 1 each. Borden classification was type I in 7, type II in 3, and type III in 24. Eight patients had undergone prior transvenous coil embolization. Complete obliteration rate was 56% immediately after embolization, 71% at follow-up angiography, and 85% after additional treatments (1 transvenous embolization and 4 direct surgery). Complications occurred in three patients, consisting of asymptomatic vessel perforations during cannulation in two patients and leakage of contrast medium resulting in medullary infarction in one patient. Transarterial glue embolization is highly effective for Borden type III DAVF with direct cortical venous drainage, but has limitations for Borden type I and II DAVFs in which the affected sinus is part of the normal venous circulation. Onyx is a new liquid embolic material and is becoming the treatment of choice for DAVF. The benefits of glue embolization compared to Onyx embolization are high thrombogenicity, and relatively low risks of cranial nerve palsies and of excessive migration into the draining veins of high flow fistula. Transarterial glue embolization continues to be useful for selected patients, and complete cure can be expected in most patients with fewer complications if combined with transvenous embolization or direct surgery.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 1276,
                "text": "DAVF"
            }
        },
        {
            "context": "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 1138,
                "text": "FOXP2"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 214,
                "text": "chordomas"
            }
        },
        {
            "context": "Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes. Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 285,
                "text": "hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 466,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Histone acetylation controls the inactive X chromosome replication dynamics. In mammals, dosage compensation between male and female cells is achieved by inactivating one female X chromosome (Xi). Late replication of Xi was proposed to be involved in the maintenance of its silenced state. Here, we show a highly synchronous replication of the Xi within 1 to 2 h during early-mid S-phase by following DNA replication in living mammalian cells with green fluorescent protein-tagged replication proteins. The Xi was replicated before or concomitant with perinuclear or perinucleolar facultative heterochromatin and before constitutive heterochromatin. Ectopic expression of the X-inactive-specific transcript (Xist) gene from an autosome imposed the same synchronous replication pattern. We used mutations and chemical inhibition affecting different epigenetic marks as well as inducible Xist expression and we demonstrate that histone hypoacetylation has a key role in controlling Xi replication. The epigenetically controlled, highly coordinated replication of the Xi is reminiscent of embryonic genome replication in flies and frogs before genome activation and might be a common feature of transcriptionally silent chromatin.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 708,
                "text": "Xist"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 900,
                "text": "coilin"
            }
        },
        {
            "context": "Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 203,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Characterization and functional expression of cDNAs encoding methionine-sensitive and -insensitive homocysteine S-methyltransferases from Arabidopsis. Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy). These reactions comprise the SMM cycle. Two Arabidopsis cDNAs specifying enzymes that mediate the SMM --> Met reaction (SMM:Hcy S-methyltransferase, HMT) were identified by homology and authenticated by complementing an Escherichia coli yagD mutant and by detecting HMT activity in complemented cells. Gel blot analyses indicate that these enzymes, AtHMT-1 and -2, are encoded by single copy genes. The deduced polypeptides are similar in size (36 kDa), share a zinc-binding motif, lack obvious targeting sequences, and are 55% identical to each other. The recombinant enzymes exist as monomers. AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM. Both enzymes also use either methyl donor in vivo because both restore the ability to utilize AdoMet or SMM to a yeast HMT mutant. However, AtHMT-1 is strongly inhibited by Met, whereas AtHMT-2 is not, a difference that could be crucial to the control of flux through the HMT reaction and the SMM cycle. Plant HMT is known to transfer the pro-R methyl group of SMM. This enabled us to use recombinant AtHMT-1 to establish that the other enzyme of the SMM cycle, AdoMet:Met S-methyltransferase, introduces the pro-S methyl group. These opposing stereoselectivities suggest a way to measure in vivo flux through the SMM cycle.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 1007,
                "text": "AdoMet"
            }
        },
        {
            "context": "The relationship among restless legs syndrome (Willis-Ekbom Disease), hypertension, cardiovascular disease, and cerebrovascular disease. Untreated sleep disorders may contribute to secondary causes of uncontrolled hypertension, cardiovascular disease (CVD), and stroke. Restless legs syndrome, or Willis-Ekbom Disease (RLS/WED), is a common sensorimotor disorder with a circadian rhythmicity defined by an uncontrollable urge to move the legs that worsens during periods of inactivity or at rest in the evening, often resulting in sleep disruptions. Sleep disorders such as insomnia and obstructive sleep apnea (OSA) are established risk factors for increased risk of hypertension and vascular diseases. This literature review outlines the lessons learned from studies demonstrating insomnia and OSA as risk factors for hypertension and vascular diseases to support the epidemiologic and physiologic evidence suggesting a similar increase in hypertension and vascular disease risk due to RLS. Understanding the relationships between RLS and hypertension, CVD, and stroke has important implications for reducing the risks associated with these diseases.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 23,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Selective estrogen receptor modulator and selective progesterone receptor modulator: therapeutic efficacy in the treatment of uterine leiomyoma. Recent advances in endocrinology open a door for clinical application of selective estrogen receptor modulator (SERM) and selective progesterone receptor modulator (SPRM) in the treatment of uterine leiomyoma. With regard to SERM, treatment with raloxifene is shown to reduce leiomyoma size in postmenopausal women. Although raloxifene causes shrinkage of leiomyomas in combination with gonadotropin-releasing hormone agonist in premenopausal women, the effects of monotherapy with raloxifene on leiomyoma growth in premenopausal women remain controversial. By contrast, tamoxifen may not be suitable for long-term treatment of leiomyomas due to an agonistic action on the endometrium. Treatment with progesterone antagonist (RU486) or SPRM (J867) has been demonstrated to inhibit leiomyoma growth and improve clinical symptoms in premenopausal women. No serious adverse effects associated with SERM or SPRM have been reported. In light of therapeutic efficacy and few adverse effects, SERM and SPRM may hold promise as novel treatment modalities for leiomyoma. Further studies are warranted to determine the optimal strategy for the treatment of leiomyoma with SERM and SPRM.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 218,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. We used [18F]altanserin and positron emission tomography (PET) to image serotonin 5-HT2A receptors in humans. The highest [18F]altanserin uptake is found in the cerebral cortex, with specific-to-nonspecific binding ratios varying from 0.53 to 1.91 in humans between 24 and 48 years of age. In all neocortical regions studied, [18F]altanserin uptake correlates negatively with age. No correlations were found between age and uptake in the cerebellum, the regional cerebral blood flow, or the time course of metabolization of [18F]altanserin. The reduction in cerebral 5-HT2A receptor binding thus directly reflects the loss of specific 5-HT2A receptors with age.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 220,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Ser67-phosphorylated inhibitor 1 is a potent protein phosphatase 1 inhibitor. Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase. Nonphosphorylated I-1 is inactive, whereas phosphorylated I-1 is a potent PP1 inhibitor. I-1 is phosphorylated in vivo on Thr(35) and Ser(67). Thr(35) is phosphorylated by cAMP-dependent protein kinase (A kinase), and Thr(35)-phosphorylated I-1 inhibits PP1. Until now the kinase that phosphorylates Ser(67) had not been identified and the physiological role of Ser(67) phosphorylation was unknown. In this study we detected a high level of kinase activity in brain extract when a glutathione S-transferase (GST) fusion I-1 mutant containing an Ala substituted for Thr(35) [GST-I-1(T35A)] was used as the substrate. GST-I-1(T35A) kinase and neuronal cdc2-like protein kinase (NCLK) in the brain extract could not be separated from each other by a series of sequential chromatographies. GST-I-1(T35A) kinase immunoprecipitated with anti-NCLK antibody from kinase-active column fractions. Purified NCLK-phosphorylated GST-I-1(T35A) and I-1 (0.7 mole of phosphate per mole of I-1). HPLC phosphopeptide mapping, amino acid sequencing, and site-directed mutagenesis determined that NCLK phosphorylates Ser(67) of I-1. NCLK-phosphorylated I-1 and I-1(T35A) inhibited PP1 with IC(50) values approximately 9.5 and 13. 8 nM, respectively. When compared, A kinase-phosphorylated I-1 was only approximately 1.2 times more inhibitory than NCLK-phosphorylated I-1. Our data indicate that NCLK is a potential in vivo I-1 kinase and that Thr(35) and Ser(67) phosphorylation independently activate I-1.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 78,
                "text": "Inhibitor 1"
            }
        },
        {
            "context": "Peripartum isolated cortical vein thrombosis in a mother with postdural puncture headache treated with an epidural blood patch. A 32-year-old woman presented with low pressure headache 3 days after delivery of her baby. An assessment of postdural puncture headache was made. This was initially treated with analgesia, caffeine, and fluids for the presumed cerebrospinal fluid (CSF) leak. The woman was readmitted two days after her hospital discharge with generalised seizures. A brain scan showed features of intracranial hypotension, and she was treated for CSF leak using an epidural blood patch. Her symptoms worsened and three days later, she developed a left homonymous quadrantanopia. An MRI scan confirmed a right parietal haematoma with evidence of isolated cortical vein thrombosis (ICVT).",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 578,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals. Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved. We investigated 94 healthy individuals (60 men, mean age 47.0±18.7, range 23-86) to determine if trait aggression and trait impulsivity were related to frontal cortex 5-HT2A receptor binding (5-HT2AR) as measured with [18F]-altanserin PET imaging. Trait aggression and trait impulsivity were assessed with the Buss-Perry Aggression Questionnaire (AQ) and the Barratt Impulsiveness Scale 11 (BIS-11). Statistical analyses were conducted using a multiple linear regression model and internal consistency reliability of the AQ and BIS-11 was evaluated by Cronbach's alpha. Contrary to our hypothesis, results revealed no significant associations between 5-HT2AR and the AQ or BIS-11 total scores. Also, there was no significant interaction between gender and frontal cortex 5-HT2AR in predicting trait aggression and trait impulsivity. This is the first study to examine how 5-HT2AR relates to trait aggression and trait impulsivity in a large sample of healthy individuals. Our findings are not supportive of a selective role for 5-HT2AR in mediating the 5-HT related effects on aggression and impulsivity in psychiatrically healthy individuals.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 559,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 189,
                "text": "tyr"
            }
        },
        {
            "context": "PPADS, a P2X receptor antagonist, as a novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger in guinea pig airway smooth muscle. The Na(+)/Ca(2+)exchanger (NCX) principal function is taking 1 Ca(2+) out of the cytoplasm and introducing 3 Na(+). The increase of cytoplasmic Na(+) concentration induces the NCX reverse mode (NCX(REV)), favoring Ca(2+) influx. NCX(REV) can be inhibited by: KB-R7943 a non-specific compound that blocks voltage-dependent and store-operated Ca(2+) channels; SEA0400 that appears to be selective for NCX(REV), but difficult to obtain and SN-6, which efficacy has been shown only in cardiomyocytes. We found that PPADS, a P2X receptor antagonist, acts as a NCX(REV) inhibitor in guinea pig tracheal myocytes. In these cells, we characterized the NCX(REV) by substituting NaCl and NaHCO(3) with LiCl, resulting in the increase of the intracellular Ca(2+) concentration ([Ca(2+)]i) using fura 2-AM. We analyzed 5 consecutive responses of the NCX(REV) every 10 min, finding no differences among them. To evaluate the effect of different NCX(REV) blockers, concentration response curves to KB-R7943 (1, 3.2 and 10 μM), and SN-6 (3.2, 10 and 30 μM) were constructed, whereas PPADS effect was characterized as time- and concentration-dependent (1, 3.2, 10 and 30 μM). PPADS had similar potency and efficacy as KB-R7943, whereas SN-6 was the least effective. Furthermore, KCl-induced contraction, sensitive to D600 and nifedipine, was blocked by KB-R7943, but not by PPADS. KCl-induced [Ca(2+)]i increment in myocytes was also significantly decreased by KBR-7943 (10 μM). Our results demonstrate that PPADS can be used as a reliable pharmacological tool to inhibit NCX(REV), with the advantage that it is more specific than KB-R7943 because it does not affect L-type Ca(2+) channels.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 366,
                "text": "NCX"
            }
        },
        {
            "context": "Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care. BACKGROUND: An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. METHODS: Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians. CONCLUSIONS: The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria. Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 21,
                "text": "malaria"
            }
        },
        {
            "context": "A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome. OBJECTIVE: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome. PATIENT & METHODS: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed. RESULTS: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation. CONCLUSIONS: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 397,
                "text": "Xq28"
            }
        },
        {
            "context": "Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. INTRODUCTION: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid , a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB. AREA COVERED: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug's safety and tolerability profiles are also considered. EXPERT OPINION: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 26,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the \"hybrid\" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 243,
                "text": "FBN1"
            }
        },
        {
            "context": "Sequestration of p53 in the cytoplasm by adenovirus type 12 E1B 55-kilodalton oncoprotein is required for inhibition of p53-mediated apoptosis. The adenovirus E1B 55-kDa protein is a potent inhibitor of p53-mediated transactivation and apoptosis. The proposed mechanisms include tethering the E1B repression domain to p53-responsive promoters via direct E1B-p53 interaction. Cytoplasmic sequestration of p53 by the 55-kDa protein would impose additional inhibition on p53-mediated effects. To investigate further the role of cytoplasmic sequestration of p53 in its inhibition by the E1B 55-kDa protein we systematically examined domains in both the Ad12 55-kDa protein and p53 that underpin their colocalization in the cytoplasmic body and show that the N-terminal transactivation domain (TAD) of p53 is essential for retaining p53 in the cytoplasmic body. Deletion of amino acids 11 to 27 or even point mutation L22Q/W23S abolished the localization of p53 to the cytoplasmic body, whereas other parts of TAD and the C-terminal domain of p53 are dispensable. This cytoplasmic body is distinct from aggresome associated with overexpression of some proteins, since it neither altered vimentin intermediate filaments nor associated with centrosome or ubiquitin. Formation of this structure is sensitive to mutation of the Ad12 55-kDa protein. Strikingly, mutation S476/477A near the C terminus of the Ad12 55-kDa protein eliminated the formation of the cytoplasmic body. The equivalent residues in the Ad5 55-kDa protein were shown to be critical for its ability to inhibit p53. Indeed, Ad12 55-kDa mutants that cannot form a cytoplasmic body can no longer inhibit p53-mediated effects. Conversely, the Ad12 55-kDa protein does not suppress p53 mutant L22Q/W23S-mediated apoptosis. Finally, we show that E1B can still sequester p53 that contains the mitochondrial import sequence, thereby potentially preventing the localization of p53 to mitochondria. Thus, cytoplasmic sequestration of p53 by the E1B 55-kDa protein plays an important role in restricting p53 activities.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 765,
                "text": "transactivation domain"
            }
        },
        {
            "context": "[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. Hypo- and hyperpigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function and melanocytoses connected with melanocyte development. The article presents some hereditary hypomelanocytoses, which are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations. It has been demonstrated that mutations of the same gene may cause different hypopigmentation syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome. It has also been demonstrated that mutations of different genes may cause an identical syndrome. For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. In turn, mutation of the KIT gene and/or heterozygous deletion of the SNAI2 gene result in piebaldism disease. The knowledge of the exact mechanisms of pigmentary disorders may be useful in the development of new therapeutic approaches to their treatment.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1080,
                "text": "MITF"
            }
        },
        {
            "context": "Christianson syndrome: spectrum of neuroimaging findings. Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. The clinical phenotypes of CS and Angelman syndrome (AS) are similar. Differentiation between CS and AS is important in terms of genetic counseling. We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. Cerebellar atrophy (CA) occurs in approximately 60% of the patients with CS and develops after the age of 12 months. Hyperintense signal of the cerebellar cortex (CbC) is less common, and may be diffuse, patchy, or involve only the inferior part of the cerebellum and is best seen on coronal fluid attenuation inversion recovery images. CA and CbC-hyperintensity are not neuroimaging features of AS. In a child with the phenotype of AS, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 111,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 187,
                "text": "MRSA"
            }
        },
        {
            "context": "Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism. Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 199,
                "text": "tyr"
            }
        },
        {
            "context": "Expression of the kallikrein gene family in normal and Alzheimer's disease brain. The human kallikrein gene family consists of 15 serine proteases. We examined the expression of the kallikrein genes in human cerebral cortex and hippocampus by RT-PCR and compared their expression between Alzheimer's disease (AD) and control tissue. KLK1, 4, 5, 6, 7, 8, 10, 11, 13 and 14 are expressed in both cerebral cortex and hippocampus. KLK9 is expressed in cortex but not hippocampus, whereas KLK2, 3, 12 and 15 are not expressed in either tissue. We demonstrate an 11.5-fold increase in KLK8 mRNA levels in AD hippocampus compared to controls. The KLK8 gene product, neuropsin, processes extracellular matrix and is important for neuronal plasticity. Therefore, the increase in KLK8 could have detrimental effects on hippocampal function in AD.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 127,
                "text": "15"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its effect on subsequent MRSA infection. BACKGROUND: Asymptomatic colonization with methicillin-resistant Staphylococcus aureus (MRSA) has been described as a risk factor for subsequent MRSA infection. MRSA is an important nosocomial pathogen but has currently been reported in patients without typical risk factors for nosocomial acquisition. This study was designed to evaluate the impact of asymptomatic nares MRSA colonization on the development of subsequent MRSA infection. The incidence of MRSA infection was examined in patients with and patients without MRSA or methicillin-susceptible S. aureus (MSSA) colonization at admission to the hospital and in those who developed colonization during hospitalization. METHODS: Patients admitted to 5 representative hospital units were prospectively evaluated. Nares samples were obtained for culture at admission and during hospitalization. Laboratory culture results were monitored to identify all MRSA infections that occurred during the study period and 1 year thereafter. RESULTS: Of the 758 patients who had cultures of nares samples performed at admission, 3.4% were colonized with MRSA, and 21% were colonized with MSSA. A total of 19% of patients with MRSA colonization at admission and 25% who acquired MRSA colonization during hospitalization developed infection with MRSA, compared with 1.5% and 2.0% of patients colonized with MSSA (P<.01) and uncolonized (P<.01), respectively, at admission. MRSA colonization at admission increased the risk of subsequent MRSA infection, compared with MSSA colonization (relative risk [RR], 13; 95% confidence interval [CI], 2.7-64) or no staphylococcal colonization (RR, 9.5; 95% CI, 3.6-25) at admission. Acquisition of MRSA colonization also increased the risk for subsequent MRSA infection, compared with no acquisition (RR, 12; 95% CI, 4.0-38). CONCLUSION: MRSA colonization of nares, either present at admission to the hospital or acquired during hospitalization, increases the risk for MRSA infection. Identifying MRSA colonization at admission could target a high-risk population that may benefit from interventions to decrease the risk for subsequent MRSA infection.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 45,
                "text": "MRSA"
            }
        },
        {
            "context": "Diagnosis of pneumoperitoneum on supine abdominal radiographs. A blinded, retrospective study was performed to determine the value of supine abdominal radiographs in diagnosing pneumoperitoneum. Supine films from 44 cases of pneumoperitoneum were randomly interspersed among supine films from 87 control subjects without free air, and the films were reviewed for the presence or absence of various signs of pneumoperitoneum, including Rigler's sign (gas on both sides of the bowel wall), the falciform ligament sign (gas outlining the falciform ligament), the football sign (gas outlining the peritoneal cavity), the inverted-V sign (gas outlining the medial umbilical folds), and the right-upper-quadrant gas sign (localized gas in the right upper quadrant). One or more of these signs were present in 26 cases (59%) of pneumoperitoneum, including the right-upper-quadrant gas sign in 18 cases (41%), Rigler's sign in 14 cases (32%), and the falciform ligament and football signs in one case each (2%). Unfortunately, there were frequent errors in the interpretation of the right-upper-quadrant gas sign and Rigler's sign, with a total of 11 false-positive cases (13%). Further analysis of the true-positive right-upper-quadrant gas signs showed that these gas collections were always triangular or linear with an inferolateral to superomedial orientation and, if triangular, a concave superolateral border. In the true-positive Rigler's signs, the bowel wall thickness ranged from 1 to 8 mm, whereas the false positives all had a bowel wall thickness of 1 mm or less. Proper interpretation of the various signs of pneumoperitoneum on supine films should lead to more accurate diagnosis of this condition.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 225,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling. BACKGROUND: Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling. METHODS AND RESULTS: Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1-PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1. CONCLUSIONS: Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1-PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.",
            "question": "Which protein phosphatase has been found to interact with the heat shock protein, HSP20?",
            "answers": {
                "answer_start": 1356,
                "text": "PP1"
            }
        },
        {
            "context": "The nerve/tunnel index: a new diagnostic standard for carpal tunnel syndrome using sonography: a pilot study. OBJECTIVES: To define the relationship between body indices of healthy adults and cross-sectional areas of the carpal tunnel and median nerve and to obtain the nerve/tunnel index, which represents a new standard for diagnosing carpal tunnel syndrome using sonography. METHODS: Body indices (height, weight, and body mass index) were analyzed in 60 healthy adults, and electromyography and sonography were also performed. The cross-sectional areas of the proximal and distal median nerve and carpal tunnel were obtained by sonography. The proximal and distal nerve/tunnel indices were obtained by calculating the ratio between the proximal and distal cross-sectional areas of the median nerve to those of the carpal tunnel and multiplying the value by 100. RESULTS: Although the proximal cross-sectional areas of the median nerve and body indices showed statistically significant relationships with weak positive correlations, the proximal and distal areas of the carpal tunnel showed relatively stronger correlations with body indices. Between sexes, there were significant differences in the proximal median nerve cross-sectional area (mean ± SD: male, 10.48 ± 3.21 mm(2); female, 8.81 ± 3.21 mm(2); P < .05) and proximal carpal tunnel area (male, 182.50 ± 21.15 mm(2); female, 151.23 ± 21.14 mm(2); P < .05). There was no difference in the proximal nerve/tunnel index (male, 5.80% ± 1.72%; female, 5.91% ± 1.63%). There was a statistically significant difference in the distal carpal tunnel cross-sectional area (male, 138.90 ± 20.95 mm(2); female, 121.50 ± 18.99 mm(2); P < .05) between sexes, but the distal median area (male, 9.99 ± 3.42 mm(2); female, 8.46 ± 1.84 mm(2)) and distal nerve/tunnel index (male, 7.15% ± 2.00%; female, 7.01% ± 1.38%) showed no significant differences. The proximal index was significantly higher than the distal index (proximal, 5.85% ± 1.66%; distal, 7.08% ± 1.71%). CONCLUSIONS: The nerve/tunnel index is unaffected by body indices or sex and thus may be a useful and objective standard for diagnosing carpal tunnel syndrome.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 239,
                "text": "median"
            }
        },
        {
            "context": "A mitotic topoisomerase II checkpoint in budding yeast is required for genome stability but acts independently of Pds1/securin. Topoisomerase II (Topo II) performs topological modifications on double-stranded DNA molecules that are essential for chromosome condensation, resolution, and segregation. In mammals, G2 and metaphase cell cycle delays induced by Topo II poisons have been proposed to be the result of checkpoint activation in response to the catenation state of DNA. However, the apparent lack of such controls in model organisms has excluded genetic proof that Topo II checkpoints exist and are separable from the conventional DNA damage checkpoint controls. But here, we define a Topo II-dependent G2/M checkpoint in a genetically amenable eukaryote, budding yeast, and demonstrate that this checkpoint enhances cell survival. Conversely, a lack of the checkpoint results in aneuploidy. Neither DNA damage-responsive pathways nor Pds1/securin are needed for this checkpoint. Unusually, spindle assembly checkpoint components are required for the Topo II checkpoint, but checkpoint activation is not the result of failed chromosome biorientation or a lack of spindle tension. Thus, compromised Topo II function activates a yeast checkpoint system that operates by a novel mechanism.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 128,
                "text": "Topoisomerase II"
            }
        },
        {
            "context": "Gene expression during normal and FSHD myogenesis. BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how. METHODS: Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods. RESULTS: Many of the ~17,000 examined genes were differentially expressed (>2-fold, p<0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked DUX4 RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types. CONCLUSIONS: DUX4's pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated DUX4 expression at the myoblast or myotube stages. Our model could explain why DUX4's inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 2100,
                "text": "FSHD"
            }
        },
        {
            "context": "The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 241,
                "text": "epidermal growth factor receptor"
            }
        },
        {
            "context": "Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. BACKGROUND: The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. METHODS: In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged > 18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. FINDINGS: Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8·8%; 95% CI -17·6 to 4·2). The lower bound of the 95% CI of -17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). INTERPRETATION: Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. FUNDING: Genzyme, a Sanofi company.",
            "question": "Which disease is treated with Eliglustat?",
            "answers": {
                "answer_start": 2548,
                "text": "Gaucher's disease type 1"
            }
        },
        {
            "context": "Microwave and magnetic (M(2) ) proteomics of the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. We hypothesized that quantitative MS/MS-based proteomics at multiple time points, incorporating rapid microwave and magnetic (M(2) ) sample preparation, could enable relative protein expression to be correlated to disease progression in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. To test our hypothesis, microwave-assisted reduction/alkylation/digestion of proteins from brain tissue lysates bound to C8 magnetic beads and microwave-assisted isobaric chemical labeling were performed of released peptides, in 90 s prior to unbiased proteomic analysis. Disease progression in EAE was assessed by scoring clinical EAE disease severity and confirmed by histopathologic evaluation for central nervous system inflammation. Decoding the expression of 283 top-ranked proteins (p <0.05) at each time point relative to their expression at the peak of disease, from a total of 1191 proteins observed in four technical replicates, revealed a strong statistical correlation to EAE disease score, particularly for the following four proteins that closely mirror disease progression: 14-3-3ε (p = 3.4E-6); GPI (p = 2.1E-5); PLP1 (p = 8.0E-4); PRX1 (p = 1.7E-4). These results were confirmed by Western blotting, signaling pathway analysis, and hierarchical clustering of EAE risk groups. While validation in a larger cohort is underway, we conclude that M(2) proteomics is a rapid method to quantify putative prognostic/predictive protein biomarkers and therapeutic targets of disease progression in the EAE animal model of multiple sclerosis.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 368,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 84,
                "text": "xa"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1136,
                "text": "telomerase"
            }
        },
        {
            "context": "Clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis from a center with a high MRSA prevalence. BACKGROUND: We describe the clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis (CF) from the U.S. CF center with the highest MRSA prevalence. METHODS: Medical records of children with CF were retrospectively reviewed from 1997-2009. MRSA clinical isolates from 2007-2009 were analyzed by polymerase chain reaction and pulsed field gel electrophoresis. RESULTS: The prevalence of MRSA was 1% in 1997 and 49% in 2009. Fifty-five children (26%) had persistent MRSA infection. Sixty-eight percent of MRSA isolates were hospital-associated (HA) MRSA, of which 52% were pulsed-field type USA 100. Ninety-three percent of HA MRSA isolates were clindamycin resistant. Twelve children acquired MRSA before 1 year of age, 83% of whom were hospitalized prior to acquisition of MRSA. Ten of 11 sibling pairs carried indistinguishable MRSA strains. Children with persistent MRSA were hospitalized more often (P = .01), required inhaled medications more frequently (P = .01), and had higher rates of Pseudomonas aeruginosa coinfection (P < .001). CONCLUSION: MRSA prevalence in children with CF is increasing, and most children are infected with HA MRSA. Exposure to health care facilities and gastrointestinal surgeries may facilitate early acquisition of MRSA. Siblings carry indistinguishable MRSA strains, indicating household transmission of MRSA. Children with persistent MRSA had worse pulmonary morbidity. Coinfection with MRSA and P aeruginosa is likely associated with further increased pulmonary morbidity.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 90,
                "text": "MRSA"
            }
        },
        {
            "context": "Molecular genetics of Marfan syndrome. PURPOSE OF REVIEW: Marfan syndrome, the founding member of connective tissue disorders, is characterized by involvement of three major systems (skeletal, ocular, and cardiovascular) due to alteration in microfibrils. FBN1 at 15q21.1 was found to cause Marfan syndrome in 1991, and in 2004 TGFBR2 at 3p24.1 was newly identified as the Marfan syndrome type II gene. Several studies implied that fibrillin-1 and transforming growth factor-beta (TGF-beta) signaling are functionally related in extracellular matrix. Identification of TGFBR2 mutations in Marfan syndrome type II provided the direct evidence of the relation in humans. RECENT FINDINGS: More than 500 FBN1 mutations have been found in Marfan syndrome, tentative genotype - phenotype correlations have emerged, and mouse models are providing insight into pathogenic mechanisms. TGFBR2 mutations are still limited, however, in 2005 were also reported to cause a new aneurysm syndrome. Functional association between fibrillin-1 and TGF-beta signaling in extracellular matrix has been presented. SUMMARY: This review focuses on recent molecular genetics advances in Marfan syndrome and overlapping connective tissue disorders. Mutation spectrum of FBN1 and TGFBR2 in relation to phenotype is presented. Functional relation between fibrillin-1 and TGF-beta signaling is discussed. Future prospects in the study of Marfan syndrome are presented.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 256,
                "text": "FBN1"
            }
        },
        {
            "context": "Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor. The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the world's pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G749T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C1351G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known \"Jewish\" mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known \"non-Jewish\" mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C1351G and G749T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor (theta) between the markers and mutated loci, and the population growth correction, we deduced that G749T occurred in a founder ancestor 44.8 +/- 14.2 generations (g) ago [95% confidence interval (CI) 17.0-72.6 g] and C1351G arose 80.4 +/- 35.9 g ago (95% CI 44.5-116.3 g). Thus, the estimated dates for introduction of mutations are: 626 +/- 426 A.D. (200-1052 A.D.) for G749T and 442 +/- 1077 B.C. (1519 B.C. to 635 A.D.) for C1351G.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 26,
                "text": "HEXA"
            }
        },
        {
            "context": "[Seizure triggered by benzodiazepine receptor antagonist]. Flumazenil is a benzodiazepine antagonist. It is widely used as an antidote in comatose patients suspected of having ingested a benzodiazepine overdose. Flumazenil is known to induce cardiac arythmias and seizures, in part because of drug interactions. We present a 75-year-old woman, who was brought to the Emergency Department with a drug overdose following a suicide attempt. She developed generalized seizures shortly after the administration of flumazenil.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 59,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Iron deficiency: beyond anemia. Iron deficiency is the most common nutritional disorder affecting at least one third of world's population. Though anemia is common manifestation of iron deficiency, other effects of iron deficiency on various tissues, organs and systems are usually under recognized. Impaired brain development and cognitive, behavioural and psychomotor impairment are most worrisome manifestations of iron deficiency. Studies have demonstrated that some of these changes occurring during period of brain growth spurt (<2 years age) may be irreversible. Association of iron deficiency with febrile seizures, pica, breath holding spells, restless leg syndrome and thrombosis is increasingly being recognized. Impaired cell-mediated immunity and bactericidal function are generally noted in iron-deficient persons; however, the findings are inconsistent. Despite proven reversible functional immunological defects in vitro studies, a clinically important relationship between states of iron deficiency and susceptibility to infections remains controversial. Studies from malaria endemic regions have reported increased incidence of malaria in association with iron supplementation. These and some other aspects of iron deficiency are reviewed in this article.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 585,
                "text": "iron"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 73,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 820,
                "text": "malaria"
            }
        },
        {
            "context": "Differential effects of stress stimuli on a JNK-inactivating phosphatase. Stress signals elicit a wide variety of cellular responses, many of which converge on the phosphorylation of JNK and p38 kinases, the activation of which has been well-characterized. How these kinases are switched off by dephosphorylation is not well understood. Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6. Both anisomycin and arsenite activate the JNK pathway and, in addition, inactivate the M3/6 phosphatase. However, while anisomycin treatment of cells leads to M3/6 protein degradation, arsenite appears to inactivate M3/6 directly. These results might have implications for the mechanism of tumour promotion by arsenic.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 548,
                "text": "JNK"
            }
        },
        {
            "context": "PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. OBJECTIVE: To determine whether there are abnormalities in the in vivo status of the serotonin type 2A (5-HT2A) receptor in late-life depression and Alzheimer's disease, the authors used positron emission tomography (PET) to assess patients with these two conditions and healthy subjects. METHOD: PET was performed by using [18F]altanserin to evaluate 5-HT2A receptor binding in 11 elderly patients with depression (four men, seven women; mean age = 65.0 years, SD = 5.5); nine Alzheimer's disease patients, including three with concurrent depression (two men, seven women; mean age = 69.7 years, SD = 5.0); and 10 age-matched healthy subjects (four men, six women; mean age = 69.8 years, SD = 5.0). Partial-volume correction of regional specific binding estimates was performed by using a method based on magnetic resonance imaging. RESULTS: No significant abnormalities in [18F]altanserin binding (binding potential) were observed in the patients with late-life depression, and no effect of depression on binding potential was present within the Alzheimer's disease group. However, the patients with Alzheimer's disease had significantly lower binding than the normal subjects in several brain regions, including the anterior cingulate, prefrontal cortex, and sensorimotor cortex. CONCLUSIONS: These results suggest that the 5-HT2A receptor is differentially affected in late-life depression and Alzheimer's disease, a finding that has implications for the etiological basis of mood and cognitive features of neuropsychiatric disorders of late life.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 436,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Friedreich's ataxia associated with mitochondrial myopathy: clinicopathologic report. A 13-year-old boy with clinical and electrophysiologic findings of Friedreich's ataxia developed unusually prominent myopathy. Skeletal muscle biopsy showed mitochondrial proliferation and structural abnormalities. No mutation was found in skeletal muscle mitochondrial DNA to explain this finding. Molecular genetic and pathologic studies confirmed a diagnosis of Friedreich's ataxia in the proband and affected relatives. Although the Friedreich's ataxia phenotype results from decreased expression of a mitochondrially targeted protein, frataxin, mitochondrial myopathy has not been described as a feature of the disease. The association between the frataxin gene mutation and mitochondrial myopathy in this case suggests that severe or cumulative insults to mitochondrial function may produce myopathic changes in some cases of Friedreich's ataxia. The patient also responded clinically to carnitine supplementation, suggesting a potential palliative therapy for the disease.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 626,
                "text": "frataxin"
            }
        },
        {
            "context": "[Aryl hydrocarbon receptor interacting protein gene and familial isolated pituitary adenomas]. Familial isolated pituitary adenoma (FIPA) is an autosomal dominant disease, characterized by low penetrance, early-onset disease, more invasive tumor growth, as well as somatotroph and lactotroph adenomas in most cases. It has been indicated that the aryl hydrocarbon receptor interacting protein (AIP) gene is a tumor suppressor gene. Many heterozygous mutations have been discovered in AIP in about 20% of FIPA families. However, the exact molecular mechanism by which its disfunction promotes tumorigenesis of pituitary is unclear.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 1,
                "text": "Aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "Correlation between the Wells score and the Quanadli index in patients with pulmonary embolism. BACKGROUND AND AIMS: Determining clinical probability of pulmonary embolism (PE) with Wells scoring system is the first step towards diagnosis of PE. Definitive diagnosis of PE is confirmed by computed tomography pulmonary angiography (CTPA). METHODS: This was a prospective study on 80 patients referred to the Institute for Pulmonary Diseases of Vojvodina with suspected PE between April 2010 and August 2012. Clinical probability of PE was determined according to the Wells and modified Wells scoring system. CTPA was performed in 60 patients. The degree of pulmonary vascular obstruction was quantified by the Qanadli index. RESULTS: Low clinical probability of PE was present in one patient (1.6%), moderate in 43 (71.6%) and high in 16 (26.6%) patients. PE was confirmed in 50 (83.3%) patients. There were 21 patients (42%) whose Quanadli index was <25%, 18 (36%) between 25%-50%, while Quanadli index was > 50 in 11 patients (22%). When compared to CTPA findings, modified Wells scoring system showed 90% sensitivity [95% confidence interval (CI) 78.2%-96.6%], and 20% specificity (95% CI 3.11%-55.6%), positive predictive value (PPV) 84.9% (95% CI 72.4%-93.2%) and negative predictive value (NPV) 28.6% (95% CI 4.5%-70.7%). There was weak positive correlation between Wells score and Quanadli index (r = 0.14; P = 0.29), without statistical significance. Wells score was significantly higher in haemodynamically unstable than in haemodynamically stable patients (6.8 vs 5.6, P = 0.014). There was no statistically significant difference between the values of Quanadli index in these two groups (31.33% vs 26.64%, P = 0.062). CONCLUSION: Modified Wells criteria have high sensitivity but low specificity in PE diagnostics. The Wells score does not correlate well with the Quanadli index.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 76,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "p53: a guide to apoptosis. Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 gene locus, while germ line mutations confer a high familial risk and are associated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein is often referred to as the \"guardian of the genome\" since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses. One of the most important functions of p53 is its ability to induce apoptosis, while disruption of this route can promote tumor progression and chemo resistance. Besides its ability to promote apoptosis through transcription dependent mechanisms, p53 may also be able to activate apoptosis independent of transcriptional regulation. Therefore, to ensure normal cell growth, p53 levels and activity are tightly regulated. Upon diverse forms of cellular stress the steady state levels and transcriptional activity of p53 are considerably increased. The stabilization and activation of p53 are a result of hindered inhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, while on the other hand activators such as HIPK2 and DYRK2 enhance the p53 response. The continually increasing understanding of the mechanisms of regulation of p53 may provide the basis for new drug designs that could eventually lead to therapeutics to reactivate p53 in cancers.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 231,
                "text": "p53"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 430,
                "text": "coilin"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 581,
                "text": "xa"
            }
        },
        {
            "context": "Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 271,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 284,
                "text": "HIV"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 609,
                "text": "xa"
            }
        },
        {
            "context": "LRRK2 as a Potential Genetic Modifier of Synucleinopathies: Interlacing the Two Major Genetic Factors of Parkinson's Disease. Parkinson's disease (PD) and related Lewy body diseases are characterized by deposition of α-synuclein aggregates in both the central nervous system and peripheral nervous system. Synucleinopathy lesions spread to larger brain areas as the disease progresses, and prion-like cell-to-cell transmission of aggregated α-synuclein is thought to be the underlying mechanism for this pathological spreading. LRRK2 is another protein linked to the pathogenesis of PD, and its presence in Lewy bodies has attracted much attention as to whether LRRK2 and α-synuclein interplay during the pathogenesis of PD. However, the relationship between these two crucial proteins still remains unclear. In this review article, we will discuss the current state of knowledge in terms of how these proteins cause the disease and provide the hypothetical mechanisms by which LRRK2 might modify the generation and progression of synucleinopathy.",
            "question": "Which disease of the central nervous system is characterized by the presence of Lewy bodies?",
            "answers": {
                "answer_start": 126,
                "text": "Parkinson's disease (PD)"
            }
        },
        {
            "context": "PTEN: a new guardian of the genome. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT signaling pathway and suppresses cell survival as well as cell proliferation. PTEN is the second most frequently mutated gene in human cancer after p53. Germline mutations of PTEN have been found in cancer susceptibility syndromes, such as Cowden syndrome, in which over 80% of patients have mutations of PTEN. Homozygous deletion of Pten causes embryonic lethality, suggesting that PTEN is essential for embryonic development. Mice heterozygous for Pten develop spontaneous tumors in a variety of organs comparable with the spectrum of its mutations in human cancer. The mechanisms of PTEN functions in tumor suppression are currently under intense investigation. Recent studies demonstrate that PTEN plays an essential role in the maintenance of chromosomal stability and that loss of PTEN leads to massive alterations of chromosomes. The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death. Through completely different mechanisms, PTEN also protects the genome from instability. Thus, we propose that PTEN is a new guardian of the genome. In this review, we will discuss new discoveries on the role of PTEN in tumor suppression and explore mechanisms by which PTEN maintains genomic stability.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 1045,
                "text": "p53"
            }
        },
        {
            "context": "The role of LOX and LOXL2 in scar formation after glaucoma surgery. PURPOSE: The aim of this study was to elucidate the role of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) 2 in pathologic wound healing after glaucoma surgery. We therefore investigated the expression of LOX and LOXL2 and evaluated the therapeutic potential of anti-LOX (GS-639556, formerly M64) and anti-LOXL2 (GS-607601, formerly AB0023) antibodies in a rabbit model of glaucoma trabeculectomy. METHODS: Ocular expression of LOX and LOXL2 was investigated by immunohistologic staining at different time points after trabeculectomy. Treatment with GS-639556 or GS-607601 was initiated in rabbits immediately after trabeculectomy by giving both intracameral and subconjunctival injections. Thereafter, the antibodies were given twice a week subconjunctivally until day 30 after surgery (day of euthanization). Treatment outcome was studied by clinical investigation of the bleb and by immunohistochemical analysis of angiogenesis, inflammation, and collagen deposition. RESULTS: LOX and LOXL2 were both upregulated in Tenon's capsule and the conjunctiva after glaucoma surgery. Repeated administration of LOX- or LOXL2-targeting monoclonal antibodies increased bleb area and bleb survival. Analyses of immunohistologic stainings showed that both antibodies significantly decreased fibrosis, whereas the anti-LOXL2 antibody also significantly reduced blood vessel density and inflammation. CONCLUSIONS: Targeting LOXL2 with an inhibitory monoclonal antibody (GS-607601) reduced pathologic angiogenesis, inflammation, and fibrosis. These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.",
            "question": "What is the drug target for Simtuzumab?",
            "answers": {
                "answer_start": 1629,
                "text": "LOXL2"
            }
        },
        {
            "context": "Empagliflozin for the treatment of type 2 diabetes. INTRODUCTION: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion. AREAS COVERED: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin. EXPERT OPINION: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 491,
                "text": "SGLT2"
            }
        },
        {
            "context": "Abbreviated right-sided heart echocardiogram and the STOP-Bang questionnaire-a useful relationship for preoperative patient evaluation? STUDY OBJECTIVE: The aims of this study were to (1) explore the incidence of right-sided heart dysfunction (RHD) and STOP-Bang questionnaire responses consistent with obstructive sleep apnea (OSA) and (2) assess the relationship between patients with STOP-Bang questionnaire responses consistent with OSA and echocardiographic findings suggestive of RHD. DESIGN: Observational study. SETTING: Tertiary academic center preoperative clinic. PATIENTS: Two hundred patients presenting for elective surgery to the University of Utah preoperative clinic. INTERVENTION: Abbreviated transthoracic right-sided echocardiogram and STOP-Bang questionnaire. MEASUREMENTS: Tricuspid annular plane systolic excursion, tissue Doppler-derived tricuspid lateral annular systolic velocity (S'), and the tricuspid inflow E wave to tricuspid annular tissue Doppler e' wave ratio (E/e') for the presence of RHD, as well as responses to STOP-Bang questionnaire. MAIN RESULTS: A total of 140 echocardiograms were analyzed after exclusion of participants with incomplete STOP-Bang questionnaires and inadequate images. Thirty-five patients (25%) reported 5 or more positive responses to the STOP-Bang questionnaire. Forty-six patients (35%) had abnormal right-sided heart measurements. Of the 35 patients with STOP-Bang scores 5 or greater, 11 (31%) had evidence of RHD. No correlation was observed between STOP-Bang scores and the echocardiography metrics of RHD. CONCLUSIONS: This preliminary study suggests that there are numerous sources of RHD, among one of which is sleep apnea, and/or the STOP-Bang questionnaire is not a sensitive tool for predicting RHD. We conclude that although the STOP-Bang questionnaire is easy to implement in a preoperative clinical setting, it is not useful in identifying patients at risk for RHD.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 303,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Menin links estrogen receptor activation to histone H3K4 trimethylation. The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-alpha (ERalpha) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ERalpha interaction. Importantly, ERalpha-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor-mediated transcription.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 272,
                "text": "H3K4"
            }
        },
        {
            "context": "Cajal bodies: the first 100 years. Cajal bodies are small nuclear organelles first described nearly 100 years ago by Ramón y Cajal in vertebrate neural tissues. They have since been found in a variety of animal and plant nuclei, suggesting that they are involved in basic cellular processes. Cajal bodies contain a marker protein of unknown function, p80-coilin, and many components involved in transcription and processing of nuclear RNAs. Among these are the three eukaryotic RNA polymerases and factors required for transcribing and processing their respective nuclear transcripts: mRNA, rRNA, and pol III transcripts. A model is discussed in which Cajal bodies are the sites for preassembly of transcriptosomes, unitary particles involved in transcription and processing of RNA. A parallel is drawn to the nucleolus and the preassembly of ribosomes, which are unitary particles involved in translation of proteins.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 355,
                "text": "coilin"
            }
        },
        {
            "context": "Genetic and molecular aspects of acromelic dysplasia. The acromelic dysplasia group includes three rare disorders: Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) all characterized by short stature, short hands and stiff joints. The clinical overlap between the three disorders is striking. Indeed, in addition to the diagnostic criteria, they all share common features including delayed bone age, cone shaped epiphyses, thick skin and heart disease. In contrast, a microspherophakic lens seems to be a characteristic feature of WMS whereas hepatomegaly and a severe outcome are encountered only in the most severe forms of GD. Finally, WMS is transmitted either by an autosomal dominant or an autosomal recessive (AR) mode of inheritance, GD by an autosomal recessive mode of inheritance and AD by an autosomal dominant mode of inheritance. Using genetic approaches, we have identified the molecular basis of WMS and GD which both involved the same superfamily of proteins, the ADAMTS [A Disintegrin-like And Metalloproteinase domain (reprolysin type) with ThromboSpondin type 1 repeats (TSR)]. We have found ADAMTS10 mutations in the recessive form of WMS and Fibrillin 1 mutations in the dominant form of WMS. More recently, we have identified ADAMTSL2 mutations in GD. The function of ADAMTS1 0 and AD AMTSL 2 are unknown. But the findings of FBN1 and ADAMTS10 mutations in WMS suggest a direct link between the two proteins. Using a yeast double hybrid screen, we have identified LTBP1 (Latent TGFbeta Binding protein 1) as a partner of ADAMTSL2. The combination of these findings suggests that ADAMTS10 and ADAMTSL2 are both involved in the microfibrillar network.",
            "question": "What is the mode of inheritance of Acromicric dysplasia?",
            "answers": {
                "answer_start": 711,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 554,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Emerging antibodies for the treatment of multiple myeloma. INTRODUCTION: Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in development for patients with MM, in order to improve tolerability and quality of life. AREAS COVERED: This manuscript reviews emerging antibodies for the treatment of MM i.e. elotuzumab, daratumumab, MOR03087, isatuximab, bevacizumab, cetuximab, siltuximab, tocilizumab, elsilimomab, azintrel, rituximab, tositumomab, milatuzumab, lucatumumab, dacetuzumab, figitumumab, dalotuzumab, AVE1642, tabalumab, pembrolizumab, pidilizumab, nivolumab. EXPERT OPINION: Amongst these antibodies, elotuzumab which targets SLAMF-7 and daratumumab which targets CD38, have been recently approved by FDA for patients with relapsed/refractory MM. Both agents are well tolerated. Multiple clinical trials incorporating these monoclonal antibodies in MM treatment are currently ongoing. Of special interest are the anticipated results of phase III clinical trials with elotuzumab [NCT0189164; NCT01335399; NCT02495922] and daratumumab [NCT02252172; NCT02195479] in newly diagnosed MM patients. Moreover, of great interest are the awaited data on pembrolizumabin combination with pomalidomide and dexamethasone in refractory/relapsed MM patients [NCT02576977] and in combination with lenalidomide and dexamethasone in newly diagnosed MM patients. It seems that the incorporation of monoclonal antibodies will change the landscape of myeloma therapy in the near future.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 783,
                "text": "CD38"
            }
        },
        {
            "context": "Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 757,
                "text": "CD38"
            }
        },
        {
            "context": "[The Marfan syndrome and related connective tissue disorders]. The Marfan syndrome is an inherited disorder of the connective tissue which is mainly caused by a mutation in the fibrillin-1 gene. The defect in the connective tissue protein can lead to several organ dysfunctions. For the life expectancy, the cardiovascular aspect is of paramount importance. Patients with Marfan syndrome may develop aortic aneurysms and valvular heart defects. The risk of aortic aneurysms consists in the development of aortic dissection or rupture with their fatal consequences. Besides the cardiovascular manifestation, the skeletal and ocular system can also be affected. The skeletal manifestation is often characterised by long limbs, arachnodactyly, and abnormal joint flexibility along with other signs. Patients may also have dislocated lenses, ectasia of the dural sac, stretch marks, spontaneous pneumothorax, recurrent hernia, or a family history suspicious for Marfan. During the past years, other related connective tissue disorders with analogous organ manifestation have been described (e.g., Loeys-Dietz syndrome). In this article we present the basic knowledge about these connective tissue disorders, and we mention new insights in the recently explored pathophysiology of the disorder which is a possible target for future medical treatment options. Furthermore, recent new concepts for the prophylactic treatment of the aortic manifestation are explained.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 115,
                "text": "connective tissue"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 587,
                "text": "stroke"
            }
        },
        {
            "context": "The natural history and management of intracranial dural arteriovenous fistulae. Part 1: benign lesions. The recently proposed classification scheme of Borden, Wu, and Shucart (Borden(*)) should have the ability to identify those intracranial dural arteriovenous fistulae (ICDAVF) which will continue to behave in a benign fashion. We examine for the first time the natural history of benign ICDAVF, including the predictive ability of this grading scale, and the implications for lesion management. A cohort of 55 Borden(*) grade I lesions was selected from a heterogeneous series of 102 consecutive lCDAVF seen at one institution between 1984 and 1995. Data were collected prospectively from 1991. Grade 1 lesions were those whose nidus drained directly into a dural venous sinus (DVS) or meningeal vein. The absence of retrograde leptomeningeal venous drainage (RLVD) was an important feature. Intracranial haemorrhage (ICH), non haemorrhagic neurological deficit (NHND), and death were considered aggressive features. There were 23 cavernous sinus, 2 foramen magnum, 1 middle cranial fossa, and 29 transverse sinus lesions. One patient received obliterative surgical treatment. Thirty-two lesions were observed only, and 22 patients developed symptoms or signs requiring palliative embolisation. Two minor complications occurred following embolisation: transient pulmonary aedema (1), and an asymptomatic pericallosal artery embolus (1). Follow-up was available on 48 (89%) patients for a total of 133 patient years (mean 33 months). This included 26 of the 32 patients observed and all 22 of the patients embolised. Aggressive interval behavior was seen in only one patient. Symptom improvement or resolution was observed in the majority of patients, whether observed only [21/26 (81%) j, or whether they required embolisation for symptom palliation [19/22 (86%)). Overall, 53 of the 54 (98%) of ICDAVF behaved in a benign fashion in the follow-up period. The predictable benign natural history of patients identified as Borden(*) grade I at presentation mandates a conservative approach to these ICDAVF. In some patients, when symptom severity demands, palliative embolisation is an effective and safe therapy.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 235,
                "text": "cranial dural arteriovenous fistula"
            }
        },
        {
            "context": "A polymorphism study of the human Agouti gene and its association with MC1R. To determine whether the Agouti Signalling Protein (ASP) gene is associated with skin and hair coloration in humans, the complete coding region of ASP was screened for polymorphisms. Analysis of ASP in Caucasian, African-American, Spanish Basque, Hispanic, Apache and Australian Aboriginal populations revealed no amino acid substitutions. A single polymorphism in the 3' untranslated region occurred at a frequency of 0.2 in African-Americans. Variants of the Melanocortin 1 Receptor (MC1R) gene have been found to be associated with red hair and fair skin in humans. Red hair individuals are usually compound heterozygotes or homozygous for one of a number of MC1R polymorphisms associated with red hair. Some individuals however are heterozygous for only one of these polymorphisms and dizygotic twins can be concordant for MC1R variants but discordant for hair colour. A recent study has also identified rare redheads carrying no MC1R variants indicating that polymorphisms of the human MC1R gene are required but not sufficient for the red hair phenotype. To address the question of whether ASP also contributes to the red hair phenotype, individuals previously identified as having unexpected MC1R genotypes were screened for polymorphisms at the ASP locus. No polymorphisms were found in any of these individuals. Results indicate that the human ASP gene is unlikely to function in normal human pigmentation in the same way as MC1R.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 739,
                "text": "MC1R"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1474,
                "text": "XA"
            }
        },
        {
            "context": "Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 175,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 222,
                "text": "xa"
            }
        },
        {
            "context": "The role of LOX and LOXL2 in scar formation after glaucoma surgery. PURPOSE: The aim of this study was to elucidate the role of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) 2 in pathologic wound healing after glaucoma surgery. We therefore investigated the expression of LOX and LOXL2 and evaluated the therapeutic potential of anti-LOX (GS-639556, formerly M64) and anti-LOXL2 (GS-607601, formerly AB0023) antibodies in a rabbit model of glaucoma trabeculectomy. METHODS: Ocular expression of LOX and LOXL2 was investigated by immunohistologic staining at different time points after trabeculectomy. Treatment with GS-639556 or GS-607601 was initiated in rabbits immediately after trabeculectomy by giving both intracameral and subconjunctival injections. Thereafter, the antibodies were given twice a week subconjunctivally until day 30 after surgery (day of euthanization). Treatment outcome was studied by clinical investigation of the bleb and by immunohistochemical analysis of angiogenesis, inflammation, and collagen deposition. RESULTS: LOX and LOXL2 were both upregulated in Tenon's capsule and the conjunctiva after glaucoma surgery. Repeated administration of LOX- or LOXL2-targeting monoclonal antibodies increased bleb area and bleb survival. Analyses of immunohistologic stainings showed that both antibodies significantly decreased fibrosis, whereas the anti-LOXL2 antibody also significantly reduced blood vessel density and inflammation. CONCLUSIONS: Targeting LOXL2 with an inhibitory monoclonal antibody (GS-607601) reduced pathologic angiogenesis, inflammation, and fibrosis. These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.",
            "question": "What is the drug target for Simtuzumab?",
            "answers": {
                "answer_start": 1629,
                "text": "LOXL2"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 57,
                "text": "SLC9A6"
            }
        },
        {
            "context": "[Clinical experience in benzodiazepine antagonist]. Flumazenil, a potent benzodiazepine antagonist, is a newly synthetic imidazo-benzodiazepine, which blocks the neurological effects of benzodiazepines. The purpose of this study was to evaluate the effects of this agent in reversal of benzodiazepine overdose and differentiation of comatous patients with drug overdose. Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration. Three cases with different drug history and variant response after flumazenil treatment were also illustrated and discussed. The dosage of flumazenil used in this study ranged from 0.25 mg to 3 mg (average 0.87 +/- 0.74 mg). We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 639,
                "text": "flumazenil"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 137,
                "text": "thyroid"
            }
        },
        {
            "context": "Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. We used [18F]altanserin and positron emission tomography (PET) to image serotonin 5-HT2A receptors in humans. The highest [18F]altanserin uptake is found in the cerebral cortex, with specific-to-nonspecific binding ratios varying from 0.53 to 1.91 in humans between 24 and 48 years of age. In all neocortical regions studied, [18F]altanserin uptake correlates negatively with age. No correlations were found between age and uptake in the cerebellum, the regional cerebral blood flow, or the time course of metabolization of [18F]altanserin. The reduction in cerebral 5-HT2A receptor binding thus directly reflects the loss of specific 5-HT2A receptors with age.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 25,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled repair. BACKGROUND: In eukaryotic cells, there are two sub-pathways of nucleotide excision repair (NER), the global genome (gg) NER and the transcription-coupled repair (TCR). TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA. This strand-specific repair in a suitable restriction fragment is usually determined by alkaline gel electrophoresis followed by Southern blotting transfer and hybridization with an indirect end-labeled single-stranded probe. Here we describe a new method of TCR assay based on strand-specific-PCR (SS-PCR). Using this method, we have investigated the role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related protein kinases (PIKK) family, in the TCR pathway of UV-induced DNA damage. RESULTS: Although depletion of DNA-PKcs sensitized HeLa cells to UV radiation, it did not affect the ggNER efficiency of UV-induced cyclobutane pyrimidine dimers (CPD) damage. We postulated that DNA-PKcs may involve in the TCR process. To test this hypothesis, we have firstly developed a novel method of TCR assay based on the strand-specific PCR technology with a set of smart primers, which allows the strand-specific amplification of a restricted gene fragment of UV radiation-damaged genomic DNA in mammalian cells. Using this new method, we confirmed that siRNA-mediated downregulation of Cockayne syndrome B resulted in a deficiency of TCR of the UV-damaged dihydrofolate reductase (DHFR) gene. In addition, DMSO-induced silencing of the c-myc gene led to a decreased TCR efficiency of UV radiation-damaged c-myc gene in HL60 cells. On the basis of the above methodology verification, we found that the depletion of DNA-PKcs mediated by siRNA significantly decreased the TCR capacity of repairing the UV-induced CPDs damage in DHFR gene in HeLa cells, indicating that DNA-PKcs may also be involved in the TCR pathway of DNA damage repair. By means of immunoprecipitation and MALDI-TOF-Mass spectrometric analysis, we have revealed the interaction of DNA-PKcs and cyclin T2, which is a subunit of the human transcription elongation factor (P-TEFb). While the P-TEFb complex can phosphorylate the serine 2 of the carboxyl-terminal domain (CTD) of RNA polymerase II and promote transcription elongation. CONCLUSION: A new method of TCR assay was developed based the strand-specific-PCR (SS-PCR). Our data suggest that DNA-PKcs plays a role in the TCR pathway of UV-damaged DNA. One possible mechanistic hypothesis is that DNA-PKcs may function through associating with CyclinT2/CDK9 (P-TEFb) to modulate the activity of RNA Pol II, which has already been identified as a key molecule recognizing and initializing TCR.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 363,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found a marked upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1) expression in human invasive breast carcinoma and metastases to lymph nodes. Compared with non-metastatic breast cancer cells, mitochondria also were more fragmented in metastatic breast cancer cells that express higher levels of total and active Drp1 and less mitochondrial fusion protein 1 (Mfn1). Silencing Drp1 or overexpression of Mfn1 resulted in mitochondria elongation or clusters, respectively, and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silencing Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics altered the subcellular distribution of mitochondria in breast cancer cells. For example, silencing Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silencing Mfn proteins resulted in more cell spreading and lamellipodia formation, causing accumulation of more mitochondria in lamellipodia regions. More importantly, treatment with a mitochondrial uncoupling agent or adenosine triphosphate synthesis inhibitor reduced lamellipodia formation and decreased breast cancer cell migration and invasion, suggesting a functional importance of mitochondria in breast cancer metastasis. Together, our findings show a new role and mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting dysregulated Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing breast cancer metastasis.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 458,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis. When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 418,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Systemic drugs that influence titanium implant osseointegration. Titanium implants are widely used on an increasing number of patients in orthopedic and dental medicine. Despite the good survival rates of these implants, failures that lead to important socio-economic consequences still exist. Recently, research aimed at improving implant fixation, a process called osseointegration, has focused on a new, innovative field: systemic delivery of drugs. Following implant fixation, patients receive systemic drugs that could either impair or enhance osseointegration; these drugs include anabolic and anti-catabolic bone-acting agents in addition to new treatments. Anabolic bone-acting agents include parathyroid hormone (PTH) peptides, simvastatin, prostaglandin EP4 receptor antagonist, vitamin D and strontium ranelate; anti-catabolic bone-acting agents include compounds like calcitonin, biphosphonates, RANK/RANKL/OPG system and selective estrogen receptor modulators (SERM). Examples of the new therapies include DKK1- and anti-sclerostin antibodies. All classes of treatments have proven to possess positive impacts such as an increase in bone mineral density and on osseointegration. In order to prevent complications from occurring after surgery, some post-operative systemic drugs are administered; these can show an impairment in the osseointegration process. These include nonsteroidal anti-inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors. The effects of aspirin, acetaminophen, opioids, adjuvants, anticoagulants and antibiotics in implant fixations are not fully understood, but studies are being carried out to investigate potential ramifications. It is currently accepted that systemic pharmacological agents can either enhance or impair implant osseointegration; therefore, proper drug selection is essential. This review aims to discuss the varying effects of three different classes of treatments on improving this process.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 934,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Continuous-infusion flumazenil in the management of chlordiazepoxide toxicity. Flumazenil is indicated for reversal of sedation from benzodiazepines administered during therapeutic or diagnostic procedures and during induction or maintenance of general anesthesia, as well as for benzodiazepine overdose. Bolus doses of flumazenil are usually adequate to achieve reversal; however, when medical conditions may lead to a prolonged half-life of the benzodiazepine involved, continuous infusion may be warranted. A 67-year-old man with chlordiazepoxide toxicity required a 9-day infusion of flumazenil to prevent resedation and respiratory insufficiency; he initially was admitted to the hospital for alcohol detoxification. Concomitant medical conditions and the metabolism characteristics of each benzodiazepine must dictate the agent of choice. When measures are required to ensure adequate recovery of a patient's respiratory function and mental awareness, such as in patients with benzodiazepine toxicity, consideration of continuous-infusion flumazenil is warranted.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1045,
                "text": "flumazenil"
            }
        },
        {
            "context": "[Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina]. Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV-hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 116,
                "text": "hypertension"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 805,
                "text": "tyr"
            }
        },
        {
            "context": "Hereditary conjugated hyperbilirubinaemia: 37 years later. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 636,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.",
            "question": "Does dasatinib promote or inhibit T-cell proliferation?",
            "answers": {
                "answer_start": 63,
                "text": "inhibits"
            }
        },
        {
            "context": "DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 694,
                "text": "FSHD"
            }
        },
        {
            "context": "[Puffy hand syndrome in drug addiction treated by low-stretch bandages]. BACKGROUND: Puffy hand syndrome is a complication of intravenous drug abuse, which has no current available treatment. Arm and forearm edema are voluminous and cause functional and aesthetic disturbances. We report two cases successfully treated by low-stretch bandages. OBSERVATIONS: A 40-year-old man and a 34-year-old woman, both intravenous drug users, with puffy hand syndrome were hospitalized for 11 days. Treatment included daily multilayer bandaging. Lymphedema volumes calculated by utilizing the formula for a truncated cone decreased by 16% on the left side and 12% on the right side for the first patient and 31 and 17% for the second. Hand circumference decreased 4.3 cm on the left side and 3.2 cm on the right side in case 1, and 2.5 cm and 1.9 cm respectively for case 2. The patients were taught self-bandaging techniques during their hospital stays. Elastic gloves were fitted at the end of treatment. Reduction of lymphedema volume remained stable after 18 months in one patient while for the second patient further treatment and hospitalization were required due to poor compliance. DISCUSSION: The pathogenesis of this edema is probably multifactorial: venous, lymphatic insufficiency and the direct toxicity of injected drugs. Lymphedema treatment currently consists of low-stretch bandaging and wearing elastic garments, which is effective in decreasing the volume of puffy hand syndrome.",
            "question": "What causes \"Puffy hand syndrome\"?",
            "answers": {
                "answer_start": 126,
                "text": "intravenous drug abuse"
            }
        },
        {
            "context": "Oligomeric interactions between phospholamban molecules regulate Ca-ATPase activity in functionally reconstituted membranes. Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, and functions as an endogenous inhibitor of Ca-ATPase transport activity. To identify whether oligomeric interactions between PLB molecules are involved in regulating Ca-ATPase transport activity, we have investigated functional interactions between PLB and the Ca-ATPase in proteoliposomes of purified PLB functionally co-reconstituted with the SERCA2a isoform of the Ca-ATPase isolated from cardiac sarcoplasmic reticulum (SR). The calcium sensitivity of this reconstituted preparation and functional stimulation by cAMP-dependent protein kinase (PKA) are virtually identical to those of the Ca-ATPase in cardiac SR microsomes, ensuring the functional relevance of this reconstituted preparation. Interactions between PLB molecules were measured following covalent modification of the single lysine (i.e., Lys(3)) in PLB isolated from cardiac SR membranes with fluorescein isothiocyanate (FITC) prior to co-reconstitution with the Ca-ATPase. FITC modification of PLB does not interfere with the ability of PLB to inhibit the Ca-ATPase, since FITC-PLB co-reconstituted with the Ca-ATPase exhibits a similar calcium dependence of Ca-ATPase activation to that observed in native SR membranes. Thus, the functional arrangement of PLB with the Ca-ATPase is not modified by FITC modification. Using changes in the anisotropy of FITC-PLB resulting from fluorescence resonance energy transfer (FRET) between proximal PLB molecules to measure the average size and spatial arrangement of FITC chromophores, we find that PLB self-associates to form oligomers whose spatial arrangement with respect to one another is in agreement with earlier suggestions that PLB exists predominantly as a homopentamer. The inability of PKA to activate PLB following covalent modification with FITC permits functional interactions between PLB molecules associated with the Ca-ATPase activation to be identified. A second-order loss of Ca-ATPase activation by PKA is observed as a function of the fractional contribution of FITC-PLB, indicating that PKA-dependent activation of two PLB molecules within a quaternary complex containing the Ca-ATPase is necessary for activation of the Ca-ATPase. We suggest that the requirement for activation of two PLB molecules by PKA represents a physiological mechanism to ensure that activation of the Ca-ATPase following beta-adrenergic stimulation in the heart only occurs above a threshold level of PKA activation.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 140,
                "text": "PLB"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 572,
                "text": "coilin"
            }
        },
        {
            "context": "Simple polymerase chain reaction for the detection of mutations and deletions in the epidermal growth factor receptor gene: applications of this method for the diagnosis of non-small-cell lung cancer. BACKGROUND: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the responses to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with non-small-cell lung cancer (NSCLC). Although various methods for detecting EGFR gene mutations have been developed, they have several disadvantages. We attempted to establish a new method for the detection of EGFR gene mutations with the use of paraffin-embedded samples. METHODS: The detections of T790M mutations in exon 20 and L858R mutations in exon 21 are based on the principle of allele-specific oligonucleotide polymerase chain reaction (PCR). We also designed PCR primers that enable to detect all types of deletions in exon 19. We assessed the basic performance efficiency of this method, and to confirm its clinical applicability, we performed PCR using DNA extracted from 66 tissue sections that were obtained from patients with NSCLC and embedded in paraffin. RESULTS: The sensitivity of this method for the detection of deletions or mutations was as low as 0.5%. In the 66 subjects whose samples were analyzed, we detected the following deletions and mutations in the EGFR gene: 11 deletions in exon 19, 8 L858R mutations, and 1 double mutation of L858R and T790M. CONCLUSION: The present method is sensitive and specific for the detection of deletions and mutations in the EGFR gene and is thus suitable for use in laboratory tests.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 238,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Immunotherapy for Gastric Cancer: A Focus on Immune Checkpoints. Gastric cancer (GC) is a major world-wide health problem. It is the third leading cause of death from cancer. The treatment of advanced GC by chemotherapy has limited efficacy. The addition of some targeted therapies like trastuzumab and ramucirumab have added a modest benefit, but only in human epidermal growth factor receptor 2 (ERBB2 or HER2)-positive patients and in the second-line setting, respectively. The development of new and effective therapeutic strategies must consider the genetic complexity and heterogeneity of GC; prognostic and predictive biomarkers should be identified for clinical implementation. Immune deregulation has been associated with some GC subtypes, especially those that are associated with virus infection and those with a high mutational rate. Different mechanisms to prevent immunologic escape have been characterized during the last years; in particular the PD-1/PD-L1 inhibitors pembrolizumab, avelumab, durvalumab and atezolizumab have shown early sign of efficacy. Therefore, immunotherapeutic strategies may provide new opportunities for GC patients. This review will discuss (1) the main characteristics of GC treatment, (2) the immune response in GC, and (3) the current status of immune-related strategies in clinical development in GC patients, focusing on immune checkpoints therapies.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 967,
                "text": "PD-L1"
            }
        },
        {
            "context": "Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women. Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 85,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1136,
                "text": "telomerase"
            }
        },
        {
            "context": "Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome's epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells.",
            "question": "Do A-type lamins bind euchromatin or heterochromatin?",
            "answers": {
                "answer_start": 790,
                "text": "both euchromatin and heterochromatin"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 2123,
                "text": "fungi"
            }
        },
        {
            "context": "Translational efficiency in patients with Diamond-Blackfan anemia. BACKGROUND AND OBJECTIVES: Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. Ribosomal protein S19 (RPS19), currently the only gene associated with DBA, is mutated in 25% of DBA patients, but its role in erythropoiesis is unknown. We attempted to elucidate the importance of RPS19 in translation in relation to the pathogenesis of DBA. DESIGN AND METHODS: We measured translation and proliferation rates in unstimulated and phytohemagglutinin (PHA)-stimulated lymphocytes isolated from DBA patients, as well as in K562 cells expressing several RPS19 mutants to directly test the effect of RPS19 mutations on translation. The effect of leucine on overall translation was also studied. RESULTS: We found that the level of translation was on average 48-73% of controls in both unstimulated and PHA-activated DBA lymphocytes irrespective of mutations in RPS19. The addition of leucine increased the translational level in RPS19-non-mutated DBA cells, but not in cells with an RPS19 mutation. In unstimulated DBA cells, proliferation was significantly impaired in both RPS19-mutated and non-mutated cells, but in both groups could be efficiently activated by PHA. Studies on K562 cells showed that RPS19 mutations affecting RPS19 conserved arginines R56Q and R62Q could significantly inhibit the rate of protein synthesis, indicating the importance of RPS19 in translation. INTERPRETATION AND CONCLUSIONS: Our results indicate that inefficient translation may be the main cause of DBA, and administration of leucine may be beneficial for at least some DBA patients.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 415,
                "text": "DBA"
            }
        },
        {
            "context": "A phenome-based functional analysis of transcription factors in the cereal head blight fungus, Fusarium graminearum. Fusarium graminearum is an important plant pathogen that causes head blight of major cereal crops. The fungus produces mycotoxins that are harmful to animal and human. In this study, a systematic analysis of 17 phenotypes of the mutants in 657 Fusarium graminearum genes encoding putative transcription factors (TFs) resulted in a database of over 11,000 phenotypes (phenome). This database provides comprehensive insights into how this cereal pathogen of global significance regulates traits important for growth, development, stress response, pathogenesis, and toxin production and how transcriptional regulations of these traits are interconnected. In-depth analysis of TFs involved in sexual development revealed that mutations causing defects in perithecia development frequently affect multiple other phenotypes, and the TFs associated with sexual development tend to be highly conserved in the fungal kingdom. Besides providing many new insights into understanding the function of F. graminearum TFs, this mutant library and phenome will be a valuable resource for characterizing the gene expression network in this fungus and serve as a reference for studying how different fungi have evolved to control various cellular processes at the transcriptional level.",
            "question": "The pathogen Fusarium graminearum affects what type of plant species?",
            "answers": {
                "answer_start": 202,
                "text": "cereal crops"
            }
        },
        {
            "context": "Aerial dispersal of meticillin-resistant Staphylococcus aureus in hospital rooms by infected or colonised patients. The aim of this study was to assess to what extent patients with meticillin-resistant Staphylococcus aureus (MRSA) at respiratory sites shed viable MRSA into the air of hospital rooms. We also evaluated whether the distance from the patient could influence the level of contamination. Air sampling was performed directly onto MRSA-selective agar in 24 hospital rooms containing patients with MRSA colonization or infection of the respiratory tract. Samplings were performed in duplicate at 0.5, 1 and 2-3 m from the patients' heads. Clinical and environmental isolates were compared using antimicrobial resistance patterns and pulsed-field gel electrophoresis. MRSA strains were isolated from 21 out of 24 rooms, in quantities varying from between 1 and 78 cfu/m3. In each of the 21 rooms, at least one of the environmental isolates was identical to a clinical isolate from the patient in that room. There was no significant difference in MRSA counts between the distance from the patient's head and the sampler. This study demonstrates that most patients with MRSA infection or colonisation of the respiratory tract shed viable MRSA into the air of their room. The results emphasise the need to study MRSA in air in more detail in order to improve infection control recommendations.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 225,
                "text": "MRSA"
            }
        },
        {
            "context": "Transrectal ultrasound versus cystography in the evaluation of anatomical stress urinary incontinence. Thirty-two female patients with clinical and urodynamic findings of genuine stress urinary incontinence were evaluated before and 6 months after surgery for stress urinary incontinence. Twenty-nine control patients had identical evaluations before and 6 months after surgery which did not involve the urethrovesical junction. Twenty-four patients with primary bladder instability had similar evaluations and served as a second control group. Anatomical landmarks indicating support to the urethrovesical junction were evaluated by the position of the urethra at the most dependent point in the bladder on straining and the urethral descent on straining to beneath the posterior ramus of the symphysis pubis on bead chain cystography. The urethrovesical junction drop on straining was evaluated by transrectal ultrasonography. Cystographic and ultrasonographic tests for the position of the urethrovesical junction at the most dependent position in the bladder during straining were very sensitive in women with stress urinary incontinence (94 and 87% respectively) but much less specific (45 and 48% respectively). When evaluating anatomical support to the urethrovesical junction and its descent on straining, these tests were both highly sensitive (97 and 94% respectively) and specific (76 and 96% respectively) in women with genuine stress urinary incontinence. Simple clinical tests for support of the urethrovesical junction, such as the Q tip test, are non-specific in patients with stress urinary incontinence. Transrectal ultrasonography is a simple and quick out-patient procedure. The availability of ultrasound equipment in most clinics and the high sensitivity and specificity of the test make it an attractive and cost-effective alternative to X-ray cystography in the pre-operative evaluation of anatomical support to the urethrovesical junction.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 1593,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 757,
                "text": "53BP1"
            }
        },
        {
            "context": "Structural comparison of mouse and human α-synuclein amyloid fibrils by solid-state NMR. Fibrillar α-synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Mouse AS (mAS) aggregates much faster than human AS (hAS), although mAS differs from hAS at only seven positions in its primary sequence. Currently, little is known about the site-specific structural differences between mAS and hAS fibrils. Here, we applied state-of-the-art solid-state nuclear magnetic resonance (ssNMR) methods to structurally characterize mAS fibrils. The assignment strategy employed a set of high-resolution 2D and 3D ssNMR spectra recorded on uniformly [(13)C, (15)N], [1-(13)C]glucose, and [2-(13)C]glucose labeled mAS fibrils. An almost complete resonance assignment (96% of backbone amide (15)N and 93% of all (13)C nuclei) was obtained for residues from Gly41 to Val95, which form the core of mAS fibrils. Six β-strands were identified to be within the fibril core of mAS based on a secondary chemical shift and NHHC analysis. Intermolecular (13)C:(15)N labeled restraints obtained from mixed 1:1 (13)C/(15)N-labeled mAS fibrils reveal a parallel, in-register supramolecular β-sheet arrangement. The results were compared in detail to recent structural studies on hAS fibrils and indicate the presence of a structurally conserved motif comprising residues Glu61-Lys80.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 99,
                "text": "α-synuclein"
            }
        },
        {
            "context": "Molecular mechanisms of selective estrogen receptor modulator (SERM) action. In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER alpha or ER beta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 414,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 127,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Skin layer-specific transcriptional profiles in normal and recessive yellow (Mc1re/Mc1re) mice. The melanocortin 1 receptor (Mc1r) plays a central role in cutaneous biology, but is expressed at very low levels by a small fraction of cells in the skin. In humans, loss-of-function MC1R mutations cause fair skin, freckling, red hair, and increased predisposition to melanoma; in mice, Mc1r loss-of-function is responsible for the recessive yellow mutation, associated with pheomelanic hair and a decreased number of epidermal melanocytes. To better understand how Mc1r signaling affects different cutaneous phenotypes, we examined large-scale patterns of gene expression in different skin components (whole epidermal sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and recessive yellow mice, starting with a 26K mouse cDNA microarray. From c. 17 000 genes whose levels could be accurately measured in neonatal skin, we identified 883, 2097 and 552 genes that were uniquely expressed in the suprabasal epidermis, basal epidermis and dermis, respectively; specific biologic roles could be assigned for each class. Comparison of normal and recessive yellow mice revealed 69 differentially expressed genes, of which the majority had not been previously implicated in Mc1r signaling. Surprisingly, many of the Mc1r-dependent genes are expressed in cells other than melanocytes, even though Mc1r expression in the skin is confined almost exclusively to epidermal melanocytes. These results reveal new targets for Mc1r signaling, and point to a previously unappreciated role for a Mc1r-dependent paracrine effect of melanocytes on other components of the skin.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 280,
                "text": "MC1R"
            }
        },
        {
            "context": "Can sudden cardiac death be prevented? Hypertrophic cardiomyopathy is regarded as the most common cause of sudden cardiac death in young people (including trained athletes). Introduction of implantable cardioverter-defibrillators to the hypertrophic cardiomyopathy patient population represents a new paradigm for clinical practice and perhaps the most significant advance in the management of this disease to date. Implantable defibrillators offer the only proven protection against sudden death by virtue of effectively terminating ventricular tachycardia/fibrillation and, in the process, altering the natural history of hypertrophic cardiomyopathy and providing the potential opportunity of normal or near-normal longevity for many patients. However, targeting the most appropriate candidates for prophylactic device therapy can be complex, compounded by the unpredictability of the underlying arrhythmogenic substrate, absence of a single dominant and quantitative risk marker in this heterogeneous disease, and the historical difficulty in assembling sufficiently powered prospective and randomized trials in large patient populations. Nevertheless, the current risk factor algorithm, when combined with a measure of individual physician judgment, is an effective strategy for identifying high-risk patients. Indeed, prevention of sudden death has now become an integral, albeit challenging, component of overall hypertrophic cardiomyopathy management.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 39,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Essential molecular determinants for thyroid hormone transport and first structural implications for monocarboxylate transporter 8. Monocarboxylate transporter 8 (MCT8, SLC16A2) is a thyroid hormone (TH) transmembrane transport protein mutated in Allan-Herndon-Dudley syndrome, a severe X-linked psychomotor retardation. The neurological and endocrine phenotypes of patients deficient in MCT8 function underscore the physiological significance of carrier-mediated TH transmembrane transport. MCT8 belongs to the major facilitator superfamily of 12 transmembrane-spanning proteins and mediates energy-independent bidirectional transport of iodothyronines across the plasma membrane. Structural information is lacking for all TH transmembrane transporters. To gain insight into structure-function relations in TH transport, we chose human MCT8 as a paradigm. We systematically performed conventional and liquid chromatography-tandem mass spectrometry-based uptake measurements into MCT8-transfected cells using a large number of compounds structurally related to iodothyronines. We found that human MCT8 is specific for L-iodothyronines and requires at least one iodine atom per aromatic ring. Neither thyronamines, decarboxylated metabolites of iodothyronines, nor triiodothyroacetic acid and tetraiodothyroacetic acid, TH derivatives lacking both chiral center and amino group, are substrates for MCT8. The polyphenolic flavonoids naringenin and F21388, potent competitors for TH binding at transthyretin, did not inhibit T(3) transport, suggesting that MCT8 can discriminate its ligand better than transthyretin. Bioinformatic studies and a first molecular homology model of MCT8 suggested amino acids potentially involved in substrate interaction. Indeed, alanine mutation of either Arg(445) (helix 8) or Asp(498) (helix 10) abrogated T(3) transport activity of MCT8, supporting their predicted role in substrate recognition. The MCT8 model allows us to rationalize potential interactions of amino acids including those mutated in patients with Allan-Herndon-Dudley syndrome.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 183,
                "text": "thyroid"
            }
        },
        {
            "context": "Primary microRNA processing is functionally coupled to RNAP II transcription in vitro. Previous studies in vivo reported that processing of primary microRNA (pri-miRNA) is coupled to transcription by RNA polymerase II (RNAP II) and can occur co-transcriptionally. Here we have established a robust in vivo system in which pri-miRNA is transcribed by RNAP II and processed to pre-miRNA in HeLa cell nuclear extracts. We show that both the kinetics and efficiency of pri-miRNA processing are dramatically enhanced in this system compared to that of the corresponding naked pri-miRNA. Moreover, this enhancement is general as it occurs with multiple pri-miRNAs. We also show that nascent pri-miRNA is efficiently processed before it is released from the DNA template. Together, our work directly demonstrates that transcription and pri-miRNA processing are functionally coupled and establishes the first in vivo model systems for this functional coupling and for co-transcriptional processing.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 200,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "[Daratumumab--breakthrough drug in multiple myeloma therapy]. Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 181,
                "text": "CD38"
            }
        },
        {
            "context": "Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], > 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 158,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "[Cryptococcal meningitis]. BACKGROUND: Cryptococcus neoformans causes systemic disease in patients with immunodeficiency. The incidence of cryptococcal meningitis has increased in parallel with that of HIV infection. Cancer is also a known predisposing factor. MATERIAL AND METHODS: We present two case reports and a review of the literature concerning the epidemiology, diagnostics and treatment of cryptococcal meningitis. RESULTS: The incidence of cryptococcal meningitis in Scandinavia seems to be lower than in other parts of the world. Clinical signs and symptoms are often uncharacteristic. Detection of antigen in spinal fluid is a sensitive and fast test. INTERPRETATION: Cryptococcal meningitis is a rare disease, often with uncharacteristic symptoms. Patients with haematological malignancies have a higher risk of contracting this disease. It is a differential diagnosis when neurological symptoms occur in these patients.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 202,
                "text": "HIV infection"
            }
        },
        {
            "context": "Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1β. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-α. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 365,
                "text": "LEKTI"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 900,
                "text": "GBshape"
            }
        },
        {
            "context": "Targeted chronic myeloid leukemia therapy: seeking a cure. BACKGROUND: Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCR-ABL fusion protein that arises from the translocation of chromosomes 9 and 22. The disease begins with an indolent chronic phase (CP) that can last for 3 to 5 years. If untreated, it progresses into accelerated phase (AP) and within a year, blast phase (BP). Survival at this point is less than 1 year. during disease progression, mutations and the Philadelphia chromosome (Ph) appear (a process called clonal evolution). The only known curative therapy for CML is allogeneic bone marrow transplant (BMT). However, toxicity is formidable, with treatment- related mortality reported in the 30% range. Thus, effective therapy that maintains the patient with CML in CP with minimal toxicity is the goal for treatment of modern therapies. Because the preeminent mutation driving CML is BCr-ABL, therapies targeting BCR-ABL are the logical choice for disease-specific therapy. BCR-ABL inhibitors, such as imatinib, are proof that targeting specific genetic mutations associated with cancer yields a high degree of efficacy with minimal toxicity. OBJECTIVE: This review will outline the evolution of therapy in CML. Preimatinib and imatinib-based treatment strategies, clinical efficacy, and the mechanism of imatinib resistance will be discussed. SUMMARY: The discovery of the Ph and, subsequently, the identification of BCr-ABL revolutionized the treatment of CML. Cytoreductive chemotherapy, such as busulfan and hydroxyurea, was a mainstay of therapy to control white blood cell (WBC) counts; however, it did not modify the progression of the disease to AP and BP. The overall survival with CML ranges from 45 to 58 months in patients treated with cytoreductive therapy only. Treatment was advanced with the introduction of interferon (IFn ) immunotherapy in the 1980s. In some studies, IFn produced a complete hematologic response (CHR) in more than 50% of patients; however, its nonspecific immunostimulatory mechanism also produced severe flulike symptoms that limited tolerability. despite the significant toxicity, cost, and inconvenience of injecting IFN thrice weekly, median survival ranged from 60 to 89 months. Allogeneic BMT is the only known curative therapy for CML; however, treatment-related mortality from infection, bleeding, and graft versus host disease, age, and the availability of suitable donors limits its widespread use. Imatinib functions by competing with adenosine triphosphate (ATP) for binding to the BCr-ABL tyrosine kinase. In the absence of ATP, BCR-ABL is not able to activate downstream effector tyrosine kinase molecules that drive wBC proliferation. The International randomized Interferon versus STI571 clinical trial was the first to document the efficacy of imatinib as a first-line therapy for patients in CP. More than 90% of these patients had a CHr. Toxicities associated with this therapy are low. response in patients with advanced CML is less pronounced than in CP and is shorter lived, with less than 30% of patients achieving a CHR. For patients with CML in BP, the only viable therapy is to attempt a temporary reduction in disease burden with a salvage chemotherapy regimen, such as VAC (etoposide, cytarabine, and carboplatin). The goal of this induction chemotherapy is to induce a second remission; then the patient may be considered for allogeneic BMT. The main toxicities seen with imatinib therapy are myelosuppression, edema, and myalgia/arthralgia. In many cases, imatinib dosage can be briefly halted or lowered while the toxicity is managed. Imatinib resistance may develop at any time and inevitably leads to disease progression. resistance is usually caused by mutations within BCr-ABL, decreasing the affinity of imatinib binding. next-generation kinase inhibitors are focused on the ability to inhibit these mutated forms of BCR-ABL. CONCLUSION: For the majority of patients with CML in CP, the standard of care is to maintain the patient in CP with imatinib therapy. Clinical trials have been extraordinarily successful, with 5-year survival rates greater than 90%. Allogeneic BMT continues to be an option for those who cannot tolerate imatinib or when CML progresses on imatinib therapy.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 1028,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data?",
            "answers": {
                "answer_start": 476,
                "text": "diffloop"
            }
        },
        {
            "context": "Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis. Epilepsy, a neurologic disorder characterized by the predisposition to recurrent unprovoked seizures, is reported in more than 300 genetic syndromes. Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion. Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Epilepsy rarely occurs in individuals with Muenke syndrome, and little detail is reported on types of epilepsy, patient characteristics, and long-term outcomes. We present seven patients with Muenke syndrome and seizures. A review of 789 published cases of Muenke syndrome, with a focus on epilepsy and intracranial anomalies in Muenke syndrome, revealed epilepsy in six patients, with intracranial anomalies in five. The occurrence of epilepsy in Muenke syndrome within our cohort of 58 patients, of whom seven manifested epilepsy, and the intracranial anomalies and epilepsy reported in the literature, suggest that patients with Muenke syndrome may be at risk for epilepsy and intracranial anomalies. Furthermore, the impact of Muenke syndrome on the central nervous system may be greater than previously thought.",
            "question": "Which gene is associated with Muenke syndrome?",
            "answers": {
                "answer_start": 540,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Germline mutations of the breast cancer 1 (BRCA1) gene are a major cause of familial breast and ovarian cancer. The BRCA1 protein displays E3 ubiquitin ligase activity, and this enzymatic function is thought to be required for tumor suppression. To test this hypothesis, we generated mice that express an enzymatically defective Brca1. We found that this mutant Brca1 prevents tumor formation to the same degree as does wild-type Brca1 in three different genetically engineered mouse (GEM) models of cancer. In contrast, a mutation that ablates phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicits tumors in each of the three GEM models. Thus, BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression.",
            "question": "What is the enzymatic activity of the breast cancer associated gene BRCA1?",
            "answers": {
                "answer_start": 235,
                "text": "E3 ubiquitin ligase activity"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 1005,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2889,
                "text": "5-HT2A"
            }
        },
        {
            "context": "International Consultation on Incontinence-Research Society (ICI-RS) report on non-invasive urodynamics: the need of standardization of ultrasound bladder and detrusor wall thickness measurements to quantify bladder wall hypertrophy. INTRODUCTION: Ultrasonic measurements of urinary bladders are suitable to quantify bladder wall hypertrophy due to bladder outlet obstruction, detrusor overactivity, or neurogenic bladder dysfunction in adult men or women and in children. Quantification of bladder wall hypertrophy seems to be useful for the assessment of diseases, prediction of treatment outcomes, and longitudinal studies investigating disease development and progression. MEASUREMENT TECHNIQUES: Four distinct measurement techniques have been published using bladder wall thickness (BWT), detrusor wall thickness (DWT), or ultrasound-estimated bladder weight (UEBW) assessed by suprapubic or transvaginal positioning of ultrasound probes and different bladder filling volumes. As a result, different threshold and reference values were established causing confusion. This ICI-RS report summarizes the agreements of different research groups in terms of ultrasonic BWT or DWT measurements, critically discusses the four ultrasonic measurement techniques, suggests criteria for quality control, and proposes future research activities to unify measurement strategies. PROPOSED STANDARDIZATION AND RESEARCH: For quality control, all future reports should provide information about frequency of the ultrasound probe, bladder filling volume at measurement, if BWT, DWT, or UEBW was measured, enlargement factor of the ultrasound image, and one ultrasound image with marker positioning. The ICI-RS intends to found a standardization committee that will initiate and judge studies on ultrasonic bladder wall measurements to clarify the most suitable, most accurate, and least invasive measurement technique.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 136,
                "text": "ultrasound"
            }
        },
        {
            "context": "Targeted chronic myeloid leukemia therapy: seeking a cure. BACKGROUND: Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCR-ABL fusion protein that arises from the translocation of chromosomes 9 and 22. The disease begins with an indolent chronic phase (CP) that can last for 3 to 5 years. If untreated, it progresses into accelerated phase (AP) and within a year, blast phase (BP). Survival at this point is less than 1 year. during disease progression, mutations and the Philadelphia chromosome (Ph) appear (a process called clonal evolution). The only known curative therapy for CML is allogeneic bone marrow transplant (BMT). However, toxicity is formidable, with treatment- related mortality reported in the 30% range. Thus, effective therapy that maintains the patient with CML in CP with minimal toxicity is the goal for treatment of modern therapies. Because the preeminent mutation driving CML is BCr-ABL, therapies targeting BCR-ABL are the logical choice for disease-specific therapy. BCR-ABL inhibitors, such as imatinib, are proof that targeting specific genetic mutations associated with cancer yields a high degree of efficacy with minimal toxicity. OBJECTIVE: This review will outline the evolution of therapy in CML. Preimatinib and imatinib-based treatment strategies, clinical efficacy, and the mechanism of imatinib resistance will be discussed. SUMMARY: The discovery of the Ph and, subsequently, the identification of BCr-ABL revolutionized the treatment of CML. Cytoreductive chemotherapy, such as busulfan and hydroxyurea, was a mainstay of therapy to control white blood cell (WBC) counts; however, it did not modify the progression of the disease to AP and BP. The overall survival with CML ranges from 45 to 58 months in patients treated with cytoreductive therapy only. Treatment was advanced with the introduction of interferon (IFn ) immunotherapy in the 1980s. In some studies, IFn produced a complete hematologic response (CHR) in more than 50% of patients; however, its nonspecific immunostimulatory mechanism also produced severe flulike symptoms that limited tolerability. despite the significant toxicity, cost, and inconvenience of injecting IFN thrice weekly, median survival ranged from 60 to 89 months. Allogeneic BMT is the only known curative therapy for CML; however, treatment-related mortality from infection, bleeding, and graft versus host disease, age, and the availability of suitable donors limits its widespread use. Imatinib functions by competing with adenosine triphosphate (ATP) for binding to the BCr-ABL tyrosine kinase. In the absence of ATP, BCR-ABL is not able to activate downstream effector tyrosine kinase molecules that drive wBC proliferation. The International randomized Interferon versus STI571 clinical trial was the first to document the efficacy of imatinib as a first-line therapy for patients in CP. More than 90% of these patients had a CHr. Toxicities associated with this therapy are low. response in patients with advanced CML is less pronounced than in CP and is shorter lived, with less than 30% of patients achieving a CHR. For patients with CML in BP, the only viable therapy is to attempt a temporary reduction in disease burden with a salvage chemotherapy regimen, such as VAC (etoposide, cytarabine, and carboplatin). The goal of this induction chemotherapy is to induce a second remission; then the patient may be considered for allogeneic BMT. The main toxicities seen with imatinib therapy are myelosuppression, edema, and myalgia/arthralgia. In many cases, imatinib dosage can be briefly halted or lowered while the toxicity is managed. Imatinib resistance may develop at any time and inevitably leads to disease progression. resistance is usually caused by mutations within BCr-ABL, decreasing the affinity of imatinib binding. next-generation kinase inhibitors are focused on the ability to inhibit these mutated forms of BCR-ABL. CONCLUSION: For the majority of patients with CML in CP, the standard of care is to maintain the patient in CP with imatinib therapy. Clinical trials have been extraordinarily successful, with 5-year survival rates greater than 90%. Allogeneic BMT continues to be an option for those who cannot tolerate imatinib or when CML progresses on imatinib therapy.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 152,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica (Bazex syndrome) presenting in a patient with metastatic breast carcinoma: possible etiologic role of zinc. BACKGROUND: Bazex syndrome (acrokeratosis paraneoplastica) is a rare paraneoplastic syndrome that usually occurs in males over 40 years old and is particularly associated with squamous cell carcinoma of the upper aerodigestive tract and adenopathy above the diaphragm. OBJECTIVE: The objectives of our article are (1) to describe a unique case of acrokeratosis paraneoplastica and (2) to review the current literature regarding skin findings, commonly associated neoplasms, and treatment options relative to this condition. PATIENT: We describe a 68-year-old female with lobular breast carcinoma, complicated by local and distant recurrences, who presented with a 1-year history of prominent acral skin and nail changes. RESULTS: Our patient's clinical skin findings improved significantly following treatment and partial remission of her underlying malignancy. CONCLUSIONS: Our patient represents one of few females described with this syndrome, which is especially rare in association with lobular breast carcinoma. Further, the patient's presentation is unique as she was discovered to demonstrate laboratory findings consistent with coexistent porphyria cutanea tarda and relative zinc deficiency.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 150,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "The essential function of Swc4p - a protein shared by two chromatin-modifying complexes of the yeast Saccharomyces cerevisiae - resides within its N-terminal part. The Swc4p protein, encoded by an essential gene, is shared by two chromatin-remodeling complexes in Saccharomyces cerevisiae cells: NuA4 (nucleosome acetyltransferase of H4) and SWR1. The SWR1 complex catalyzes ATP-dependent exchange of the nucleosomal histone H2A for H2AZ (Htz1p). The activity of NuA4 is responsible mainly for the acetylation of the H4 histone but also for the acetylation of H2A and H2AZ. In this work we investigated the role of the Swc4p protein. Using random mutagenesis we isolated a collection of swc4 mutants and showed that the essential function of Swc4p resides in its N-terminal part, within the first 269 amino acids of the 476-amino acid-long protein. We also demonstrated that Swc4p is able to accommodate numerous mutations without losing its functionality under standard growth conditions. However, when swc4 mutants were exposed to methyl methanesulfonate (MMS), hydroxyurea or benomyl, severe growth deficiencies appeared, pointing to an involvement of Swc4p in many chromatin-based processes. The mutants' phenotypes did not result from an impairment of histone acetylation, as in the mutant which bears the shortest isolated variant of truncated Swc4p, the level of overall H4 acetylation was unchanged.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 342,
                "text": "SWR1"
            }
        },
        {
            "context": "JTV-519 Japan Tobacco. Japan Tobacco is developing the mixed action ion channel blocker, JTV-519, which has potential use as an antiarrhythmic [285800]. The drug is a novel cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were completed in the third quarter of 1998; phase II trials started in the fourth quarter of 1998 for the potential treatment of myocardial infarction [320195]. Studies have shown that JTV-519 has a strong cardioprotective effect against catecholamine-induced myocardial injury and against ischemia/reperfusion injury [316749]. In experimental myofibrillar overcontraction models, it demonstrated greater cardioprotectant effects than propranolol, verapamil and diltiazem [171668].",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 204,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1586,
                "text": "FSHD"
            }
        },
        {
            "context": "[Analysis of the small supernumerary marker chromosome in Turner syndrome with 45, X/46, X, + mar karyotype]. OBJECTIVE: To identify the origin and study the morphology of small supernumerary marker chromosome (sSMC) in Turner syndrome with 45, X/46, X, + mar karyotype. METHODS: Using the conventional chromosome G-banding technique, 10 cases of Turner syndrome with 45, X/46, X, + mar chromosome karyotype were obtained, dual-color fluorescence in situ hybridization was applied to study the origin and morphology of the sSMC. RESULTS: In the 10 cases of Turner syndrome with 45, X/46, X, + mar karyotype, the sSMC of 7 cases was derived from X chromosome [sSMC(X)], the sSMC of 2 cases was derived from Y chromosome [sSMC(Y)] and the remaining 1 case was derived from the autosome. There were 4 cases of ring(r) chromosomes and 3 of centric minutes (min) in the 7 sSMC (X) cases. In the 2 sSMC(Y), one case was dicentric (dic) and the other was centric minute (min). The sSMC originated from the autosome was a centric minute (min). CONCLUSION: The origin of sSMC of Turner syndrome with 45, X/46, X, + mar karyotype was almost all from sex chromosomes, and rarely from autosomes. sSMC can exist as isodicentric, ring, or centric minute. The molecular cytogenetic features of the sSMC can provide useful information for genetic counseling, prenatal diagnosis and treatment of the Turner syndrome patients with a 45, X/46, X, + mar karyotype.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 251,
                "text": "X"
            }
        },
        {
            "context": "The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na+-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep<ob>/WiscJ (BTBR ob/ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ob mice received 1 μg·kg body wt(-1)·day(-1) ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 4,
                "text": "SGLT2"
            }
        },
        {
            "context": "Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. OBJECTIVE: In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). METHODS: The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED. RESULTS: Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions. CONCLUSIONS: These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 221,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 1004,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Teriflunomide for the treatment of multiple sclerosis. Teriflunomide is a new active drug which has recently been approved as a first-line treatment of relapsing forms of MS in the US, Australia, Argentina, and the European Union. It is characterized by a once-daily oral application and a well-established long-term safety profile. The main therapeutic effect is considered to be mediated via the inhibition of the de novo synthesis of pyrimidine in proliferating immune cells. Two phase III clinical trials (TEMSO, TOWER) tested teriflunomide in patients with relapsing forms of MS: efficacy was shown, with positive effects on relapse rates and disease progression for 14 mg/day. Overall, the safety profile in these studies was favorable. In patients treated with teriflunomide, the regular monitoring of blood cell counts and liver enzymes is required. Teriflunomide must not be used during pregnancy. In this article, we review recent phase II and phase III clinical trial data, and discuss the potential of teriflunomide for the treatment of relapsing forms of MS.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 531,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Expression and Structural Analyses of Human DNA Polymerase θ (POLQ). DNA polymerase theta (pol θ) is an evolutionarily conserved protein encoded by the POLQ gene in mammalian genomes. Pol θ is the defining enzyme for a pathway of DSB repair termed \"alternative end-joining\" (altEJ) or \"theta-mediated end-joining.\" This pathway contributes significantly to the radiation resistance of mammalian cells. It also modulates accuracy in repair of breaks that occur at stalled DNA replication forks, during diversification steps of the mammalian immune system, during repair of CRISPR-Cas9, and in many DNA integration events. Pol θ is a potentially important clinical target, particularly for cancers deficient in other break repair strategies. The enzyme is uniquely able to mediate joining of single-stranded 3' ends. Because of these unusual biochemical properties and its therapeutic importance, it is essential to study structures of pol θ bound to DNA. However, challenges for expression and purification are presented by the large size of pol θ (2590 residues in humans) and unusual juxtaposition of domains (a helicase-like domain and distinct DNA polymerase, separated by a region predicted to be largely disordered). Here we summarize work on the expression and purification of the full-length protein, and then focus on the design, expression, and purification of an active C-terminal polymerase fragment. The generation of this active construct was nontrivial and time consuming. Almost all published biochemical work to date has been performed with this domain fragment. Strategies to obtain and improve crystals of a ternary pol θ complex (enzyme:DNA:nucleotide) are also presented, along with key elements of the structure.",
            "question": "Which human gene encode for DNA polymerase θ?",
            "answers": {
                "answer_start": 69,
                "text": "DNA polymerase theta (pol θ) is an evolutionarily conserved protein encoded by the POLQ gene in mammalian genomes"
            }
        },
        {
            "context": "E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 144,
                "text": "Poly(ADP-ribose) Polymerase"
            }
        },
        {
            "context": "Enhancer Sharing Promotes Neighborhoods of Transcriptional Regulation Across Eukaryotes. Enhancers physically interact with transcriptional promoters, looping over distances that can span multiple regulatory elements. Given that enhancer-promoter (EP) interactions generally occur via common protein complexes, it is unclear whether EP pairing is predominantly deterministic or proximity guided. Here, we present cross-organismic evidence suggesting that most EP pairs are compatible, largely determined by physical proximity rather than specific interactions. By reanalyzing transcriptome datasets, we find that the transcription of gene neighbors is correlated over distances that scale with genome size. We experimentally show that nonspecific EP interactions can explain such correlation, and that EP distance acts as a scaling factor for the transcriptional influence of an enhancer. We propose that enhancer sharing is commonplace among eukaryotes, and that EP distance is an important layer of information in gene regulation.",
            "question": "Which effects create neighborhoods of transcriptional regulation in eukaryotes?",
            "answers": {
                "answer_start": 0,
                "text": "Enhancer Sharing"
            }
        },
        {
            "context": "Quality evaluation of umbilical cord blood progenitor cells cryopreserved with a small-scale automated liquid nitrogen system. The performance of a small-scale automated cryopreservation and storage system (Mini-BioArchive system) used in the banking of umbilical cord blood (UCB) units was evaluated. After thawing the units, the viability and recovery of cells, as well as the recovery rate of hematopoietic progenitor cells (HPCs) such as CD34+ cells, colony-forming unit-granulocyte-macrophage (CFU-GM), and total CFU were analyzed. Twenty UCB units cryopreserved using the automated system and stored for a median of 34 days were analyzed. Mean CD34+ cell viabilities before freezing were 99.8+/-0.5% and after thawing were 99.8+/-0.4% in the large bag compartments and 99.7+/-0.5% in the small compartments. The mean recovery values for total nucleated cells, CD34+ cells, CFU-GM, and total CFU were 94.8+/-16.0%, 99.3+/-18.6%, 103.9+/-20.6%, and 94.3+/-12.5%, respectively in the large compartments, and 95.8+/-25.9%, 106.8+/-23.9%, 101.3+/-23.3%, and 93.8+/-19.2%, respectively in the small compartments. A small-scale automated cryopreservation and storage system did not impair the clonogenic capacity of UCB HPCs. This cryopreservation system could provide cellular products adequate for UCB banking and HPC transplantation.",
            "question": "What is the BioArchive system?",
            "answers": {
                "answer_start": 160,
                "text": "automated cryopreservation and storage system"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 138,
                "text": "FSHD"
            }
        },
        {
            "context": "Functional asymmetry and electron flow in the bovine respirasome. Respirasomes are macromolecular assemblies of the respiratory chain complexes I, III and IV in the inner mitochondrial membrane. We determined the structure of supercomplex IIIIIV from bovine heart mitochondria by cryo-EM at 9 Å resolution. Most protein-protein contacts between complex I, III and IV in the membrane are mediated by supernumerary subunits. Of the two Rieske iron-sulfur cluster domains in the complex III dimer, one is resolved, indicating that this domain is immobile and unable to transfer electrons. The central position of the active complex III monomer between complex I and IV in the respirasome is optimal for accepting reduced quinone from complex I over a short diffusion distance of 11 nm, and delivering reduced cytochrome c to complex IV. The functional asymmetry of complex III provides strong evidence for directed electron flow from complex I to complex IV through the active complex III monomer in the mammalian supercomplex.",
            "question": "Where is the respirasome located?",
            "answers": {
                "answer_start": 158,
                "text": "in the inner mitochondrial membrane"
            }
        },
        {
            "context": "Origin of human chromosome 2: an ancestral telomere-telomere fusion. We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 710,
                "text": "2"
            }
        },
        {
            "context": "[Cryptococcal meningitis]. BACKGROUND: Cryptococcus neoformans causes systemic disease in patients with immunodeficiency. The incidence of cryptococcal meningitis has increased in parallel with that of HIV infection. Cancer is also a known predisposing factor. MATERIAL AND METHODS: We present two case reports and a review of the literature concerning the epidemiology, diagnostics and treatment of cryptococcal meningitis. RESULTS: The incidence of cryptococcal meningitis in Scandinavia seems to be lower than in other parts of the world. Clinical signs and symptoms are often uncharacteristic. Detection of antigen in spinal fluid is a sensitive and fast test. INTERPRETATION: Cryptococcal meningitis is a rare disease, often with uncharacteristic symptoms. Patients with haematological malignancies have a higher risk of contracting this disease. It is a differential diagnosis when neurological symptoms occur in these patients.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 202,
                "text": "HIV infection"
            }
        },
        {
            "context": "Skewing X chromosome choice by modulating sense transcription across the Xist locus. The X-inactive-specific transcript (Xist) locus is a cis-acting switch that regulates X chromosome inactivation in mammals. Over recent years an important goal has been to understand how Xist is regulated at the initiation of X inactivation. Here we report the analysis of a series of targeted mutations at the 5' end of the Xist locus. A number of these mutations were found to cause preferential inactivation, to varying degrees, of the X chromosome bearing the targeted allele in XX heterozygotes. This phenotype is similar to that seen with mutations that ablate Tsix, an antisense RNA initiated 3' of Xist. Interestingly, each of the 5' mutations causing nonrandom X inactivation was found to exhibit ectopic sense transcription in embryonic stem (ES) cells. The level of ectopic transcription was seen to correlate with the degree of X inactivation skewing. Conversely, targeted mutations which did not affect randomness of X inactivation also did not exhibit ectopic sense transcription. These results indicate that X chromosome choice is determined by the balance of Xist sense and antisense transcription prior to the onset of random X inactivation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 121,
                "text": "Xist"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 248,
                "text": "thyroid"
            }
        },
        {
            "context": "NOXO1 phosphorylation on serine 154 is critical for optimal NADPH oxidase 1 assembly and activation. Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 145,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 432,
                "text": "CD38"
            }
        },
        {
            "context": "[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. Hypo- and hyperpigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function and melanocytoses connected with melanocyte development. The article presents some hereditary hypomelanocytoses, which are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations. It has been demonstrated that mutations of the same gene may cause different hypopigmentation syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome. It has also been demonstrated that mutations of different genes may cause an identical syndrome. For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. In turn, mutation of the KIT gene and/or heterozygous deletion of the SNAI2 gene result in piebaldism disease. The knowledge of the exact mechanisms of pigmentary disorders may be useful in the development of new therapeutic approaches to their treatment.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1275,
                "text": "MITF"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 379,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "McLeod syndrome resulting from a novel XK mutation. McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 411,
                "text": "XK"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 419,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Current strategies for treatment of relapsed/refractory multiple myeloma. In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 885,
                "text": "orally"
            }
        },
        {
            "context": "Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL) Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most common progressive encephalopathy of childhood, is caused by mutations in a novel lysosomal membrane protein (CLN3) with unknown function. In this study, we have confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by co-localizing it with soluble and membrane-associated lysosomal proteins. We have analysed the intracellular processing and localization of two mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the classical JNCL, and E295K [corrected], which is a rare missense mutation associated with an atypical form of JNCL. Pulse-chase labelling and immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461-677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 polypeptide. Transient expression of the two mutants in BHK cells showed that 461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected] was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wild-type CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutant was arrested in the cell soma. Interestingly, co-localization of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle marker indicates that the CLN3 protein might participate in synaptic vesicle transport/transmission. The data presented here provide clear evidence for a cellular distinction between classical and atypical forms of Batten disease both in neural and non-neural cells.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 90,
                "text": "Batten disease"
            }
        },
        {
            "context": "DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability.",
            "question": "Which technique led to the elucidation of the role of HOXD10 in regulating lymphatic endothelial responses to VEGF-C?",
            "answers": {
                "answer_start": 0,
                "text": "DeepCAGE"
            }
        },
        {
            "context": "Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 943,
                "text": "ADAR"
            }
        },
        {
            "context": "Methods to study transcription-coupled repair in chromatin. Transcription-coupled repair (TCR) is a sub-pathway of nucleotide excision repair that allows for the enhanced repair of the transcribed strand of active genes. A classical method to study DNA repair in vivo consists in the molecular analysis of UV-induced DNA damages at specific loci. Cells are irradiated with a defined dose of UV light leading to the formation of DNA lesions and incubated in the dark to allow repair. About 90% of the photoproducts consist of cyclobutane pyrimidine dimers, which can be cleaved by the DNA nicking activity of the T4 endonuclease V (T4endoV) repair enzyme. Strand-specific repair in a suitable restriction fragment is determined by alkaline gel electrophoresis followed by Southern blot transfer and indirect end-labeling using a single-stranded probe. Recent approaches have assessed the role of transcription factors in TCR by analyzing RNA polymerase II occupancy on a damaged template by chromatin immunoprecipitation (ChIP). Cells are treated with formaldehyde in vivo to cross-link proteins to DNA and enrichment of a protein of interest is done by subsequent immunoprecipitation. Upon reversal of the protein-DNA cross-links, the amount of coprecipitated DNA fragments can be detected by quantitative PCR. To perform ChIP on UV-damaged templates, we included an in vitro photoreactivation step prior to PCR analysis to ensure that all precipitated DNA fragments serve as substrates for the PCR reaction. Here, we provide a detailed protocol for both the DNA repair analysis and the ChIP approaches to study TCR in chromatin.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 181,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 217,
                "text": "tyr"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 542,
                "text": "Genomiser"
            }
        },
        {
            "context": "In vivo regulation of precursor cells in the subventricular zone of adult rat brain by thyroid hormone and retinoids. The mature central nervous system contains precursor cells in the subventricular zone of the lateral ventricle. In this study we examined the possibility to affect fate of precursor cells through exogenous manipulations. The results indicate that administration of thyroid hormone and retinoic acid increases the expression of Ki67, a nuclear antigen associated with cell proliferation, and of nestin, a marker protein for precursor cells in the subventricular zone of adult male rats. Moreover, retinoic acid increases polysialated-neural cell adhesion molecules (PSA-NCAM)-immunoreactivity. These data suggest that nuclear receptor ligands are potential candidates for fate determination of precursor cells in the subventricular zone also in the adult brain.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 512,
                "text": "nestin"
            }
        },
        {
            "context": "[Alpha-synucleinopathies]. The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 373,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade > 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed > 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 215,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 453,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor. Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.",
            "question": "Which is the receptor for substrates of Chaperone Mediated Autophagy?",
            "answers": {
                "answer_start": 332,
                "text": "lamp2a"
            }
        },
        {
            "context": "Malaria vaccine: a bright prospect for elimination of malaria. Malaria remains one of the few diseases those continue to scourge human civilization despite the significant advances in disease control strategies over the last century. Malaria is responsible for more than 500 million cases and 1-3 million deaths annually. Approximately 85% of these deaths are among children, mostly in Africa, primarily due to P. falciparum. Whole cell vaccines, irradiated sporozoites and genetically attenuated sporozoites have demonstrated long lasting, sterile protection against plasmodium infection in animal and experimental clinical studies. Atypical membrane protein 1 and merozoite surface protein 1 are the two most extensively studied asexual blood stage vaccine candidates. The most promising candidate vaccine under development is RTS, S combined with AS01 adjuvant. Initial results from phase III trials of this candidate vaccine show 50% reduction of malaria in 5-17 mo aged children during the 12 mo after vaccination. WHO anticipates that the RTS,S/AS01 vaccine will be recommended for the 6-14 week age group for co-administration together with other vaccines as part of routine immunization programs in malaria endemic countries. Malaria vaccine could play an important role in elimination and eventual eradication of malaria.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 1207,
                "text": "malaria"
            }
        },
        {
            "context": "Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. We report on maternal first cousins with bilateral microtia, micrognathia, cleft palate and hematologic findings of Diamond-Blackfan anemia (DBA). The similarity of findings shared between our cases and a female reported by Hasan and Inoue [1993] suggests that this is a distinctive syndrome, rather than a chance association. DBA is a heterogeneous disorder, caused in about 25% of cases by heterozygous mutations in the RPS19 gene (DBA1). Mutation analysis in our cases did not show an RPS19 mutation, and 2 alleles were present in each. Segregation analysis for DBA1 on chromosome 19 and DBA2 on 8p23 was not consistent with linkage. We conclude that this syndrome of microtia, cleft palate and DBA is not allelic to known DBA loci.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 404,
                "text": "DBA"
            }
        },
        {
            "context": "Dialectical behavior therapy skills use as a mediator and outcome of treatment for borderline personality disorder. A central component of Dialectical Behavior Therapy (DBT) is the teaching of specific behavioral skills with the aim of helping individuals with Borderline Personality Disorder (BPD) replace maladaptive behaviors with skillful behavior. Although existing evidence indirectly supports this proposed mechanism of action, no study to date has directly tested it. Therefore, we examined the skills use of 108 women with BPD participating in one of three randomized control trials throughout one year of treatment and four months of follow-up. Using a hierarchical linear modeling approach we found that although all participants reported using some DBT skills before treatment started, participants treated with DBT reported using three times more skills at the end of treatment than participants treated with a control treatment. Significant mediation effects also indicated that DBT skills use fully mediated the decrease in suicide attempts and depression and the increase in control of anger over time. DBT skills use also partially mediated the decrease of nonsuicidal self-injury over time. Anger suppression and expression were not mediated. This study is the first to clearly support the skills deficit model for BPD by indicating that increasing skills use is a mechanism of change for suicidal behavior, depression, and anger control.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 261,
                "text": "Borderline Personality Disorder"
            }
        },
        {
            "context": "A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data. PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 278,
                "text": "liver"
            }
        },
        {
            "context": "Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation. Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-γ and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 413,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Who, when, and how to reverse non-vitamin K oral anticoagulants. Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1268,
                "text": "Xa"
            }
        },
        {
            "context": "NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 235,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Heterogeneity of genomes: measures and values. Genomic homogeneity is investigated for a broad base of DNA sequences in terms of dinucleotide relative abundance distances (abbreviated delta-distances) and of oligonucleotide compositional extremes. It is shown that delta-distances between different genomic sequences in the same species are low, only about 2 or 3 times the distance found in random DNA, and are generally smaller than the between-species delta-distances. Extremes in short oligonucleotides include underrepresentation of TpA and overrepresentation of GpC in most temperate bacteriophage sequences; underrepresentation of CTAG in most eubacterial genomes; underrepresentation of GATC in most bacteriophage; CpG suppression in vertebrates, in all animal mitochondrial genomes, and in many thermophilic bacterial sequences; and overrepresentation of GpG/CpC in all animal mitochondrial sets and chloroplast genomes. Interpretations center on DNA structures (dinucleotide stacking energies, DNA curvature and superhelicity, nucleosome organization), context-dependent mutational events, methylation effects, and processes of replication and repair.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 265,
                "text": "delta-distance"
            }
        },
        {
            "context": "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in approximately 30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 0,
                "text": "Ribosomal protein genes"
            }
        },
        {
            "context": "Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Although no specific phenotype was found to be associated with mutations in either gene, clinical and histological features together with pedigree data may be used in guiding mutation detection. Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication.",
            "question": "What is the mode of inheritance of nemaline myopathy?",
            "answers": {
                "answer_start": 866,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Direct comparison of [(18) F]MH.MZ and [(18) F] altanserin for 5-HT2A receptor imaging with PET. Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 1411,
                "text": "5-HT2A"
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 52,
                "text": "Slc9a6"
            }
        },
        {
            "context": "Septin ring assembly is regulated by Spt20, a structural subunit of the SAGA complex. Accurate cell division requires the proper assembly of high-order septin structures. In fission yeast (Schizosaccharomyces pombe), Spn1-Spn4 are assembled into a primary septin ring at the division site, and the subsequent recruitment of Mid2 to the structure results in a stable septin ring. However, not much is known about the regulation of this key process. Here, we found that deletion of Spt20, a structural subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional activation complex, caused a severe cell separation defect. The defect was mainly due to impaired septin ring assembly, as 80% of spt20Δ cells lost septin rings at the division sites. Spt20 regulates septin ring assembly partially through the transcriptional activation of mid2(+). Spt20 also interacted with Spn2 and Mid2 in vitro and was associated with other components of the ring in vivo. Spt20 colocalized with the septin ring, but did not separate when the septin ring split. Importantly, Spt20 regulated the stability of the septin ring and was required for the recruitment of Mid2. The transcription-dependent and -independent roles of Spt20 in septin ring assembly highlight a multifaceted regulation of one process by a SAGA subunit.",
            "question": "What does the SAGA complex acronym stands for?",
            "answers": {
                "answer_start": 515,
                "text": "Spt-Ada-Gcn5-acetyltransferase"
            }
        },
        {
            "context": "Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS: An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 254,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy. RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase. SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1318,
                "text": "xa"
            }
        },
        {
            "context": "Canine Butterfly Glioblastomas: A Neuroradiological Review. In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a \"butterfly\" glioma (BG). While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here, we describe the magnetic resonance imaging (MRI) characteristics of BG in three dogs and review the potential differential diagnoses based on neuroimaging findings. All dogs presented for generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3) or symmetrical (1/3), bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (GBM), including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 1227,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "PHYLUCE is a software package for the analysis of conserved genomic loci. UNLABELLED: Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales (<5 Ma to > 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. AVAILABILITY AND IMPLEMENTATION: PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth-lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. CONTACT: brant@faircloth-lab.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which software package is available for the analysis of conserved genomic loci?",
            "answers": {
                "answer_start": 0,
                "text": "PHYLUCE"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 224,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensory-motor neurological disorder with a circadian component. RLS is characterized by uncomfortable sensations in the extremities, generally at night or during sleep, which often leads to an uncontrollable urge to move them for relief. Recently, genomic studies identified single-nucleotide polymorphisms in BTBD9, along with three other genes, as being associated with a higher risk of RLS. Little is known about the function of BTBD9 or its potential role in the pathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we recently generated for phenotypes similar to symptoms found in RLS patients. We observed that the Btbd9 mutant mice had motor restlessness, sensory alterations likely limited to the rest phase, and decreased sleep and increased wake times during the rest phase. Additionally, the Btbd9 mutant mice had altered serum iron levels and monoamine neurotransmitter systems. Furthermore, the sensory alterations in the Btbd9 mutant mice were relieved using ropinirole, a dopaminergic agonist widely used for RLS treatment. These results, taken together, suggest that the Btbd9 mutant mice model several characteristics similar to RLS and would therefore be the first genotypic mouse model of RLS. Furthermore, our data provide further evidence that BTBD9 is involved in RLS, and future studies of the Btbd9 mutant mice will help shine light on its role in the pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 mutant mice to discover and screen novel therapeutics for RLS.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 121,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1592,
                "text": "flumazenil"
            }
        },
        {
            "context": "Novel aberrant genetic and epigenetic events in Friedreich's ataxia. It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas. However, there is little knowledge as to other possible genes that may be affected in this disorder, and which can contribute to its complexity. In the current study we compared human periodontal ligament cells gene expression of healthy individuals and FRDA patients. The expression of active-caspase 3, as well as other apoptosis-related genes, was increased in the FRDA cells. Furthermore, iron-sulphur cluster genes, as well as oxidative stress-related genes were overexpressed in FRDA. Moreover, brain-derived neurotrophic factor, neuregulin 1 and miR-132 were all upregulated. These three genes are capable of regulating the expression of each other. Interestingly, when the cells from FRDA patients were co-cultured in the presence of idebenone and deferiprone, caspase expression decreased while antioxidant gene expression, as well as frataxin expression, increased. Regarding epigenetic mechanisms, the frataxin gene was hypermethylated, compared to the healthy counterparts, in the upstream GAA repetitive region. Of the three DNA methyltransferases, DNMT1 but not DNMT3׳s gene expression was higher in FRDA cells. In conclusion, our data show that FRDA cells present altered expression of genes related to cell cycle, oxidative stress and iron homeostasis which may be implicated in the increased apoptotic levels. Also, the altered expression is in a certain degree normalized in the presence of idebenone and deferiprone.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 155,
                "text": "frataxin"
            }
        },
        {
            "context": "Diagnosing diabetic foot osteomyelitis: is the combination of probe-to-bone test and plain radiography sufficient for high-risk inpatients? AIMS: To investigate the accuracy of the sequential combination of the probe-to-bone test and plain X-rays for diagnosing osteomyelitis in the foot of patients with diabetes. METHODS: We prospectively compiled data on a series of 338 patients with diabetes with 356 episodes of foot infection who were hospitalized in the Diabetic Foot Unit of La Paloma Hospital from 1 October 2002 to 31 April 2010. For each patient we did a probe-to-bone test at the time of the initial evaluation and then obtained plain X-rays of the involved foot. All patients with positive results on either the probe-to-bone test or plain X-ray underwent an appropriate surgical procedure, which included obtaining a bone specimen that was processed for histology and culture. We calculated the sensitivity, specificity, predictive values and likelihood ratios of the procedures, using the histopathological diagnosis of osteomyelitis as the criterion standard. RESULTS: Overall, 72.4% of patients had histologically proven osteomyelitis, 85.2% of whom had positive bone culture. The performance characteristics of both the probe-to-bone test and plain X-rays were excellent. The sequential diagnostic approach had a sensitivity of 0.97, specificity of 0.92, positive predictive value of 0.97, negative predictive value of 0.93, positive likelihood ratio of 12.8 and negative likelihood ratio of 0.02. Only 6.6% of patients with negative results on both diagnostic studies had osteomyelitis. CONCLUSIONS: Clinicians seeing patients in a setting similar to ours (specialized diabetic foot unit with a high prevalence of osteomyelitis) can confidently diagnose diabetic foot osteomyelitis when either the probe-to-bone test or a plain X-ray, or especially both, are positive.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 1774,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: advocacy for standard autopsy. Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. Here we report a fetal case of MWS well described, suspected at standard autopsy. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Classical fetopathological examination still keeps indications in cases of syndromic association in the era of virtual autopsy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 217,
                "text": "ZEB2"
            }
        },
        {
            "context": "Current strategies for treatment of relapsed/refractory multiple myeloma. In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 885,
                "text": "orally"
            }
        },
        {
            "context": "A role for p53 in the frequency and mechanism of mutation. The tumor suppressor protein, p53, is often referred to as the guardian of the genome. When p53 function is impaired, its ability to preserve genomic integrity is compromised. This may result in an increase in mutation on both a molecular and chromosomal level and contribute to the progression to a malignant phenotype. In order to study the effect of p53 function on the acquisition of mutation, in vitro and in vivo models have been developed in which both the frequency and mechanism of mutation can be analyzed. In human lymphoblastoid cells in which p53 function was impaired, both the spontaneous and induced mutant frequency increased at the autosomal thymidine kinase (TK) locus. The mutant frequency increased to a greater extent in cell lines in which p53 harbored a point mutation than in those lines in which a \"null\" mutation had been introduced by molecular targeting or by viral degradation indicating a possible \"gain-of-function\" associated with the mutant protein. Further, molecular analysis revealed that the loss of p53 function was associated with a greater tendency towards loss-of-heterozygosity (LOH) within the TK gene that was due to non-homologous recombination than that found in wild-type cells. Most data obtained from the in vivo models uses the LacI reporter gene that does not efficiently detect mutation that results in LOH. However, studies that have examined the effect of p53 status on mutation in the adenine phosphoribosyl transferase (APRT) gene in transgenic mice also suggest that loss of p53 function results in an increase in mutation resulting from non-homologous recombination. The results of these studies provide clear and convincing evidence that p53 plays a role in modulating the mutant frequency and the mechanism of mutation. In addition, the types of mutation that occur within the p53 gene are also of importance in determining the mutant frequency and the pathways leading to mutation.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 89,
                "text": "p53"
            }
        },
        {
            "context": "Giant axonal neuropathy diagnosed on skin biopsy. Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 506,
                "text": "GAN gene"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 1054,
                "text": "malaria"
            }
        },
        {
            "context": "[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 531,
                "text": "xa"
            }
        },
        {
            "context": "Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 1335,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Importance of correlation between gene expression levels: application to the type I interferon signature in rheumatoid arthritis. BACKGROUND: The analysis of gene expression data shows that many genes display similarity in their expression profiles suggesting some co-regulation. Here, we investigated the co-expression patterns in gene expression data and proposed a correlation-based research method to stratify individuals. METHODOLOGY/PRINCIPAL FINDINGS: Using blood from rheumatoid arthritis (RA) patients, we investigated the gene expression profiles from whole blood using Affymetrix microarray technology. Co-expressed genes were analyzed by a biclustering method, followed by gene ontology analysis of the relevant biclusters. Taking the type I interferon (IFN) pathway as an example, a classification algorithm was developed from the 102 RA patients and extended to 10 systemic lupus erythematosus (SLE) patients and 100 healthy volunteers to further characterize individuals. We developed a correlation-based algorithm referred to as Classification Algorithm Based on a Biological Signature (CABS), an alternative to other approaches focused specifically on the expression levels. This algorithm applied to the expression of 35 IFN-related genes showed that the IFN signature presented a heterogeneous expression between RA, SLE and healthy controls which could reflect the level of global IFN signature activation. Moreover, the monitoring of the IFN-related genes during the anti-TNF treatment identified changes in type I IFN gene activity induced in RA patients. CONCLUSIONS: In conclusion, we have proposed an original method to analyze genes sharing an expression pattern and a biological function showing that the activation levels of a biological signature could be characterized by its overall state of correlation.",
            "question": "Which is the most common gene signature in Rheumatoid Arthritis patients?",
            "answers": {
                "answer_start": 84,
                "text": "interferon signature"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 151,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2. Shprintzen-Goldberg syndrome (SGS) is a rare disorder characterized by a Marfan-like habitus, mental retardation and craniosynostosis. Cardiac abnormalities, such as aortic root dilation have also been noted as well as several skeletal abnormalities. Its nosological status is unclear as it is hard to delineate SGS from similar disorders, such as Furlong, Marfan type II, Camurati-Engelmann and Loeys-Dietz syndromes. It has been suggested that these conditions represent a phenotypical spectrum associated with aberrant TGF-beta signalling. In support of this notion, we found a novel TGFBR2 missense mutation in a patient with features of SGS.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 199,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Subviral pathogens of plants: viroids and viroidlike satellite RNAs. Contrary to earlier beliefs, viruses are not the smallest causative agents of infectious diseases. Single-stranded RNAs as small as 246 nucleotides exist in certain higher plants and cause more than a dozen crop diseases. These RNAs have been termed viroids. Despite their extremely limited information content, viroids replicate autonomously in susceptible cells--that is, they do not require helper functions from simultaneously replicating conventional viruses. Viroids are covalently closed circular molecules with a characteristic rodlike secondary structure in which short helical regions are interrupted by internal and bulge loops. Viroids are not translated; they are replicated by a host enzyme (or enzymes) (probably RNA polymerase II) via oligomeric RNA intermediates by a rolling circle mechanism. Viroidlike satellite RNAs resemble viroids in size and molecular structure, but are found within the capsids of specific helper viruses on which they depend for their own replication. These RNAs are of great interest to molecular biology for at least two reasons: 1) they are the smallest and simplest replicating molecules known, and 2) they may represent living fossils of precellular evolution in a hypothetical RNA world.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 319,
                "text": "viroids"
            }
        },
        {
            "context": "SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 766,
                "text": "NCX"
            }
        },
        {
            "context": "Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. UNLABELLED: Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene (INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the β subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation. CONCLUSION: Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 111,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Knockdown of BMI-1 causes cell-cycle arrest and derepresses p16INK4a, HOXA9 and HOXC13 mRNA expression in HeLa cells. The human oncogene B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is a member of the mammalian Polycomb group family. The overexpression of BMI-1 is associated with human malignancies. In this study, the effects of knockdown of BMI-1 by shRNA-mediated RNA interference on cell cycle and possible downstream targets in human cervical adenocarcinoma HeLa cells were investigated. As a result, when the shRNA plasmid was stably introduced into the cell line, the mRNA and protein of BMI-1 were specifically down-regulated, and the cells increased in the phase of G1 and cells in S phase significantly decreased by flow cytometric analysis; the knockdown of BMI-1 expression could lead to significant up-regulation of p16INK4a, HOXA9 and HOXC13 mRNA expression, but hTERT and HOXB4 mRNA expression did not change significantly. In conclusion, RNAi-mediated knockdown of BMI-1 expression can induce cell-cycle arrest and up-regulate p16INK4a, HOXA9 and HOXC13 in HeLa cells. Our results suggest that targeting BMI-1 might be a therapeutic potential for the treatment of cancer.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 858,
                "text": "p16INK4"
            }
        },
        {
            "context": "Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. OBJECTIVES: To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 ( >  75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). RESULTS: Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. CONCLUSIONS: Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 192,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 151,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Krabbe disease: isolation and characterization of a full-length cDNA for human galactocerebrosidase. Human galactocerebrosidase, the enzyme deficient in Krabbe disease, was purified, through several hydrophobic column steps and gel filtration, 22,650-fold from human lymphocytes. Using information on its N-terminal and internal amino acid sequences, and the polymerase chain reaction method, we cloned a full-length cDNA for the enzyme. The deduced amino acid sequence matched all amino acid sequences determined. The 3780 nucleotide sequence included 2007 nucleotides which encoded a single chain peptide of 669 amino acid residues with a 26 amino acid N-terminal signal peptide and six potential asparagine-linked glycosylation sites. The galactocerebrosidase cDNA detected an about 4 kb mRNA band material in human cultured skin fibroblasts. A nonsense mutation was found at codon 369 (GAA-->TAA) in the coding sequence of cDNA amplified from cultured skin fibroblast mRNA from a patient with typical Krabbe disease.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 107,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Chromosome condensation and sister chromatid pairing in budding yeast. We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 740,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Clinical and molecular heterogeneity in brazilian patients with sotos syndrome. Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 289,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family. p63 and p73 express two main classes of isoforms: isoforms which contain the transactivation domain (TAp73 and TAp63) executing transcriptional activity and dominant-negative isoforms which are truncated at the NH2-terminus acting as operant inhibitors of TAp73, TAp63 and wild-type p53, and thus possessing oncogenic potential. Like wt p53, TAp63 and TAp73 isoforms transactivate target genes that activate apoptosis signaling pathways. In an attempt to understand how the CD95 gene is regulated by the p53 family, we investigated the contributions of a p53-responsive element (RE) within the first intron of the CD95 gene as well as three elements within the promoter. The intronic element conferred transcriptional activation by p53, TAp63 and TAp73 and cooperated with the p53-REs in the promoter of the CD95 gene. Cooperation between the p53-REs in the promoter and the intronic p53-binding site resulted in maximal transcriptional activation of the CD95 gene by the p53 family.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 436,
                "text": "7"
            }
        },
        {
            "context": "Continuous-infusion flumazenil in the management of chlordiazepoxide toxicity. Flumazenil is indicated for reversal of sedation from benzodiazepines administered during therapeutic or diagnostic procedures and during induction or maintenance of general anesthesia, as well as for benzodiazepine overdose. Bolus doses of flumazenil are usually adequate to achieve reversal; however, when medical conditions may lead to a prolonged half-life of the benzodiazepine involved, continuous infusion may be warranted. A 67-year-old man with chlordiazepoxide toxicity required a 9-day infusion of flumazenil to prevent resedation and respiratory insufficiency; he initially was admitted to the hospital for alcohol detoxification. Concomitant medical conditions and the metabolism characteristics of each benzodiazepine must dictate the agent of choice. When measures are required to ensure adequate recovery of a patient's respiratory function and mental awareness, such as in patients with benzodiazepine toxicity, consideration of continuous-infusion flumazenil is warranted.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 79,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Oral health in prevalent types of Ehlers-Danlos syndromes. BACKGROUND: The Ehlers-Danlos syndromes (EDS) comprise a heterogenous group of heritable disorders of connective tissue, characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Most EDS types are caused by mutations in genes encoding different types of collagen or enzymes, essential for normal processing of collagen. METHODS: Oral health was assessed in 31 subjects with EDS (16 with hypermobility EDS, nine with classical EDS and six with vascular EDS), including signs and symptoms of temporomandibular disorders (TMD), alterations of dental hard tissues, oral mucosa and periodontium, and was compared with matched controls. RESULTS: All EDS subjects were symptomatic for TMD and reported recurrent temporomandibular joint (TMJ) dislocations. Abnormal pulp shape (13%) and pulp calcification (78%) were observed in subjects affected with classical EDS. Caries experience was higher in EDS compared with controls and was related to poor oral hygiene, influenced by increased mucosal fragility and restraint of (wrist) joint mobility. The overall periodontal status in EDS was poor, with 62% of EDS subjects presenting high periodontal treatment needs (community periodontal index for treatment need, CPITN = II). CONCLUSION: Oral health may be severely compromised in EDS as a result of specific alterations of collagen in orofacial structures. When considering dental treatment in EDS, a number of tissue responses (mucosa, periodontium, pulp) and precautions (TMJ dislocation) should be anticipated.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 161,
                "text": "connective tissue"
            }
        },
        {
            "context": "Post-dural puncture headache: pathophysiology, prevention and treatment. Post-dural puncture headache (PDPHA) has been a vexing problem for patients undergoing dural puncture for spinal anaesthesia, as a complication of epidural anaesthesia, and after diagnostic lumbar puncture since Bier reported the first case in 1898. This Chapter discusses the pathophysiology of low-pressure headache resulting from leakage of cerebrospinal fluid (CSF) from the subarachnoid to the epidural spaces. Clinical and laboratory research over the last 30 years has shown that use of small-gauge needles, particularly of the pencil-point design, is associated with a lower risk of PDPHA than traditional cutting point needle tips (Quincke-point needles). A careful history can rule out other causes of headache. A positional component of headache is the sine qua non of PDPHA. In high-risk patients (e.g. age < 50 years, post-partum, large-gauge-needle puncture), patients should be offered early (within 24-48 h of dural puncture) epidural blood patch. The optimum volume of blood has been shown to be 12-20 ml for adult patients. Complications of autologous epidural blood patch are rare.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 1015,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson-Mendenhall syndrome. Homozygous or compound heterozygous mutations within the insulin binding domain of the human insulin receptor (INSR) are usually associated with severe impairment of insulin binding leading to Donohue syndrome (\"Leprechaunism\"), which is characterized by excessive hyperglycemia with hyperinsulinism, pre- and postnatal growth retardation, distinct dysmorphism and early death. Missense mutations in the beta subunits are commonly associated with a milder impairment of insulin binding and milder phenotype with prolonged survival and less dysmorphism, the so called Rabson-Mendenhall syndrome. We report on a 13-year-old girl with Donohue syndrome like dysmorphism, hyperinsulinism and prolonged survival due to two novel INSR missense mutations within the insulin binding domain. Unexpectedly, insulin binding assays and investigations of activation of central insulin signaling pathways in fibroblasts revealed no significant alterations. Instead, immunofluorescence studies showed abnormal perinuclear distribution of the INSR alpha and beta subunits. Our data indicate that the quality of insulin binding activity is correlated with survival, not with the dysmorphic phenotype, and it is not always a valid parameter for predicting INSR mutations as proposed.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 254,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1827,
                "text": "iron"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 297,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Insulin-like growth factor-binding protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes. Non-melanoma skin cancers (NMSC) are the most common malignancies in caucasians worldwide. Insulin-like growth factor-binding protein-7 (IGFBP7) was suggested to function as a tumor suppressor gene in several cancers, and to play a role in the proliferation of keratinocytes. A-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells. A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function. Two editing sites were identified within the IGFBP7 transcript. To evaluate the expression and editing of IGFBP7 mRNA in NMSC compared to normal epidermis. We examined the expression and mRNA editing level of IGFBP7 in 22 basal cell carcinoma (BCC), 15 squamous cell carcinoma (SCC), and 18 normal epidermis samples that were surgically removed from patients by the Mohs Micrographic Surgery procedure. We studied the effect of IGFBP7 editing on an immortalized HaCaT keratinocyte cell model. IGFBP7 mRNA is over expressed in BCC and SCC compared to normal epidermis. Moreover, the IGFBP7 transcript is highly edited in normal epidermis, but its editing is significantly reduced in BCC and SCC. The edited form of IGFBP7 can inhibit proliferation and induce senescence in cultured keratinocytes. This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 563,
                "text": "A-to-I"
            }
        },
        {
            "context": "No effect of anti-interleukin-5 therapy (mepolizumab) on the atopy patch test in atopic dermatitis patients. BACKGROUND: The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens in atopic dermatitis (AD) patients. Mepolizumab is a monoclonal antibody to interleukin-5, which reduces peripheral blood eosinophils. Previously, we reported that mepolizumab treatment did not result in clinical improvement in AD. The current study investigates the effect of mepolizumab therapy on the APT in the same patients. METHODS: Mepolizumab treatment was given at days 0 and 7 in a double-blind placebo-controlled design. The APT was applied at days -2, 0, 14 and 28. Clinical evaluation of each APT was conducted 48 h after application at days 0, 2, 16 and 30. Skin biopsies were taken at days 0, 2 and 16 for eosinophil counts. RESULTS: The mepolizumab-treated group showed no significant reduction in macroscopic outcome of the APT. Tissue eosinophils were reduced in the mepolizumab-treated group at day 16 compared with placebo; however, this was not significant. CONCLUSION: Mepolizumab therapy cannot prevent the eczematous reaction induced by the APT. Furthermore, the influx of tissue eosinophil numbers in the APT is not significantly inhibited after mepolizumab treatment compared with placebo, despite a significant reduction in peripheral blood eosinophils.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 299,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis. OBJECTIVE: To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. METHODS: Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to  AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. RESULTS: The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. CONCLUSIONS: Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1289,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention. INTRODUCTION: Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. METHODS: ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. RESULTS: Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18-45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22-31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. CONCLUSIONS: African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 864,
                "text": "HIV"
            }
        },
        {
            "context": "RAPIDR: an analysis package for non-invasive prenatal testing of aneuploidy. UNLABELLED: Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package) is an easy-to-use open-source R package that implements several published NIPT analysis methods. The input to RAPIDR is a set of sequence alignment files in the BAM format, and the outputs are calls for aneuploidy, including trisomies 13, 18, 21 and monosomy X as well as fetal sex. RAPIDR has been extensively tested with a large sample set as part of the RAPID project in the UK. The package contains quality control steps to make it robust for use in the clinical setting. AVAILABILITY AND IMPLEMENTATION: RAPIDR is implemented in R and can be freely downloaded via CRAN from here: http://cran.r-project.org/web/packages/RAPIDR/index.html. CONTACT: kitty.lo@ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package has been developed for analyzing Non-invasive prenatal testing (NIPT) data?",
            "answers": {
                "answer_start": 219,
                "text": "RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package)"
            }
        },
        {
            "context": "The future of osteoporosis treatment - a research update. Osteoporosis is characterised by a progressive loss of bone mass and microarchitecture which leads to increased fracture risk. Some of the drugs available to date have shown reductions in vertebral and non-vertebral fracture risk. However, in the ageing population of industrialised countries, still more fractures happen today than are avoided, which highlights the large medical need for new treatment options, models, and strategies. Recent insights into bone biology, have led to a better understanding of bone cell functions and crosstalk between osteoblasts, osteoclasts, and osteocytes at the molecular level. In the future, the armamentarium against osteoporotic fractures will likely be enriched by (1.) new bone anabolic substances such as antibodies directed against the endogenous inhibitors of bone formation sclerostin and dickkopf-1, PTH and PTHrp analogues, and possibly calcilytics; (2.) new inhibitors of bone resorption such as cathepsin K inhibitors which may suppress osteoclast function without impairing osteoclast viability and thus maintain bone formation by preserving the osteoclast-osteoblast crosstalk, and denosumab, an already widely available antibody against RANKL which inhibits osteoclast formation, function, and survival; and (3.) new therapeutic strategies based on an extended understanding of the pathophysiology of osteoporosis which may include sequential therapies with two or more bone active substances aimed at optimising the management of bone capital acquired during adolescence and maintained during adulthood in terms of both quantity and quality. Finally, one of the future challenges will be to identify those patients and patient populations expected to benefit the most from a given drug therapy or regimen. The WHO fracture risk assessment tool FRAX® and improved access to bone mineral density measurements by DXA will play a key role in this regard.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1250,
                "text": "RANKL"
            }
        },
        {
            "context": "A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 210,
                "text": "dabigatran"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 1759,
                "text": "2"
            }
        },
        {
            "context": "Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: no higher DAT availability in patients with homozygosity for the 10-repeat allele. In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [(99m)Tc]TRODAT-1 SPECT and correlated with 3' VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9-10). No statistically significant difference in DAT availability was found between patients with 10-10 carriers (DAT 1.28 +/- 0.34) and with at least one 9 allele (DAT 1.31 +/- 0.27); when smokers were excluded, DAT availability was 1.38 +/- 0.28 in the 10-10 carriers (n = 12) and 1.42 +/- 0.19 in the 9-10 and 9-9 carriers (n = 7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10-10 carriers showed higher DAT availability in [(123)I]IPT SPECT. Discrepancies may be explained by differences in patient's age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 388,
                "text": "5p15.3"
            }
        },
        {
            "context": "Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma. BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. PATIENTS AND METHODS: Patients aged > 18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by > 30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. RESULTS: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. CONCLUSIONS: In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 130,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Immunotherapy for chronic lymphocytic leukemia in the era of BTK inhibitors. Understanding the pathogenesis of CLL has uncovered a plethora of novel targets for human application of monoclonal antibodies, engineered T cells, or inhibitors of signal transduction pathways. The B-cell receptor signaling pathway is being actively explored as a therapeutic target in CLL. Ibrutinib, an inhibitor of Bruton's tyrosine kinase is showing impressive responses in heavily pre-treated high-risk CLL, whether alone or in combination with MoAbs or chemotherapy. Other key components of the BCR pathway, namely PI3K-δ, are also being targeted with novel therapies with promising results as well. Future trials would likely evaluate ibrutinib in the front-line setting. Moreover, improvements in allogeneic HCT mostly by continuing to reduce associated toxicity as well as incorporating cellular therapies such as autologous CLL tumor vaccines, among others, will continue to expand. This is also the case for the next generation of chimeric antigen receptor therapy for CLL once genetically modified T cells are available at broad scale and with improved efficacy. As our ability to further refine and integrate these therapies continues to improve, and we gain further knowledge from gene sequencing, we anticipate that treatment algorithms will continue to be revised to a more personalized approach to treat this disease with improved efficacy and devoid of unnecessary toxicity.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 369,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "In vivo Bacillus anthracis gene expression requires PagR as an intermediate effector of the AtxA signalling cascade. Transcription of the major Bacillus anthracis virulence genes is triggered by CO2, a signal mimicking the host environment. A 182-kb plasmid, pXO1, carries the anthrax toxin genes and the genes responsible for their regulation of transcription, namely atxA and, pagR, the second gene of the pag operon. AtxA has major effects on the physiology of B. anthracis. It coordinates the transcription activation of the toxin genes with that of the capsule biosynthetic enzyme operon, located on the second virulence plasmid, pXO2. In rich medium, B. anthracis synthesises alternatively two S-layer proteins (Sap and EA1). An exponential phase \"Sap-layer\" is subsequently replaced by a stationary phase \"EA1-layer\". S-layer gene transcription is controlled by alternative sigma factors and by Sap acting as a transcriptional repressor of eag. Furthermore, in vitro in presence of CO2 and in vivo, AtxA is part of the sap and eag regulatory network. Only eag is significantly expressed in these conditions and this is due to AtxA activating eag and repressing sap transcription. PagR, and not AtxA itself, is the direct effector of this regulation by binding to sap and eag promoter regions. Therefore, PagR mediates the effect of AtxA on eag and sap and is the most downstream element of a signalling cascade initiated by AtxA. Taken together, these results indicate that the B. anthracis transcriptional regulator AtxA is controlling the synthesis of the three toxin components and of the surface elements (capsule and S-layer). Thus, AtxA is a master regulator that coordinates the response to host signals by orchestrating positive and negative controls over genes located on all genetic elements.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 195,
                "text": "CO2"
            }
        },
        {
            "context": "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia. BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic. METHODOLOGY AND PRINCIPLE FINDINGS: In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006. The severity of the core clinical picture with predominant sensory ataxia, gait apraxia, lower limb spasticity, cognitive impairment and bladder dysfunction correlated with the degree of MRI findings showing enlargement of inner ventricular spaces as in communicating hydrocephalus. Laboratory studies revealed transient eosinophilia during the preceding acute meningitis-like phase, but no ongoing inflammatory process in the CSF. We found immune reactions against Toxocara canis in the majority of chronic VE patients but rarely in controls (P = 0.025; Fisher's exact test). Histological analysis of subacute to subchronic VE brain samples showed eosinophilic infiltrations with no signs of persistent Toxocara canis infection. CONCLUSIONS AND SIGNIFICANCE: Our data showed that pressure by the communicating hydrocephalus as a mechanical factor is the major pathogenic mechanism in chronic VE, most likely triggered by eosinophilic meningitis. There are no signs for an ongoing inflammatory process in chronic VE. The past eosinophilic reaction in VE might be caused by Toxocara ssp. infection and might therefore represent the first hint for an initial cause leading to the development of chronic VE. Our data provide a framework for future studies and potential therapeutic interventions for this enigmatic epidemic neurological disease potentially spreading in Sakha Republic.",
            "question": "Viliuisk encephalomyelitis is diagnosed in which geographical area?",
            "answers": {
                "answer_start": 222,
                "text": "Northeast Siberia"
            }
        },
        {
            "context": "Shprintzen-Goldberg syndrome: a clinical analysis. Shprintzen-Goldberg syndrome is one of a group of disorders characterized by craniosynostosis and marfanoid habitus. Eleven cases were reported previously. We present 4 new patients and review one of the patients of the original report of Shprintzen and Goldberg [1982: J Craniofac Genet Dev Biol 2:65-74], 15 years later. The clinical and radiologic findings on our patients are compared with those of the previously reported patients and also with those of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224], who share many of the characteristics of Shprintzen-Goldberg syndrome. Some of the clinical data are helpful in determining if the patients of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224] have a separate syndrome or represent a variant of Shprintzen-Goldberg syndrome. However, radiologic investigations appear to be more specific, since an abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. The apparently diagnostic findings of the 15 patients with this syndrome may be helpful in differentiating between Shprintzen-Goldberg syndrome and other syndromes with craniosynostosis and marfanoid habitus.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 128,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 45,
                "text": "MRSA"
            }
        },
        {
            "context": "Sleep apnea risk in subjects with asthma with or without comorbid rhinitis. BACKGROUND: As many as 80% of patients with asthma suffer from allergic rhinitis (AR), and rhinitis symptoms are associated with sleep complaints The aim of this cross-sectional study was to assess the prevalence of obstructive sleep apnea syndrome risk in patients with asthma and to explore the association between comorbid rhinitis and obstructive sleep apnea syndrome risk. METHODS: Subjects with asthma were recruited by general practitioners during a control visit. Physicians compiled a questionnaire that assessed the presence of AR according to ARIA (Allergic Rhinitis and Its Impact on Asthma) guidelines and factors influencing the risk of obstructive sleep apnea syndrome (gastroesophageal reflux disease, obesity, smoking). Subjects completed a questionnaire evaluating the presence and severity of AR and the STOP-BANG questionnaire (snoring, tiredness during daytime, observed apnea, high blood pressure, body mass index, age, neck circumference, gender), a validated screening method to identify obstructive sleep apnea syndrome risk. Physicians were blinded to the subjects' questionnaires, ensuring objectivity of the method. RESULTS: The analyses were conducted on 1,941 subjects (males 58%, mean age 48.2 ± 15.2 y): 740 with asthma alone and 1,201 with asthma and AR. STOP-BANG revealed that 52.6% of the subjects were at increased risk of obstructive sleep apnea syndrome: 47.3% of subjects with asthma alone and 55.9% of patients with asthma and AR. Rhinitis was associated with a 1.44 times higher odds ratio for having obstructive sleep apnea syndrome risk. Rhinitis duration and severity were associated with obstructive sleep apnea syndrome risk, although the latter deserved greater importance. The results showed that, once a correction for each of these factors was performed, subjects with AR with an odds ratio of 1.99 were reported to be at risk of obstructive sleep apnea syndrome. CONCLUSIONS: The probable increased risk of obstructive sleep apnea syndrome is associated with the concomitant presence of rhinitis, independent of obesity and other contributors to risk of obstructive sleep apnea syndrome.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 1088,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. BACKGROUND & AIMS: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 196,
                "text": "liver"
            }
        },
        {
            "context": "[Insulin receptor defect as a cause of Rabson-Mendenhall syndrome and other rare genetic insulin resistance syndromes]. Insulin plays a very important role in maintaining homeostasis of the whole organism. It regulates glucose metabolism, glycogen synthesis, lipid and protein metabolism. Insulin receptors are present in virtually all cells, which is reflected by the diversity of regulatory processes in which this hormone is involved. Any dysfunction of insulin signalling pathway as a result of insulin receptor gene mutations is linked with various forms of insulin resistance, including insulin resistance type A, Donohue or Rabson-Mendenhall syndrome, which differ in the level of severity. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop a more efficient treatment. They may also be used as a powerful tool in prenatal diagnostics as well as in pregnancy planning.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 499,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 704,
                "text": "CD38"
            }
        },
        {
            "context": "The use of cffDNA in fetal sex determination during the first trimester of pregnancy of female DMD carriers. Chorionic villus sampling (CVS) or amniocentesis for fetal sex determination is generally the first step in the prenatal diagnosis of X-linked genetic disorders such as Duchenne muscular dystrophy (DMD). However, non-invasive prenatal diagnostic (NIPD) techniques such as measurement of cell-free fetal DNA (cffDNA) in maternal plasma are preferable given the procedure-related miscarriage rate of CVS. We determined fetal sex during the first trimester using a quantitative real-time polymerase chain reaction (PCR) assay of cffDNA in pregnant carriers of DMD. The fetal sex was confirmed by amniocentesis karyotype analysis and multiplex ligation-dependent probe amplification (MLPA) at 16 weeks. This procedure may avoid unnecessary CVS or amniocentesis of female fetuses.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 56,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "Species identification by analysis of bone collagen using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. Species identification of fragmentary bone, such as in rendered meat and bone meal or from archaeological sites, is often difficult in the absence of clear morphological markers. Here we present a robust method of analysing genus-specific collagen peptides by mass spectrometry simply by using solid-phase extraction (a C18 ZipTip) for peptide purification, rather than liquid chromatography/mass spectrometry (LC/MS). Analysis of the collagen from 32 different mammal species identified a total of 92 peptide markers that could be used for species identification, for example, in processed food and animal feed. A set of ancient (>100 ka@10 degrees C) bone samples was also analysed to show that the proposed method has applications to archaeological bone identification.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 571,
                "text": "collagen"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 319,
                "text": "Stroke"
            }
        },
        {
            "context": "Yeast DNA topoisomerase II is encoded by a single-copy, essential gene. The gene TOP2 encoding yeast topoisomerase II has been cloned by immunological screening of a yeast genomic library constructed in the phage lambda expression vector, lambda gt11. The ends of the message encoded by the cloned DNA fragment were delimited by the Berk and Sharp procedure (S1 nuclease mapping) for the 5' end and mapping of the polyA tail portion of a cDNA fragment for the 3' end. The predicted size of the message agrees with the length of the message as determined by Northern blot hybridization analysis. The identity of the gene was confirmed by expressing the gene in E. coli from the E. coli promoter lac UV5 to give catalytically active yeast DNA topoisomerase II. Disruption of one copy of the gene in a diploid yeast creates a recessive lethal mutation, indicating that the single DNA topoisomerase II gene of yeast has an essential function.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 10,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Non-invasive evaluation of voiding function in asymptomatic primary school children. This study aimed to evaluate the voiding characteristics of primary school children by using questionnaires and non-invasive diagnostic tools. The voiding characteristics of 212 healthy children in two primary schools were evaluated with ultrasound for bladder wall thickness (BWT) in association with the Pediatric Lower Urinary Tract Symptom Score (PLUTSS), familial questionnaire, uroflowmetry (UF) and urinalysis. Most of the children (70%) had achieved urinary and fecal continence between the ages of 18 months and 36 months. Twenty-five per cent of healthy children void fewer than four times or more than seven times per day. Ninety percent of children had a PLUTSS within normal ranges (< 9). Fifteen percent of patients had a uroflowmetric pattern other than bell-shaped. The peak and average flow rates were higher in girls. Enuresis nocturna was detected in 10% of children. None of the children had documented urinary tract infection. The average BWT from posterior wall at full bladder in healthy children was 1.1 mm. The anterior and posterior BWT measurements before and after micturition were found to be thicker in boys. Regarding the UF pattern, in post-voiding measurements in children with abnormal UF pattern, the bladder walls were thicker. Non-invasive tests in non-symptomatic children showed a range of variability, and these deviations should be kept in mind during the evaluation of voiding characteristics of a child. The symptom scoring system, with the high sensitivity and specificity rates it possesses, is one of the promising tools for this purpose.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 323,
                "text": "ultrasound"
            }
        },
        {
            "context": "Prognostic performance of MR-pro-adrenomedullin in patients with community acquired pneumonia in the Emergency Department compared to clinical severity scores PSI and CURB. AIM: (i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65. METHODS: Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis. RESULTS: The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR-pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone. CONCLUSIONS: The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR-pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 84,
                "text": "pneumonia"
            }
        },
        {
            "context": "High yield purification of JNK1β1 and activation by in vitro reconstitution of the MEKK1→MKK4→JNK MAPK phosphorylation cascade. The c-Jun N-terminal kinase (JNK) pathway forms part of the mitogen-activated protein kinase (MAPK) signaling pathways comprising a sequential three-tiered kinase cascade. Here, an upstream MAP3K (MEKK1) phosphorylates and activates a MAP2K (MKK4 and MKK7), which in turn phosphorylates and activates the MAPK, JNK. The C-terminal kinase domain of MEKK1 (MEKK-C) is constitutively active, while MKK4/7 and JNK are both activated by dual phosphorylation of S/Y, and T/Y residues within their activation loops, respectively. While improvements in the purification of large quantities of active JNKs have recently been made, inadequacies in their yield, purity, and the efficiency of their phosphorylation still exist. We describe a novel and robust method that further improves upon the purification of large yields of highly pure, phosphorylated JNK1β1, which is most suitable for biochemical and biophysical characterization. Codon harmonization of the JNK1β1 gene was used as a precautionary measure toward increasing the soluble overexpression of the kinase. While JNK1β1 and its substrate ATF2 were both purified to >99% purity as GST fusion proteins using GSH-agarose affinity chromatography and each cleaved from GST using thrombin, constitutively-active MEKK-C and inactive MKK4 were separately expressed in E. coli as thioredoxin-His(6)-tagged proteins and purified using urea refolding and Ni(2+)-IMAC, respectively. Activation of JNK1β1 was then achieved by successfully reconstituting the JNK MAPK activation cascade in vitro; MEKK-C was used to activate MKK4, which in turn was used to efficiently phosphorylate and activate large quantities of JNK1β1. Activated JNK1β1 was thereafter able to phosphorylate ATF2 with high catalytic efficiency.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 157,
                "text": "JNK"
            }
        },
        {
            "context": "Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state. Ficolin-3 (Hakata antigen or H-ficolin) is a soluble pattern recognition molecule in the lectin complement pathway. We speculated whether common genetic variations in the FCN3 gene contribute to deficiency of Ficolin-3. The FCN3 gene was sequenced in 237 healthy Danish Caucasians. The relevance of polymorphisms was assessed with antibodies against Ficolin-3 in a novel ELISA system and by production of recombinant Ficolin-3 variants. Ficolin-3 serum profiles were analyzed by SDS-PAGE and western blotting. Ficolin-3 serum concentration varied 10-fold (median, 24microg/ml; range, 3-54microg/ml). Out of several polymorphisms one FCN3+1637delC causing a reading frame shift and a distortion of the C-terminal end of the molecule with an allele frequency of 0.011 was particularly interesting. In individuals heterozygous for the FCN3+1637delC deletion lowered Ficolin-3 concentration was observed (P=0.025). SDS-PAGE and western blotting of serum revealed a weak band corresponding to the truncated molecule in addition to the normal Ficolin-3 pattern. Characterization of recombinant Ficolin-3 derived from FCN3+1637delC showed that in the homozygous situation this allelic variant would lead to Ficolin-3 deficiency. In conclusion an FCN3+1637delC deletion variant disrupting the possibility for pattern recognition was detected. Characterization of recombinant variant Ficolin-3 shows that homozygosity for the FCN3+1637delC deletion may lead to Ficolin-3 deficiency and may thus be the basis for a novel complement deficiency state.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 215,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "[The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis]. Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs) are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN). MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs) and endothelial cells (ECs). MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT). MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM.",
            "question": "What is needed for MMP proteins to be functional?",
            "answers": {
                "answer_start": 223,
                "text": "zinc"
            }
        },
        {
            "context": "dsPIG: a tool to predict imprinted genes from the deep sequencing of whole transcriptomes. BACKGROUND: Dysregulation of imprinted genes, which are expressed in a parent-of-origin-specific manner, plays an important role in various human diseases, such as cancer and behavioral disorder. To date, however, fewer than 100 imprinted genes have been identified in the human genome. The recent availability of high-throughput technology makes it possible to have large-scale prediction of imprinted genes. Here we propose a Bayesian model (dsPIG) to predict imprinted genes on the basis of allelic expression observed in mRNA-Seq data of independent human tissues. RESULTS: Our model (dsPIG) was capable of identifying imprinted genes with high sensitivity and specificity and a low false discovery rate when the number of sequenced tissue samples was fairly large, according to simulations. By applying dsPIG to the mRNA-Seq data, we predicted 94 imprinted genes in 20 cerebellum samples and 57 imprinted genes in 9 diverse tissue samples with expected low false discovery rates. We also assessed dsPIG using previously validated imprinted and non-imprinted genes. With simulations, we further analyzed how imbalanced allelic expression of non-imprinted genes or different minor allele frequencies affected the predictions of dsPIG. Interestingly, we found that, among biallelically expressed genes, at least 18 genes expressed significantly more transcripts from one allele than the other among different individuals and tissues. CONCLUSION: With the prevalence of the mRNA-Seq technology, dsPIG has become a useful tool for analysis of allelic expression and large-scale prediction of imprinted genes. For ease of use, we have set up a web service and also provided an R package for dsPIG at http://www.shoudanliang.com/dsPIG/.",
            "question": "How many genes are imprinted in the human genome?",
            "answers": {
                "answer_start": 304,
                "text": " fewer than 100"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 35,
                "text": "Factor Xa"
            }
        },
        {
            "context": "The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic. The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors. In tyrosine kinase inhibitor-resistant lung tumors, rociletinib and AZD9291 are highly active when T790M is present and modestly active when T790M is absent.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 89,
                "text": "EGFR"
            }
        },
        {
            "context": "Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats. Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 42,
                "text": "CYP17A1"
            }
        },
        {
            "context": "diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data?",
            "answers": {
                "answer_start": 0,
                "text": "diffloop"
            }
        },
        {
            "context": "A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 399,
                "text": "FBN1"
            }
        },
        {
            "context": "KIAA1530 protein is recruited by Cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR). Transcription-coupled repair (TCR) is the major pathway involved in the removal of UV-induced photolesions from the transcribed strand of active genes. Two Cockayne syndrome (CS) complementation group proteins, CSA and CSB, are important for TCR repair. The molecular mechanisms by which CS proteins regulate TCR remain elusive. Here, we report the characterization of KIAA1530, an evolutionarily conserved protein that participates in this pathway through its interaction with CSA and the TFIIH complex. We found that UV irradiation led to the recruitment of KIAA1530 onto chromatin in a CSA-dependent manner. Cells lacking KIAA1530 were highly sensitive to UV irradiation and displayed deficiency in TCR. In addition, KIAA1530 depletion abrogated stability of the CSB protein following UV irradiation. More excitingly, we found that a unique CSA mutant (W361C), which was previously identified in a patient with UV(s)S syndrome, showed defective KIAA1530 binding and resulted in a failure of recruiting KIAA1530 and stabilizing CSB after UV treatment. Together, our data not only reveal that KIAA1530 is an important player in TCR but also lead to a better understanding of the molecular mechanism underlying UV(s)S syndrome.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 255,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 481,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 1416,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. The tumor suppressor p53 is often referred to as \"the guardian of the genome\" because of its central role in the cellular response to oncogenic stress and prevention of tumor development. Mutations of p53 in acute myeloid leukemia (AML) are rare but resistance to chemotherapy has been reported because of the deregulation of the p53 signaling and differentiation pathways. It is known that the interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25D) with its functional vitamin D receptor leads to differentiation, G(1) arrest, and increased cell survival in p53-null AML cells. However, there are no reports on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we examine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing wild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We find that 1,25D alone induces monocytic differentiation in these cell lines similar to that seen in p53-null AML cells, suggesting that the presence of wild-type p53 is compatible with activation of vitamin D signaling. Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely because of enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, and phosphorylated extracellular signal-regulated kinase 2.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 165,
                "text": "p53"
            }
        },
        {
            "context": "Evaluation of three chromogenic media (MRSA-ID, MRSA-Select and CHROMagar MRSA) and ORSAB for surveillance cultures of methicillin-resistant Staphylococcus aureus. Screening specimens were homogenised in saline 0.9% w/v before either direct inoculation or following enrichment in broth on three chromogenic media (MRSA-ID, CHROMagar MRSA and MRSA Select) and ORSAB medium for the detection of methicillin-resistant Staphylococcus aureus (MRSA). In total, 102 of 466 specimens yielded MRSA on at least one medium. After incubation for 16-18 h, the sensitivity was 51%, 59%, 47% and 65% on MRSA-ID, CHROMagar MRSA, ORSAB and MRSA Select, respectively, compared with 82%, 75%, 67% and 80%, respectively, after 42 h, and 93%, 95%, 79% and not tested, respectively, following broth enrichment. There were significantly more MRSA colonies on MRSA-Select after 16-18 h than on ORSAB or MRSA ID (p 0.001 and 0.0022, respectively), whereas there were more MRSA colonies after 42 h on MRSA-ID and MRSA-Select than on ORSAB (p 0.0004 and 0.012, respectively). The specificity of the media for identifying MRSA based on the colour of colonies after incubation for 16-18 h was 100%, 99%, 99% and 100%, respectively, compared with 98%, 97%, 98% and 98%, respectively, after 42 h, and 100%, 99%, 100% and not tested, respectively, following broth enrichment. The speed of detection (mean time to report a positive result) was 1.65, 1.72, 2.31 and 1.35 days, respectively. For each of the three media tested following enrichment, the use of an enrichment broth increased the detection rate of MRSA by 16-24%.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 438,
                "text": "MRSA"
            }
        },
        {
            "context": "Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia. OBJECTIVE: To review the efficacy, safety, and pharmacology data available for suvorexant and determine its role in therapy as compared with other agents available for the treatment of insomnia. DATA SOURCES: A PubMed search using the terms suvorexant and MK-4305 (the original name given to suvorexant during early trials) was conducted in December 2014 to identify initial literature sources. No time frame was used for exclusion of older trials. STUDY SELECTION AND DATA EXTRACTION: Animal studies and trials written in a language other than English were excluded. Abstracts of the remaining trials were evaluated for determination of relevance to this review. References from these studies along with suvorexant prescriber information were used to identify additional literature. DATA SYNTHESIS: Three randomized, double-blind, placebo-controlled clinical trials were identified showing suvorexant to be safe, effective, and tolerable for the treatment of insomnia. After 4 weeks of therapy, relative to placebo, the 10- and 20-mg doses improved subjective total sleep time (22.3 and 49.9 minutes, respectively), wake after sleep onset (-21.4 and -28.1 minutes), and latency to persistent sleep (-2.3 and -22.3 minutes). CONCLUSION: Suvorexant is the first dual orexin receptor antagonist approved for the treatment of insomnia. Clinical trials have shown that it is relatively safe and effective for the treatment of both sleep onset and sleep maintenance at doses of 20 mg or less. Higher doses were studied but not approved because of concerns for next-day somnolence and effects on driving. Further studies are needed to assess this medication in patients with a history of addiction, because they were excluded from clinical trials, as well as to compare suvorexant with other insomnia medications available because no head-to-head studies have yet been conducted. However, its novel mechanism of action and theoretically lower addiction liability make suvorexant an appealing new option.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 1377,
                "text": "orexin"
            }
        },
        {
            "context": "Lack of prognostic significance of survivin in pediatric medulloblastoma. Medulloblastoma (MDB) is the most common malignant cerebellar tumor in children. Because of the significant rate of mortality and treatment-related morbidity, the identification of prognostic factors could lead to a more accurate selection of patients who can benefit from a less aggressive therapy and improve risk stratification. Survivin is an inhibitor of apoptosis protein (IAP), the expression of which has been associated with worse prognosis in MDB. However, both of its subcellular localizations may contribute to tumor progression, and ultimately, survivin subcellular localization prognostic value depends on tumor type biological features. The goal of this study was to analyze these survivin features in the pediatric MDB tumor samples and its impact on clinical outcome. Survivin expression and subcellular localization were accessed by immunohistochemistry in a series of 41 tumor samples. Kaplan-Meier survival curves were compared using the log-rank test. Survivin expression ranged from completely absent to fully present in a notably higher pattern of nuclear localization than cytoplasmic (19 of 41 versus 4 of 41, respectively). However, survivin expression and subcellular localization were not associated with five-year overall survival or metastasis status at diagnosis, which was the only statistically significant prognostic factor in our series (p = 0.008). Taken together, our results suggest that survivin expression should be further studied in large, multicenter series to determine its accurate impact on prognosis and pathobiology of pediatric MDB.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 74,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1033,
                "text": "xa"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 432,
                "text": "CD38"
            }
        },
        {
            "context": "Carpal Tunnel Syndrome: Initial Management and the Treatment of Recalcitrant Patients. Carpal tunnel syndrome (CTS) is a focal compressive neuropathy of the median nerve at the level of the wrist. CTS is the most common type of compressive neuropathy that occurs in the upper extremity. Typically, patients with CTS have paresthesia, pain, and numbness in the radial three and one-half digits. Nighttime symptoms are more common earlier in the disease process, with daytime symptoms becoming more frequent as CTS progresses. Electrodiagnostic studies may be performed to confirm a diagnosis of CTS or to obtain a baseline before surgical treatment; however, electrodiagnostic studies may be normal in a subset of patients who have CTS. Patients who have mild CTS should undergo an initial trial of nonsurgical treatment that includes lifestyle modifications, nighttime splinting, and corticosteroid injections. Carpal tunnel release should be performed in patients in whom nonsurgical treatment fails and patients who have acute CTS secondary to infection or trauma or have advanced symptoms. Recalcitrant CTS, which may occur in as many as 25% of patients who undergo carpal tunnel release, most commonly results from an incomplete transverse carpal ligament release or an incorrect initial diagnosis. Patients with recurrent symptoms often have perineural fibrosis that tethers the median nerve.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 157,
                "text": "median"
            }
        },
        {
            "context": "The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 511,
                "text": "PLN"
            }
        },
        {
            "context": "The molecular genetics of Marfan syndrome and related microfibrillopathies. Mutations in the gene for fibrillin-1 (FBN1) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues. Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies. There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 (FBN2) is highly homologous to FBN1, and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules. The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 115,
                "text": "FBN1"
            }
        },
        {
            "context": "Who, when, and how to reverse non-vitamin K oral anticoagulants. Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1181,
                "text": "xa"
            }
        },
        {
            "context": "Response to gefitinib in bronchioloalveolar carcinoma in the absence of EGFR mutation. Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity such as gefitinib and erlotinib. Responses to TK inhibitors in the absence of EGFR gene mutation for BAC patients have not been reported. A case of a patient with BAC refractory to chemotherapy who responded to gefitinib in the absence of EGFR gene mutations is reported. Tyrosine kinase inhibitors may have a role in BAC in the absence of EGFR gene mutations. Additional studies on other molecular alterations of the EGFR family members are needed to better predict response to these agents.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 139,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Gangliosidoses. The gangliosidoses comprise a family of lysosomal storage diseases characterized by the accumulation of complex glycosphingolipids in the nervous system and other tissues, secondary to the deficient activity of lysosomal hydrolases or their associated activator proteins. GM1 and GM2 gangliosidosis are associated with deficiency of β-galactosidase and β-hexosaminidase respectively. All gangliosidoses are characterized by progressive neurodegeneration, the severity of which is proportional to the residual enzyme activity. The GM1 gangliosidoses are characterized by dysostosis, organomegaly and coarsening in their most severe forms, whereas children with classic infantile GM2 gangliosidosis (Tay-Sachs disease) are usually spared systemic involvement, except in the case of the Sandhoff variant, in which organomegaly may occur. Cherry-red macular spots occur in the early onset forms of the gangliosidoses, but are less frequently seen in the less severe, later onset phenotypes. Macrocephaly, an exaggerated startle response, cognitive decline, seizures, ataxia, and progressive muscular atrophy may occur in different forms of gangliosidosis. The diagnosis is made by assay of enzyme activity, and can be confirmed by mutation analysis. Carrier screening for Tay-Sachs disease has been remarkably successful in reducing the incidence of this disease in the at-risk Ashkenazi population. There are no proven disease-modifying therapies for the gangliosidoses.",
            "question": "Which enzyme deficiency can cause GM1 gangliosidoses?",
            "answers": {
                "answer_start": 349,
                "text": "β-galactosidase"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1323,
                "text": "xa"
            }
        },
        {
            "context": "Dinutuximab: first global approval. United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 634,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. INTRODUCTION: Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. METHODS: General clinical assessment, sural nerve biopsy, and genetic analysis were performed. RESULTS: Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular-like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. CONCLUSION: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 212,
                "text": "GAN gene"
            }
        },
        {
            "context": "alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse \"cloud-like\" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 740,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 499,
                "text": "xa"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 844,
                "text": "Xa"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1775,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Does the linear Sry transcript function as a ceRNA for miR-138? The sense of antisense. Recently, the sex determining region Y ( Sry) and the cerebellar degeneration-related protein 1 ( CDR1as) RNA transcripts have been described to function as a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7, respectively. A special feature of the Sry gene is its ability to generate linear and circular transcripts, both transcribed in the sense orientation. Here we remark that both sense (e.g. Sry RNA) and antisense (e.g. CDR1as) transcripts could circularize and behave as miRNAs sponges, and importantly, that also protein-coding segments of mRNAs could also assume this role. Thus, it is reasonable to think that the linear Sry sense transcript could additionally act as a miRNA sponge, or as an endogenous competing RNA for miR-138.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 55,
                "text": "miR-138"
            }
        },
        {
            "context": "Outcome of longitudinal versus transverse incision in de Quervain's disease and its implications in Indian population. BACKGROUND: de Quervain's disease is an inadequacy into the first extensor compartment of wrist between the osteofibrous tunnel and the tendons. This mechanical conflict generates a tenosynovitis of the extensor pollicis brevis and the abductor pollicis longus tendons in first dorsal extensor compartment of the wrist. AIM: (1) To compare the clinical results obtained by longitudinal and transverse incisions and (2) the implication of clinical results in Indian population. MATERIALS AND METHODS: This study was conducted at Kalpana Chawla Government Medical College, Karnal, Haryana. The inclusion criteria were positive Finkelstein's test and no response to non-surgical treatment for 6 weeks. Forty-eight patients with de Quervain's disease who did not respond to conservative treatment were operated with two different incisions. The patients were followed at 6 weeks, 3 and 6 months to compare the surgical outcomes. RESULTS: During a three-month follow-up, a significant difference was shown between the two methods (p = 0.0001). Results of surgical treatment with longitudinal incision were better (only one hypertrophic scar), but there were 12 postoperative complications with transverse incision. Visual analog scale (VAS) was used to evaluate the hypertrophic scar. In transverse incision group, out of five patients, four patients who developed hypertrophic scar have poor score according to VAS. CONCLUSION: Overall, longitudinal incision should be used for surgical treatment for de Quervain's disease due to lower risk of complications.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 844,
                "text": "de Quervain's disease"
            }
        },
        {
            "context": "Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received > 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade > 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade > 3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 270,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Visualization of genomic data with the Hilbert curve. UNLABELLED: In many genomic studies, one works with genome-position-dependent data, e.g. ChIP-chip or ChIP-Seq scores. Using conventional tools, it can be difficult to get a good feel for the data, especially the distribution of features. This article argues that the so-called Hilbert curve visualization can complement genome browsers and help to get further insights into the structure of one's data. This is demonstrated with examples from different use cases. An open-source application, called HilbertVis, is presented that allows the user to produce and interactively explore such plots. AVAILABILITY: http://www.ebi.ac.uk/huber-srv/hilbert/.",
            "question": "Which R/bioconductor package utilizes the Hilbert curve in order to visualize genomic data?",
            "answers": {
                "answer_start": 554,
                "text": "HilbertVis"
            }
        },
        {
            "context": "Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis. The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 158,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. OBJECTIVES: Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. DESIGN: Prospective analysis. PATIENTS: 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses. SETTING: All analyses were performed in a large German laboratory specialised in genetic diagnostics. RESULTS: 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. CONCLUSIONS: On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1403,
                "text": "MITF"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 359,
                "text": "FSHD"
            }
        },
        {
            "context": "Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling. BACKGROUND: Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling. METHODS AND RESULTS: Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1-PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1. CONCLUSIONS: Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1-PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.",
            "question": "Which protein phosphatase has been found to interact with the heat shock protein, HSP20?",
            "answers": {
                "answer_start": 1525,
                "text": "PP1"
            }
        },
        {
            "context": "DeepLoc: prediction of protein subcellular localization using deep learning. Motivation: The prediction of eukaryotic protein subcellular localization is a well-studied topic in bioinformatics due to its relevance in proteomics research. Many machine learning methods have been successfully applied in this task, but in most of them, predictions rely on annotation of homologues from knowledge databases. For novel proteins where no annotated homologues exist, and for predicting the effects of sequence variants, it is desirable to have methods for predicting protein properties from sequence information only. Results: Here, we present a prediction algorithm using deep neural networks to predict protein subcellular localization relying only on sequence information. At its core, the prediction model uses a recurrent neural network that processes the entire protein sequence and an attention mechanism identifying protein regions important for the subcellular localization. The model was trained and tested on a protein dataset extracted from one of the latest UniProt releases, in which experimentally annotated proteins follow more stringent criteria than previously. We demonstrate that our model achieves a good accuracy (78% for 10 categories; 92% for membrane-bound or soluble), outperforming current state-of-the-art algorithms, including those relying on homology information. Availability and implementation: The method is available as a web server at http://www.cbs.dtu.dk/services/DeepLoc. Example code is available at https://github.com/JJAlmagro/subcellular_localization. The dataset is available at http://www.cbs.dtu.dk/services/DeepLoc/data.php. Contact: jjalma@dtu.dk.",
            "question": "Which algorithm has been developed for prediction of protein subcellular localization using deep learning?",
            "answers": {
                "answer_start": 0,
                "text": "DeepLoc"
            }
        },
        {
            "context": "Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 330,
                "text": "Phospholamban"
            }
        },
        {
            "context": "JAMM: a peak finder for joint analysis of NGS replicates. MOTIVATION: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets. RESULTS: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy. AVAILABILITY AND IMPLEMENTATION: JAMM is available for free and can run on Linux machines through the command line: http://code.google.com/p/jamm-peak-finder.",
            "question": "Which peak calling algorithm employs mixture model clustering under the hood?",
            "answers": {
                "answer_start": 745,
                "text": "JAMM"
            }
        },
        {
            "context": "Identification of an FBN1 mutation in bovine Marfan syndrome-like disease. Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause Marfan syndrome (MFS). Frequent observation of cattle with a normal withers height, but lower body weight than age-matched normal cattle, was recently reported among cattle sired by phenotypically normal Bull A, in Japanese Black cattle. These cattle also showed other characteristic features similar to the clinical phenotype of human MFS, such as a long phalanx proximalis, oval face and crystalline lens cloudiness. We first screened a paternal half-sib family comprising 36 affected and 10 normal offspring of Bull A using the BovineSNP50 BeadChip (illumina). Twenty-two microsatellite markers mapped to a significant region on BTA10 were subsequently genotyped on the family. The bovine Marfan syndrome-like disease (MFSL) was mapped onto BTA10. As FBN1 is located in the significant region, FBN1 was sequenced in Bull A, and three affected and one normal cattle. A G>A mutation at the intron64 splicing accepter site (c.8227-1G>A) was detected in 31 of 36 affected animals (84.7%). The c.8227-1G>A polymorphism was not found in 20 normal offspring of Bull A or in 93 normal cattle unrelated to Bull A. The mutation caused a 1-base shift of the intron64 splicing accepter site to the 3' direction, and a 1-base deletion in processed mRNA. This 1-base deletion creates a premature termination codon, and a 125-amino acid shorter Fibrillin-1 protein is produced from the mutant mRNA. We therefore conclude that the c.8227-1G>A mutation is causative for MFSL. Furthermore, it was suggested that Bull A exhibited germline mosaicism for the mutation, and that the frequency of the mutant sperm was 14.9%.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 119,
                "text": "FBN1"
            }
        },
        {
            "context": "RAPIDR: an analysis package for non-invasive prenatal testing of aneuploidy. UNLABELLED: Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package) is an easy-to-use open-source R package that implements several published NIPT analysis methods. The input to RAPIDR is a set of sequence alignment files in the BAM format, and the outputs are calls for aneuploidy, including trisomies 13, 18, 21 and monosomy X as well as fetal sex. RAPIDR has been extensively tested with a large sample set as part of the RAPID project in the UK. The package contains quality control steps to make it robust for use in the clinical setting. AVAILABILITY AND IMPLEMENTATION: RAPIDR is implemented in R and can be freely downloaded via CRAN from here: http://cran.r-project.org/web/packages/RAPIDR/index.html. CONTACT: kitty.lo@ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package has been developed for analyzing Non-invasive prenatal testing (NIPT) data?",
            "answers": {
                "answer_start": 219,
                "text": "RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package)"
            }
        },
        {
            "context": "Early non-invasive detection of fetal Y chromosome sequences in maternal plasma using multiplex PCR. OBJECTIVE: Clinical indications for fetal sex determination include risk of X-linked disorders, a family history of conditions associated with ambiguous development of the external genitalia, and some fetal ultrasound findings. It is usually performed in the first trimester from fetal material obtained through CVS and is associated with an approximately 1% risk of miscarriage. Ultrasound fetal sex determination is often performed after 11 weeks of gestation. This study aims to validate a reliable method for non-invasive prenatal diagnosis of fetal gender using maternal plasma cell-free fetal DNA (cffDNA) for fetal sex assessment in the first trimester of pregnancy and test its clinical utility in the diagnosis of potentially affected pregnancies in carriers of X-linked disorders. STUDY DESIGN: In the validation study, blood samples from 100 pregnant women at 6-11 weeks of gestation were analysed. In the clinical study, 17 pregnancies at risk of having an affected fetus were tested. 7 ml of maternal blood in EDTA were obtained and cffDNA was extracted using a commercially available kit. DNA was enzymatically digested using a methylation sensitive endonuclease (AciI) to remove maternal unmethylated sequences of the RASSF1A gene. A multiplex PCR was performed for the simultaneous amplification of target sequences of SRY and DYS14 from chromosome Y, along with RASSF1A and ACTB sequences. Amplification of these loci indicates fetal gender, confirms the presence of cffDNA and allows assessment of digestion efficiency. RESULTS: After establishing the appropriate experimental conditions, validation studies were successful in all 100 cases tested with no false negative or false positive results. Y chromosome-specific sequences were detected in 68 samples, and 32 cases were diagnosed as female based on the amplification of RASFF1A sequences only, in the absence of ACTB. In the clinical studies, fetal sex was correctly diagnosed in 16 pregnancies, and one case was reported as inconclusive. CONCLUSIONS: Fetal sex assessment by detecting Y chromosome sequences in maternal blood can be routinely used from the 6th week of gestation. Reliable fetal sex determination from maternal blood in the 1st trimester of gestation can avoid conventional invasive methods of prenatal diagnosis.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 745,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 499,
                "text": "xa"
            }
        },
        {
            "context": "Gene expression analysis of normal appearing brain tissue in an animal model for multiple sclerosis revealed grey matter alterations, but only minor white matter changes. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that, beside focal lesions, diffuse inflammatory and degenerative processes take place throughout the MS brain. Especially, molecular alterations in the so-called normal appearing white matter suggest the induction of neuroprotective mechanisms against oxidative stress preserving cellular homeostasis and function. In this study we investigated whether in an animal model for MS, namely in experimental autoimmune encephalomyelitis (EAE), similar changes occur. We isolated normal appearing white and grey matter from the corpus callosum and the above lying cerebral cortex from DA rats with rMOG-induced EAE and carried out a gene expression analysis. Examination of corpus callosum revealed only minor changes in EAE rats. In contrast, we identified a number of gene expression alterations in the cerebral cortex even though morphological and cellular alterations were not evident. One of the most striking observations was the downregulation of genes involved in mitochondrial function as well as a whole set of genes coding for different glutamate receptors. Our data imply that molecular alterations are present in neurons far distant to inflammatory demyelinating lesions. These alterations might reflect degenerative processes induced by lesion-mediated axonal injury in the spinal cord. Our results indicate that the MOG-induced EAE in DA rats is a valuable model to analyze neuronal alterations due to axonal impairment in an acute phase of a MS-like disease, and could be used for development of neuroprotective strategies.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 694,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Monitoring and reversal strategies for new oral anticoagulants. Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and edoxaban form a new class of non-vitamin K antagonist oral anticoagulants and have been extensively studied in patients with venous thromboembolism and atrial fibrillation. They offer anticoagulation that is as effective and at least as safe compared to warfarin without the need for routine laboratory monitoring; however, no reversal strategies are currently validated in case of a non-vitamin K antagonist oral anticoagulant-associated bleed. In emergency situations, laboratory drug measurement and well-defined management for non-vitamin K antagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. In this review, the merits and limitations of the routine coagulation tests and some of the more specific laboratory assays are compared. Furthermore, prohemostatic measures are reviewed and the recommended strategies in case of bleeding are summarized. Specific reversal agents are currently under development (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and PER977 for both Xa- and thrombin inhibitors), which will facilitate clinical management of severe bleeding and emergency surgery.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1164,
                "text": "Xa"
            }
        },
        {
            "context": "Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation. Mitochondria are dynamic organelles forming a tubular network that is continuously fusing and dividing to control their morphology and functions. Recent literature has shed new light on a potential link between the dynamic behavior of mitochondria and muscle development. In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation. We found that differentiation of C2C12 myoblasts induced by serum starvation was accompanied by a gradual increase in Drp1 protein expression (to ∼350% up to 3 days) and a fast reduction of Drp1 phosphorylation at Ser-637 (to ∼30%) resulting in translocation of Drp1 protein from the cytosol to mitochondria. During differentiation, treatment of myoblasts with mitochondrial division inhibitor (mdivi-1), a specific inhibitor of Drp1 GTPase activity, caused extensive formation of elongated mitochondria, which coincided with increased apoptosis evidenced by both enhanced caspase-3 activity and increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1-treated myotubes (day 3 in differentiation media) showed a reduction in mitochondrial DNA content, mitochondrial mass, and membrane potential in a dose-dependent manner indicating defects in mitochondrial biogenesis during myogenic differentiation. Most interestingly, mdivi-1 treatment significantly suppressed myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial division is a necessary step for successful myogenic differentiation, and perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations during muscle development. Therefore, in the present study, we report a novel physiological role of mitochondrial dynamics in myogenic differentiation.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 400,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Designing calcium release channel inhibitors with enhanced electron donor properties: stabilizing the closed state of ryanodine receptor type 1. New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 565,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Topoisomerase II: its functions and phosphorylation. The gene encoding topoisomerase II in yeast is unique and essential, required for both mitotic and meiotic proliferation. The use of temperature-sensitive mutants in topoisomerase II have demonstrated roles in the relaxation of tortional stress, reduction of recombination rates, and in the separation of sister chromatids after replication. In vertebrate cells, topoisomerase II was shown to be the most abundant component of the metaphase chromosomal scaffold, and has been shown to play a role in chromosome condensation in vitro. The cell cycle control of chromosome condensation may well require phosphorylation of topoisomerase II, since the enzyme is more highly phosphorylated in metaphase than in G1. Recent studies have identified casein kinase II as the major enzyme phosphorylating topoisomerase II in intact yeast cells. The target sites of CKII are exclusively in the C-terminal 400 amino acids of topoisomerase II, the region that is most divergent among the eukaryotic type II enzymes and which is absent in the bacterial gyrase homologues.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 71,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 456,
                "text": "tyr"
            }
        },
        {
            "context": "New therapeutic perspectives in CCDC6 deficient lung cancer cells. Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p < 0.02) and negatively correlated to the disease free survival (p < 0.01) and the overall survival (p < 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 884,
                "text": "PARP"
            }
        },
        {
            "context": "Calsequestrin, a calcium sequestering protein localized at the sarcoplasmic reticulum, is not essential for body-wall muscle function in Caenorhabditis elegans. Calsequestrin is the major calcium-binding protein of cardiac and skeletal muscles whose function is to sequester Ca(2+ )in the lumen of the sarcoplasmic reticulum (SR). Here we describe the identification and functional characterization of a C. elegans calsequestrin gene (csq-1). CSQ-1 shows moderate similarity (50% similarity, 30% identity) to rabbit skeletal calsequestrin. Unlike mammals, which have two different genes encoding cardiac and fast-twitch skeletal muscle isoforms, csq-1 is the only calsequestrin gene in the C. elegans genome. We show that csq-1 is highly expressed in the body-wall muscles, beginning in mid-embryogenesis and maintained through the adult stage. In body-wall muscle cells, CSQ-1 is localized to sarcoplasmic membranes surrounding sarcomeric structures, in the regions where ryanodine receptors (UNC-68) are located. Mutation in UNC-68 affects CSQ-1 localization, suggesting that the two possibly interact in vivo. Genetic analyses of chromosomal deficiency mutants deleting csq-1 show that CSQ-1 is not essential for initiation of embryonic muscle formation and contraction. Furthermore, double-stranded RNA injection resulted in animals completely lacking CSQ-1 in body-wall muscles with no observable defects in locomotion. These findings suggest that although CSQ-1 is one of the major calcium-binding proteins in the body-wall muscles of C. elegans, it is not essential for body-wall muscle formation and contraction.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 161,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability. Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.",
            "question": "Which is the most widely used anti-TNF drug?",
            "answers": {
                "answer_start": 359,
                "text": "etanercept"
            }
        },
        {
            "context": "Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae. OBJECTIVE: Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system. APPROACH AND RESULTS: Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, membrane integrity, and morphology are readily seen. Using flow cytometry, we find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress induced by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading as evidenced by blunted lysosomal dysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β, enhanced cholesterol efflux, and decreased polyubiquitinated protein aggregation. CONCLUSIONS: Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 1212,
                "text": "Transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Flumazenil in benzodiazepine antagonism. Actions and clinical use in intoxications and anaesthesiology. In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to 1.0mg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour). Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 524,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 239,
                "text": "TYR"
            }
        },
        {
            "context": "Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs. MicroRNAs (miRNAs) play a major part in the post-transcriptional regulation of gene expression. Mammalian miRNA biogenesis begins with cotranscriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex. Although most miRNAs are located within introns of protein-coding transcripts, a substantial minority of miRNAs originate from long noncoding (lnc) RNAs, for which transcript processing is largely uncharacterized. We show, by detailed characterization of liver-specific lnc-pri-miR-122 and genome-wide analysis in human cell lines, that most lncRNA transcripts containing miRNAs (lnc-pri-miRNAs) do not use the canonical cleavage-and-polyadenylation pathway but instead use Microprocessor cleavage to terminate transcription. Microprocessor inactivation leads to extensive transcriptional readthrough of lnc-pri-miRNA and transcriptional interference with downstream genes. Consequently we define a new RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 270,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Establishment and biological characteristics of acquired gefitinib resistance in cell line NCI-H1975/gefinitib-resistant with epidermal growth factor receptor T790M mutation. Non - small cell lung cancer (NSCLC) cells harboring mutations in the epidermal growth factor receptor (EGFR) gene initially respond well to EGFR tyrosine kinase inhibitors (TKI), including gefitinib. However the tumor cells will invariably develop acquired resistance to the drug. The EGFR T790M mutation is generally considered to be the molecular genetic basis of acquired TKI resistance. The present study aimed to explore how the T790M mutation induces tumor cells to escape inhibition by TKI treatment. An acquired gefitinib - resistant cell line (NCI - H1975/GR) was generated from the NCI - H1975 human NSCLC cell line, which harbors the sensitive L858R and resistant T790M mutations of EGFR. The resistant cell line was established by exposing the cells intermittently to increasing concentrations of gefitinib. The mechanisms by which NSCLC acquires resistance to TKIs based on the T790M mutation, were investigated by detecting the protein expression levels of the EGFR/Kirsten rat sarcoma viral oncogene homolog (KRAS)/v - Raf murine sarcoma viral oncogene homolog B (BRAF) transduction pathway, and epithelial - mesenchymal transition (EMT) with immunocytochemistry. The resistance of the NCI - H1975/GR cells to gefitinib was 2.009 - fold, as compared with the parent cells; however, the protein expression levels of EGFR, KRAS and BRAF were lower in the resistant cells. Some mesenchymal morphology was observed in the NCI - H1975/GR cells, alongside a decreasing E - cadherin expression and increasing vimentin expression. These results suggest that the reactivation of the EGFR/KRAS/BRAF transduction pathway was not detected in the NCI - H1975/GR cells. EMT may have an important role in the development of acquired resistance to EGFR - TKIs in NSCLC cells with sensitivity and resistance mutations.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 461,
                "text": "EGFR"
            }
        },
        {
            "context": "Onyx 18 embolisation of dural arteriovenous fistula via arterial and venous pathways: preliminary experience and evaluation of the short-term outcomes. OBJECTIVE: This paper mainly focuses on our preliminary experience and short-term outcome evaluation of embolisation of non-cavernous dural arteriovenous fistulas (ncsDAVFs) and cavernous sinus dural arteriovenous fistulas (csDAVFs) using Onyx 18 (ev3, Plymouth, MN), and in combination with coils, via arterial and venous approaches, respectively. METHODS: Between August 2008 and March 2010, 21 DAVFs (11 ncsDAVFs and 10 csDAVFs; age range: 28-68 years; 12 females and 9 males) were undertaken. Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs. Onyx 18 was used in 11 ncsDAVFs (10 via single feeder and 1 via 2 feeders). Onyx 18 or in combination with coils was used in 10 csDAVFs (9 via the inferior petrosal sinus and 1 via the superior ophthalmic vein). RESULTS: Total occlusion in immediate angiography was achieved in 18 cases (85.7%; 10 ncsDAVFs and 8 csDAVFs), and near-total occlusion in 1 ncsDAVF and 2 csDAVFs. Onyx 18 was migrated into normal vasculature in two ncsDAVFs without any sequelae. One csDAVF had VI cranial nerve palsy post-operatively, which completely recovered 2 weeks post-embolisation. Follow-up angiography at 3-12 months showed complete occlusion in 20 cases (95.2%; 10 ncsDAVFs and 10 csDAVFs). One ncsDAVF (4.8%) recurred after 3 months and was successfully re-embolised. CONCLUSION: Preliminary results achieved after embolising 11 ncsDAVFs and 10 csDAVFs using Onyx 18 and in combination with coils via arterial and venous pathways, respectively, appeared to be safe, feasible and effective, as 95.2% of cases were totally occluded without any clinical sequelae.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 713,
                "text": "DAVF"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1043,
                "text": "CO2"
            }
        },
        {
            "context": "[Regional sympathetic disturbances in carpal tunnel syndrome--a review]. Carpal tunnel syndrome is a complex of symptoms as a result of compression of the median nerve in the carpal tunnel. As nerve entrapment induces impairment of somatic fibres followed by clinical symptoms and signs of the syndrome, one can assume that sympathetic fibres are involved too. Results of studies focused on this problem show presence of sympathetic symptoms in about half of patients, including Raynaud phenomenon, blanching of hands, painful swelling of fingers, dry or excessive sweating of palms. Activity of sympathetic system can be investigated by means of sympathetic skin response and vasomotor response. Eight papers presenting the results of sympathetic skin response from median nerve in carpal tunnel syndrome were analysed. Results of 4 studies showed decreased sympathetic activity, in 2 findings were equivocal and 2 studies failed to reveal any abnormalities. The following variables were considered in the interpretation of sympathetic skin response curve: amplitude, latency and area under the chart, each of them having limited diagnostic value due to inter-and intrasubject variation of these parameters. Vasomotor response was investigated in 2 studies by means of Doppler ultrasound flow examination in digital arteries. Results of both studies showed decreased vasomotor response in carpal tunnel syndrome. The review of current knowledge on sympathetic impairment in carpal tunnel syndrome fails to provide a definitive determination of its range and clinical consequences. It confirms, however, that routine examination of sympathetic disturbances is unnecessary due to their minor clinical significance.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 155,
                "text": "median"
            }
        },
        {
            "context": "Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. PURPOSE: Interleukin-6 (IL-6) induces tumor growth, invasion, metastasis, and angiogenesis. Siltuximab (CNTO 328) is a chimeric, murine-human monoclonal antibody that specifically binds human IL-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity. Reductions in CRP may correlate with clinical activity and IL-6 bioactivity. EXPERIMENTAL DESIGN: Starting-dose selection for this study was based on a previous siltuximab study in multiple myeloma patients. Pharmacokinetic (PK)/PD modeling explored the relationship between siltuximab PK and CRP suppression following i.v. siltuximab infusion in a three-part phase I/II study in 68 metastatic renal cell carcinoma patients. Modeling results were then used to simulate and determine which siltuximab dosage regimens would maintain CRP suppression below the lower limit of quantification (4 mg/L). Siltuximab was given at 1, 3, 6, or 12 mg/kg at weeks 1 and 4 and then every 2 weeks for 2 cycles in part 1; at 3 or 6 mg/kg every 3 weeks for 4 cycles in part 2; and at 6 mg/kg every 2 weeks for 6 cycles in part 3. RESULTS: A two-compartment PK model adequately described the serum siltuximab concentration-time data. An inhibitory indirect response PD model examined the relationship between siltuximab concentrations and CRP suppression. PD parameter estimates seemed reliable and physiologically relevant. Simulations showed that 6 mg/kg siltuximab every 2 weeks or 9 mg/kg every 3 weeks would reduce serum CRP to below 4 mg/L. CONCLUSIONS: Using a stepwise design, PK/PD modeling was used to select the dose levels in this study. Furthermore, PK/PD modeling results were used to help select doses to be used in future siltuximab clinical development.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 56,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence. Patient adherence to many osteoporosis treatments, primarily bisphosphonates, is generally poor, thus leading to a significant reduction in antifracture efficacy. Patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence, in addition to other factors, such as difficult dosing regimens and high dosing frequency. Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. It is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis. Preference and adherence to Dmab treatment were assessed in various clinical trials. Although with some limitations, available data suggest that Dmab is preferred to bisphosphonates, produces greater satisfaction than bisphosphonates, and would be preferentially chosen for long-term treatment. Moreover, patient perceptions about the necessity of Dmab treatment clearly outweigh the concerns about the injections, and positive beliefs about treatment positively influence medication-taking behavior. According to these data, Dmab may represent a reasonable alternative to bisphosphonates, particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected.",
            "question": "Which is the target of the drug Denosumab?",
            "answers": {
                "answer_start": 636,
                "text": "receptor activator of nuclear factor-κB ligand"
            }
        },
        {
            "context": "[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1986,
                "text": "CD38"
            }
        },
        {
            "context": "Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. OBJECTIVE: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. METHODS: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. RESULTS: Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. CONCLUSIONS: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 418,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "To screen or not to screen for methicillin-resistant Staphylococcus aureus. There are few more compelling questions in clinical microbiology today than the issue of whether or not to screen for the presence of methicillin-resistant Staphylococcus aureus (MRSA), with the results being used to institute infection control interventions aimed at preventing transmission of MRSA in health care environments. Numerous different matters must be addressed when considering a screening program. Who is to be screened, what method is to be employed to detect MRSA, and what sites should be sampled? When and how often should the screening be performed? Who is going to pay for the screening, and, finally and perhaps most importantly, how are screening results to be communicated to health care providers and what kind of interventions are best undertaken based on the results? Numerous governmental agencies have mandated MRSA screening programs, and yet several authorities in infection control organizations have questioned the appropriateness of mandated screening. In this Point-Counterpoint feature, Dr. Lance Peterson of Evanston Hospital (Evanston, IL) offers his perspective on why screening for MRSA is to be encouraged. Dr. Daniel Diekema of the University of Iowa Carver College of Medicine (Iowa City, IA) offers an opposing view.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 255,
                "text": "MRSA"
            }
        },
        {
            "context": "Chromatin Constrains the Initiation and Elongation of DNA Replication. Eukaryotic chromosomal DNA is faithfully replicated in a complex series of cell-cycle-regulated events that are incompletely understood. Here we report the reconstitution of DNA replication free in solution with purified proteins from the budding yeast Saccharomyces cerevisiae. The system recapitulates regulated bidirectional origin activation; synthesis of leading and lagging strands by the three replicative DNA polymerases Pol α, Pol δ, and Pol ε; and canonical maturation of Okazaki fragments into continuous daughter strands. We uncover a dual regulatory role for chromatin during DNA replication: promoting origin dependence and determining Okazaki fragment length by restricting Pol δ progression. This system thus provides a functional platform for the detailed mechanistic analysis of eukaryotic chromosome replication.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 660,
                "text": "DNA replication"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 96,
                "text": "stroke"
            }
        },
        {
            "context": "Adult bone marrow transplantation after stroke in adult rats. We transplanted adult whole bone marrow prelabeled with bromodeoxyuridine (BrdU) into the ischemic boundary zone of the adult rat brain at 1 day after 2 h of middle cerebral artery occlusion (MCAo). Approximately 3.3% of 10(6) transplanted bone marrow cells were BrdU reactive at 14 days after MCAo. BrdU-reactive cells expressed neuronal and astrocytic proteins, neuronal nuclei protein (NeuN, 1%), and glial fibrillary acidic protein (GFAP, 5%) immunoreactivities, respectively. In addition, bone marrow transplantation promoted proliferation of ependymal and subependymal cells, identified by nestin (a neuroepithelial stem cell marker), within the ventricular zone and subventricular zone (VZ/SVZ). These data suggest that intracerebral transplantation of bone marrow could potentially be used to induce plasticity in ischemic brain.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 658,
                "text": "nestin"
            }
        },
        {
            "context": "Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B). MWS has been reported in association with Hirschsprung disease (HSCR). MWS is sometimes difficult to diagnose clinically, especially when HSCR is absent. Thus, it is necessary to detect gene abnormalities at the molecular level. Here we report two Japanese girls with MWS, who showed a distinct facial phenotype, severe intellectual disability and epileptic seizures. Major congenital anomalies of the patients were very different. Patient 1 suffered from severe congenital heart disease, but did not show apparent HSCR. Patient 2 suffered from typical HSCR and underwent surgical treatment, but did not have congenital heart disease. According to the gene analysis using white blood cells, they had nonsense mutations in ZFHX1B, R695X and Q433X, respectively. In conclusion, molecular genetic analysis of ZFHX1B is important for a definite diagnosis of MWS which has a wide phenotypic spectrum of congenital anomalies.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 26,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Follow-up of childhood chronic myelogenous leukemia with monitoring the BCR-ABL fusion gene expression in peripheral blood. UNLABELLED: Chronic myelogenous leukemia (CML) accounts for 15-20% of adult leukemias but is very rare in children (2%). Fewer than 10% of CML patients are younger than 20 years. CML is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome or the BCR-ABL fusion oncogene. The objective of this paper is to present the monitoring of imatinib therapy in two children with CML by the BCR-ABL fusion gene expression assessment from peripheral blood with quantitative real-time polymerase chain reaction (PCR) method. PATIENTS AND METHODS: The 18 and six months follow-up of the patients included clinical examination, routine laboratory tests, bone marrow aspirate investigation including cytogenetic tests and the major BCR-ABL fusion gene expression measurement with qRT-PCR method from the peripheral blood. RESULTS: Patient No. 1 diagnosed with chronic phase CML showed excellent adherence to daily 400 mg imatinib treatment and achieved complete hematologic (CHR) and cytogenetic response (CCR) by three months and major molecular response (MMR) by 12 months, with lack of side effects due to imatinib. Patient No. 2 experienced severe hematologic toxicity, which necessitated temporary withdrawal of the drug. Transient non-compliance together with imatinib dose reduction has driven to treatment failure. In this case, mutational analysis is warranted. CONCLUSIONS: BCR-ABL fusion gene expression level measurement from peripheral blood with qRT-PCR method is an excellent tool in the follow-up of CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 408,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 321,
                "text": "SCFbeta-Trcp"
            }
        },
        {
            "context": "Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. The gene encoding the small subunit ribosomal protein 19 (RPS19) is mutated in about 25% of cases of the bone marrow failure syndrome Diamond Blackfan Anemia (DBA), a childhood disease characterized by failure of red cell production. In these cases DBA is inherited as an autosomal dominant trait and RPS19 haploinsufficiency is thought to cause the disease. To study the molecular pathogenesis of DBA we used siRNA to decrease the level of RPS19 in two human cell lines, HeLa cells and U-2 OS osteosarcoma cells. Cells with reduced RPS19 levels showed a dramatic reduction in the amounts of small 40S ribosome subunits and mature 80S ribosomes and an excess of large 60S subunits. These cells were defective in 18S rRNA production and accumulated 21S and 20S nuclear pre-rRNA molecules, suggesting that RPS19 is required for specific steps in rRNA processing. RPS19 depletion produced a reduction in steady-state levels of RPS6 and RPS16 via a post-transcriptional mechanism while the levels of RPL7 and RPL26 were unaltered, indicating that levels of ribosomal proteins are determined by subunit assembly. This has interesting implications for the pathogenesis of DBA suggesting that deficiency of any of the RPS proteins might have a similar effect and thus may be responsible for causing DBA. Finally in cell lines from DBA patients with mutations we find increased levels of 21S rRNA precursors but no abnormality in the ribosome profile on sucrose gradients or in the steady-state levels of RPS19 suggesting that some cells can partially compensate for the loss of one allele of RPS19. We conclude that defects in ribosome biogenesis may underlie the pathology of Diamond Blackfan Anemia.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 320,
                "text": "DBA"
            }
        },
        {
            "context": "p63 protein expression in high risk diffuse large B-cell lymphoma. BACKGROUND: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. AIMS: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high-intermediate and high risk DLBCL populations. METHODS: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high-intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. RESULTS: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01). CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 316,
                "text": "7"
            }
        },
        {
            "context": "Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons. The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. We have compared the chromosomal mobilization efficiency and insertion site preference of the two transposons mobilized from the same donor site in mouse embryonic stem (ES) cells under conditions in which there were no selective constraints on the transposons' insertion sites. Compared with Sleeping Beauty, PiggyBac exhibits higher transposition efficiencies, no evidence for local hopping and a significant bias toward reintegration in intragenic regions, which demonstrate its utility for insertional mutagenesis. Although Sleeping Beauty had no detectable genomic bias with respect to insertions in genes or intergenic regions, both Sleeping Beauty and PiggyBac transposons displayed preferential integration into actively transcribed loci.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 870,
                "text": "PiggyBac"
            }
        },
        {
            "context": "Characterization of mutations in Gaucher patients by cDNA cloning. Mutated cDNA clones containing the entire coding sequence of human glucocerebrosidase were isolated from libraries originated from Gaucher patients. Sequence analysis of a mutated cDNA derived from a type II Gaucher patient revealed a C-to-G transversion causing a substitution of an arginine for a proline at residue 415. This change creates a new cleavage site for the enzyme HhaI in the mutated cDNA. Allele-specific oligonucleotide hybridization made it possible to show that this mutation exists in the genomic DNA of the patient. From a cDNA library originated from a type I Gaucher patient, a mutated allele was cloned that contains a T-to-C transition causing a substitution of proline for leucine at residue 444 and creating a new NciI site. This mutation is identical to that described by S. Tsuji and colleagues in genomic DNA from type I, type II, and type III patients. Since the new NciI site generates RFLP, it was used to test the existence of this mutated allele in several Gaucher patients by Southern blot analysis. This allele was found in type I (Jewish and non-Jewish), type II, and type III Gaucher patients. These findings led us to conclude that the patient suffering from type II disease (denoted GM1260) carried both mutations described above. Any one of the amino acid changes described reduces the glucocerebrosidase activity as tested by transfection of COS cells with expression vectors harboring the mutated cDNAs. The base changes in the two mutated cDNAs do not affect the electrophoretic mobility of the corresponding polypeptides on an SDS polyacrylamide gel.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 134,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Ubiquilins in the crosstalk among proteolytic pathways. Protein degradation occurs through several distinct proteolytic pathways for membrane and cytosolic proteins. There is evidence that these processes are linked and that crosstalk among these major protein degradation pathways occurs. Ubiquilins, a family of ubiquitin-binding proteins, are involved in all protein degradation pathways. This minireview provides an overview of ubiquilin function in protein degradation and contrasts it with sequestosome-1 (p62), a protein that also has been implicated in multiple proteolytic pathways.",
            "question": "Which is the function of ubiquilins?",
            "answers": {
                "answer_start": 290,
                "text": "Ubiquilins, a family of ubiquitin-binding proteins, are involved in all protein degradation pathways."
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1037,
                "text": "PD-L1"
            }
        },
        {
            "context": "Molecular and cellular bases of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients. Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis. Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet. CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML. However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML. In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors. A critical issue to resolve this problem is to fully understand the biology of LSCs, and to identify key genes that play significant roles in survival and self-renewal of LSCs. In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 773,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Intracranial artery dissection in an adolescent with Marfan syndrome. Marfan syndrome is an autosomal dominant connective tissue disorder commonly due to mutation of the fibrillin-1 (FBN-1) gene that causes disruption of elastic fibers in large- and medium-size arteries and predisposes to aneurysm formation and arterial dissection. Cardiovascular complications occur in most patients with Marfan syndrome, but interestingly, neurovascular complications of Marfan syndrome are rare. We present a novel case of an adolescent with Marfan syndrome with spontaneous intracranial cerebral artery dissection and ischemic stroke with hemorrhagic transformation. This case is novel in that it reports spontaneous intracranial dissection in a young patient with Marfan syndrome and highlights the rare intrinsic neurovascular complications that can occur in these patients.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 111,
                "text": "connective tissue"
            }
        },
        {
            "context": "Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73gamma in lung cancer. The p73 gene possesses an extrinsic P1 promoter and an intrinsic P2 promoter, resulting in TAp73 and DeltaNup73 isoforms, respectively. The ultimate effect of p73 in oncogenesis is thought to depend on the apoptotic TA to antiapoptotic DeltaN isoforms' ratio. This study was aimed at identifying novel transcription factors that affect TA isoform synthesis. With the use of bioinformatics tools, in vitro binding assays, and chromatin immunoprecipitation analysis, a region extending -233 to -204 bp upstream of the transcription start site of the human p73 P1 promoter, containing conserved Sp1-binding sites, was characterized. Treatment of cells with Sp1 RNAi and Sp1 inhibitor functionally suppress TAp73 expression, indicating positive regulation of P1 by the Sp1 protein. Notably Sp1 inhibition or knockdown also reduces DeltaNup73 protein levels. Therefore, Sp1 directly regulates TAp73 transcription and affects DeltaNup73 levels in lung cancer. TAp73gamma was shown to be the only TA isoform overexpressed in several lung cancer cell lines and in 26 non-small cell lung cancers, consistent with Sp1 overexpression, thereby questioning the apoptotic role of this specific p73 isoform in lung cancer.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 202,
                "text": "7"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1590,
                "text": "xa"
            }
        },
        {
            "context": "DeepLoc: prediction of protein subcellular localization using deep learning. Motivation: The prediction of eukaryotic protein subcellular localization is a well-studied topic in bioinformatics due to its relevance in proteomics research. Many machine learning methods have been successfully applied in this task, but in most of them, predictions rely on annotation of homologues from knowledge databases. For novel proteins where no annotated homologues exist, and for predicting the effects of sequence variants, it is desirable to have methods for predicting protein properties from sequence information only. Results: Here, we present a prediction algorithm using deep neural networks to predict protein subcellular localization relying only on sequence information. At its core, the prediction model uses a recurrent neural network that processes the entire protein sequence and an attention mechanism identifying protein regions important for the subcellular localization. The model was trained and tested on a protein dataset extracted from one of the latest UniProt releases, in which experimentally annotated proteins follow more stringent criteria than previously. We demonstrate that our model achieves a good accuracy (78% for 10 categories; 92% for membrane-bound or soluble), outperforming current state-of-the-art algorithms, including those relying on homology information. Availability and implementation: The method is available as a web server at http://www.cbs.dtu.dk/services/DeepLoc. Example code is available at https://github.com/JJAlmagro/subcellular_localization. The dataset is available at http://www.cbs.dtu.dk/services/DeepLoc/data.php. Contact: jjalma@dtu.dk.",
            "question": "Which algorithm has been developed for prediction of protein subcellular localization using deep learning?",
            "answers": {
                "answer_start": 0,
                "text": "DeepLoc"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers. METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 and 1,200 mg) were administered to eight groups of eight subjects per group (two subjects randomized to placebo and six subjects to opicapone), under a double-blind, randomized, placebo-controlled design. In an additional group of 12 subjects, a 50 mg single dose of opicapone was administered on two occasions, once having fasted overnight and once with a high-fat high-calorie meal. RESULTS: Opicapone was well tolerated at all doses tested. The extent of systemic exposure (area under the plasma concentration-time curve and maximum plasma concentration) to opicapone and metabolites increased in an approximately dose-proportional manner and showed a decrease following concomitant ingestion of a high-fat high-calorie meal. The apparent terminal elimination half-life of opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway for opicapone, and both opicapone and the main sulphated metabolite are likely excreted by the biliary route. Maximum COMT inhibition by opicapone was dose dependent, ranged from 36.1% (10 mg) to 100% (200 mg and above), and reached statistical significance at all doses tested. The long duration of COMT inhibition by opicapone, however, tended to be independent from the dose taken. The observed half-life of opicapone-induced COMT inhibition in human erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an underlying dissociative process with a kinetic rate constant of 3.1 × 10(-6) s(-1) (SD = 1.9 × 10(-6) s(-1)). Such a process compares well to the estimated dissociation rate constant (k(off)) of the COMT-opicapone molecular complex (k(off) = 1.9 × 10(-6) s(-1)). CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 290,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "Inhibitory profile of SEA0400 [2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline] assessed on the cardiac Na+-Ca2+ exchanger, NCX1.1. SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) has recently been described as a potent and selective inhibitor of Na(+)-Ca(2+) exchange in cardiac, neuronal, and renal preparations. The inhibitory effects of SEA0400 were investigated on the cloned cardiac Na(+)-Ca(2+) exchanger, NCX1.1, expressed in Xenopus laevis oocytes to gain insight into its inhibitory mechanism. Na(+)-Ca(2+) exchange currents were measured using the giant excised patch technique using conditions to evaluate both inward and outward currents. SEA0400 inhibited outward Na(+)-Ca(2+) exchange currents with high affinity (IC(50) = 78 +/- 15 and 23 +/- 4 nM for peak and steady-state currents, respectively). Considerably less inhibitory potency (i.e., micromolar) was observed for inward currents. The inhibitory profile was reexamined after proteolytic treatment of excised patches with alpha-chymotrypsin, a procedure that eliminates ionic regulatory mechanisms. After this treatment, an IC(50) value of 1.2 +/- 0.6 microM was estimated for outward currents, whereas inward currents became almost insensitive to SEA0400. The inhibitory effects of SEA0400 on outward exchange currents were evident at both high and low concentrations of regulatory Ca(2+), although distinct features were noted. SEA0400 accelerated the inactivation rate of outward currents. Based on paired pulse experiments, SEA0400 altered the recovery of exchangers from the Na(+)(i)-dependent inactive state, particularly at higher regulatory Ca(2+)(i) concentrations. Finally, the inhibitory potency of SEA0400 was strongly dependent on the intracellular Na(+) concentration. Our data confirm that SEA0400 is the most potent inhibitor of the cardiac Na(+)-Ca(2+) exchanger described to date and provide a reasonable explanation for its apparent transport mode selectivity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 445,
                "text": "NCX"
            }
        },
        {
            "context": "Development of endometrial carcinoma in a patient with leprechaunism (donohue syndrome). Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 231,
                "text": "insulin receptor"
            }
        },
        {
            "context": "TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules. Summary: The molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton. Contact: luis.sanchez-pulido@igmm.ed.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "What is the function of the TMEM132 genes?",
            "answers": {
                "answer_start": 864,
                "text": "cellular adhesion function"
            }
        },
        {
            "context": "Systemic RNAi in the small hive beetle Aethina tumida Murray (Coleoptera: Nitidulidae), a serious pest of the European honey bee Apis mellifera. BACKGROUND: Aethina tumida is a serious pest of the European honey bee (Apis mellifera) in North America and Australia. Here we investigate whether Laccase 2, the phenoloxidase gene essential for cuticle sclerotisation and pigmentation in many insects, and vacuolar-ATPase V-type subunit A, vital for the generation of proton gradients used to drive a range of transport processes, could be potential targets for RNAi-mediated control of A. tumida. RESULTS: Injection of V-ATPase subunit A (5 ng) and Laccase 2 (12.5 ng) dsRNAs resulted in 100% larval mortality, and qPCR confirmed significant decreases and enhanced suppression of transcript levels over time. Oral delivery of V-ATPase subunit A dsRNA in solutions resulted in 50% mortality; however, gene suppression could not be verified. We suggest that the inconsistent RNAi effect was a consequence of dsRNA degradation within the gut owing to the presence of extracellular nucleases. Target specificity was confirmed by a lack of effect on survival or gene expression in honey bees injected with A. tumida dsRNAs. CONCLUSION: This is the first study to show evidence for systemic RNAi in A. tumida in response to injected dsRNA, but further research is required to develop methods to induce RNAi effects via ingestion. © 2016 Crown copyright. Pest Management Science © 2016 Society of Chemical Industry.",
            "question": "What is the genus for the common European honey bee?",
            "answers": {
                "answer_start": 217,
                "text": "Apis"
            }
        },
        {
            "context": "Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment. Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeurotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of erythroid and megakaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bach1 and the relationship or redundancy between Bach1 and p45 in megakaryocytes remain to be clarified. To address these issues, we generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired maturation of the megakaryocytes, and they developed myelofibrosis. The megakaryocytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes. These findings thus provide evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megakaryocytes.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 1497,
                "text": "repressor"
            }
        },
        {
            "context": "Additional phenotypic features of Muenke syndrome in 2 Dutch families. In about 30% of the patients with syndromal craniosynostosis, a genetic mutation can be traced. For the purpose of adequate genetic counseling and treatment of these patients, the full spectrum of clinical findings for each specific mutation needs to be appreciated. The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes. A number of studies on the relationship between genotype and phenotype concerning this specific mutation have been published. Two Dutch families with Muenke syndrome were screened for the reported characteristics of this syndrome and for additional features. New phenotypical findings were hypoplasia of the frontal sinus, ptosis of the upper eyelids, dysplastic elbow joints with restricted elbow motion, and mild cutaneous syndactyly. Incidentally, polydactyly, severe ankylosis of the elbow, fusion of cervical vertebrae, and epilepsy were found. Upper eyelid ptosis is thought to be pathognomonic for Saethre-Chotzen syndrome but was also observed in our series of patients with Muenke syndrome. Because Muenke and Saethre-Chotzen syndrome can have similar phenotypes, DNA analysis is needed to distinguish between these syndromes, even when a syndrome diagnosis is already made in a family member.",
            "question": "How many different mutations have been associated with Muenke syndrome?",
            "answers": {
                "answer_start": 428,
                "text": "one"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1044,
                "text": "Thyroid"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1564,
                "text": "factor Xa"
            }
        },
        {
            "context": "Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation. BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 35,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 224,
                "text": "SLC9A6"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2246,
                "text": "stroke"
            }
        },
        {
            "context": "Using Mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes. Plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. To understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. Since extensive data support the proposal that foreign DNA acquires the host's nucleotide composition during long-term residence, comparison of nucleotide composition of plasmids and chromosomes could shed light on a plasmid's evolutionary history. The average absolute dinucleotide relative abundance difference, termed delta-distance, has been commonly used to measure differences in dinucleotide composition, or 'genomic signature', between bacterial chromosomes and plasmids. Here, we introduce the Mahalanobis distance, which takes into account the variance-covariance structure of the chromosome signatures. We demonstrate that the Mahalanobis distance is better than the delta-distance at measuring genomic signature differences between plasmids and chromosomes of potential hosts. We illustrate the usefulness of this metric for proposing candidate long-term hosts for plasmids, focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from Escherichia coli O157:H7, as well as the broad host range multi-drug resistance plasmid pB10 from an unknown host.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 1124,
                "text": "delta-distance"
            }
        },
        {
            "context": "Mutational analysis of copper binding by human tyrosinase. Tyrosinase (EC 1.14.18.1) is a copper-containing enzyme that catalyzes several reactions in the biosynthesis of melanin pigments and is deficient in patients with type I oculocutaneous albinism (OCA1). Tyrosinase is thought to bind two copper ions, one at each of two conserved sequence motifs, termed CuA and CuB, but to date this has been directly proved only for the Neurospora and mushroom enzyme. Here, we demonstrate that mammalian tyrosinase directly binds copper, and that the CuA and CuB sites are both required for copper binding and for catalytic activity. We show that in human tyrosinase, copper binding by the CuB site is most likely coordinated by residues His363, His367, and His389, and that copper binding may be cooperative, with copper binding at one site facilitating copper binding by the other site. Furthermore, correct folding of the tyrosinase polypeptide appears to be necessary for copper binding, and a number of human OCA1 mutations disrupt copper binding and thus catalytic function of tyrosinase.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 59,
                "text": "Tyrosinase"
            }
        },
        {
            "context": "Regulating heart development: the role of Nf1. Neurofibromatosis type 1 (NF1) is one of the most common human genetic disorders and is associated with significant morbidity and mortality. The gene responsible for this disorder, NF1, encodes neurofibromin, which can function to down-regulate ras activity. Mutations that inactivate NF7 result in elevated levels of ras signaling and increased cell proliferation in some tissues. NF7 functions as a tumor suppressor gene; patients inherit one mutated copy and are believed to acquire a \"second hit\" in tissues that go on to form benign or malignant tumors. NF7 is expressed widely, yet certain tissues are more susceptible to growth dysregulation in NF1 patients. Cardiovascular defects also contribute to NF1, though the cause remains unclear. In a recent study, we used tissue-specific gene inactivation in mice to study the role of neurofibromin in heart development. A further understanding of neurofibromin function will help to elucidate the pathophysiology of NF1 and will also lead to a better understanding of cell cycle regulation and ras pathways in specific cell types. Finally, we comment on how similar genetic strategies can be used in mice to study the role of additional signaling pathways involved in heart development.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 228,
                "text": "NF1"
            }
        },
        {
            "context": "Augmentation of restless leg syndrome (Willis-Ekbom disease) during long-term dopaminergic treatment. Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common sensorimotor disorder that can generally be effectively managed in the primary care clinic. However, some treatment complications may arise. According to the recommendations of the International Restless Legs Syndrome Study Group, non-ergot dopamine-receptor agonists have over the past years been one of the first-line treatments for patients with RLS/WED requiring pharmacological therapy. Augmentation is the main complication of long-term dopaminergic treatment of RLS/WED and is defined as an overall worsening of symptoms beyond pretreatment levels in patients who experienced an initial positive therapeutic response. Once identified on the basis of its characteristic clinical features, augmentation requires careful management. In order to provide clinicians with a comprehensive understanding of this common treatment complication, this review discusses the clinical features of augmentation, and its differentiation from morning rebound, symptom fluctuations and natural disease progression. Reported incidences of augmentation in clinical trials of dopaminergic RLS/WED therapies are summarized. Finally, the hypothetical pathophysiology of augmentation and the current recommendations for management of patients with augmented RLS/WED symptoms are discussed.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 102,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. PURPOSE: p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM). EXPERIMENTAL DESIGN: We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3. RESULTS: The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells. CONCLUSIONS: This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy.",
            "question": "Which protein is the E3-ubiquitin ligase that targets the tumor suppressor p53 for proteasomal degradation?",
            "answers": {
                "answer_start": 206,
                "text": "the human homologue of Mdm2 (Hdm2)"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 288,
                "text": "xa"
            }
        },
        {
            "context": "Characterization of mammalian selenoproteomes. In the genetic code, UGA serves as a stop signal and a selenocysteine codon, but no computational methods for identifying its coding function are available. Consequently, most selenoprotein genes are misannotated. We identified selenoprotein genes in sequenced mammalian genomes by methods that rely on identification of selenocysteine insertion RNA structures, the coding potential of UGA codons, and the presence of cysteine-containing homologs. The human selenoproteome consists of 25 selenoproteins.",
            "question": "How many selenoproteins are encoded in the human genome?",
            "answers": {
                "answer_start": 532,
                "text": "25"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1699,
                "text": "Xa"
            }
        },
        {
            "context": "Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells. The heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here, we report the antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy.",
            "question": "Which heat shock protein is found to be upregulated during Hsp90 inhibition?",
            "answers": {
                "answer_start": 1202,
                "text": "HSP70"
            }
        },
        {
            "context": "Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. STUDY OBJECTIVE: The literature suggests that the d -dimer is useful in patients suspected of having pulmonary embolism and who have a low pretest probability of disease. A previously defined clinical decision rule, the Wells Criteria, may provide a reliable and reproducible means of determining this pretest probability. We evaluate the interrater agreement and external validity of Wells Criteria in determining pretest probability in patients suspected of having pulmonary embolism. METHODS: This was a prospective observational study. Trained research assistants enrolled patients during 120 random 8-hour shifts. Patients who underwent imaging for pulmonary embolism after a medical history, physical examination, and chest radiograph were enrolled. Treating providers and research assistants determined pretest probability according to Wells Criteria in a blinded fashion. Two d -dimer assays were run. Three-month follow-up for the diagnosis of pulmonary embolism was performed. Interrater agreement tables were created. kappa Values, sensitivities, and specificities were determined. RESULTS: Of the 153 eligible patients, 3 patients were missed, 16 patients declined, and 134 (88%) patients were enrolled. Sixteen (12%) patients were diagnosed with pulmonary embolism. The kappa values for Wells Criteria were 0.54 and 0.72 for the trichotomized and dichotomized scorings, respectively. When Wells Criteria were trichotomized into low pretest probability (n=59, 44%), moderate pretest probability (n=61, 46%), or high pretest probability (n=14, 10%), the pulmonary embolism prevalence was 2%, 15%, and 43%, respectively. When Wells Criteria were dichotomized into pulmonary embolism-unlikely (n=88, 66%) or pulmonary embolism-likely (n=46, 34%), the prevalence was 3% and 28%, respectively. The immunoturbidimetric and rapid enzyme-linked immunosorbent assay d -dimer assays had similar sensitivities (94%) and specificities (45% versus 46%). CONCLUSION: Wells Criteria have a moderate to substantial interrater agreement and reliably risk stratify pretest probability in patients with suspected pulmonary embolism.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 1780,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "[Prevention of MRSA spread in the neurosurgical field]. We investigated the distribution of MRSA (methicillin-resistant Staphylococcus aureus) on and around six patients with MRSA infection in our neurosurgical ward. All patients had a disturbance of consciousness and had sputum colonization of MRSA. Samples were obtained from 11 sites (patients' hands, attendances' hands, floors, sidetables, bedclothes, chairs, walls, curtains, door knobs, faucets and disposable gloves) in the patients' rooms by the wiping method. High counts of MRSA were detected on horizontal planes such as floors, sidetables and chairs, but MRSA was not detected on vertical planes such as curtains and walls. The reason why MRSA was detected on the horizontal planes was due to a fall of MRSA spread from sputum in the air. These findings indicate that the disinfection of horizontal planes is important for preventing the spread of MRSA. We also evaluated what disinfectant was useful for floor disinfection and concluded that 0.5% chlorhexidine digluconate (Hibitane) and 0.5% benzalkonium chloride (Osvan) were more effective than the other usually-used disinfectants such as alkyldiaminoethyl glycine (Tego-51).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 92,
                "text": "MRSA"
            }
        },
        {
            "context": "Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 28,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 466,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Necrobiosis lipoidica diabeticorum: a clinicopathologic study. Necrobiosis lipoidica diabeticorum is an unusual dermatologic condition with a characteristic clinical appearance and a clear association with diabetes mellitus. There is currently no treatment that reverses the atrophic changes associated with this lesion. We have carried out a clinicopathologic study on 15 subjects and, in addition, have reviewed 10 further biopsy specimens of necrobiosis lipoidica diabeticorum. We found a frequent association of necrobiosis lipoidica diabeticorum with other chronic complications of diabetes mellitus, including limited joint mobility. It is possible that nonenzymatic glucosylation or other changes in collagen may be important in the etiology of necrobiosis lipoidica diabeticorum and the limited joint mobility. We confirmed that cutaneous anesthesia is usually present in the necrobiosis lipoidica diabeticorum lesions. With the use of an antibody to S100 protein and an immunohistochemical method, there was an apparent decreased number of nerves in the skin lesions. We suggest that sensory loss results from local destruction of cutaneous nerves by the inflammatory process. Finally, in six elliptical biopsies extending into clinically normal skin, we demonstrated that the inflammatory infiltrate of necrobiosis lipoidica diabeticorum extended from the lesion into apparently normal skin surrounding clinically active lesions. Thus, intradermal steroids might be administered to perilesional areas surrounding active lesions in the hope of halting progression.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 206,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model. BACKGROUND & AIMS: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 14,
                "text": "Liver"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 473,
                "text": "FSHD"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 874,
                "text": "2"
            }
        },
        {
            "context": "Detection of tomatinase from Fusarium oxysporum f. sp. lycopersici in infected tomato plants. The antifungal glycoalkaloid alpha-tomatine of the tomato plant (Lycopersicon esculentum) is proposed to protect the plant against phytopathogenic fungi. Fusarium oxysporum f. sp. lycopersici, a vascular pathogen of tomato, produces a tomatinase enzyme which hydrolyses the glycoalkaloid into non-fungitoxic compounds. Detoxification of alpha-tomatine may be how this fungus avoids the plant glycoalkaloid barrier. As an initial step to evaluate this possibility we have studied the induction of tomatinase; (i) in fungal cultures containing extracts from leaf, stem or root of tomato plants; and (ii) in stem and root of tomato plants infected with the pathogen at different infection stages. The kinetics of tomatinase induction with leaf extract (0.6% dry weight) was similar to that observed with 20 micrograms ml-1 of alpha-tomatine. In the presence of stem extract, tomatinase activity was less than 50% of that induced with leaf extract, whereas in the presence of root extract tomatinase activity was very low. In the stem of infected tomato plants tomatinase activity was higher at the wilt stage than in previous infections stages and in root, tomatinase activity appeared with the first symptoms and was maintained until wilting. TLC analysis showed that the tomatinase induced in culture medium with plant extracts and in infected tomato plants had the same mode of action as the enzyme induced with pure alpha-tomatine, hydrolysing the glycoalkaloid into its non-fungitoxic forms, tomatidine and beta-lycotetraose. The antisera raised against purified tomatinase recognized in extracts of root and stem of infected tomato plants a protein of 50000 (45000 when proteins were deglycosylated), corresponding to the tomatinase enzyme. Therefore, it is concluded that F. oxysporum f. sp. lycopersici express tomatinase in vivo as a result of the infection of tomato plant.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 310,
                "text": "tomato"
            }
        },
        {
            "context": "Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1603,
                "text": "PD-L1"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 0,
                "text": "INCA"
            }
        },
        {
            "context": "Childhood ADHD symptoms are associated with lifetime and current illicit substance-use disorders and in-site health risk behaviors in a representative sample of Latino prison inmates. OBJECTIVE: This study aimed to explore retrospective childhood ADHD symptomatology, psychiatric comorbidity, rates of substance-use disorders (SUD), as well as their association with high-risk health behaviors in prison and adverse health outcomes. METHOD: A randomly selected representative sample of inmates in the Puerto Rico correctional system (N = 1,179) was assessed with the Spanish-language Wender Utah Rating Scale (WURS); the Composite International Diagnostic Interview (CIDI) modules for lifetime/current major depression disorder (MDD), generalized anxiety disorder (GAD), and SUD; the Davidson Trauma Scale (DTS; posttraumatic stress disorder [PTSD]); and self-reports of in-site high-risk behaviors. RESULTS: Wald χ(2) tests revealed significant associations of ADHD with MDD and PTSD, as well as increased risk for overdosing and intravenous drug use in prison. A logistic regression model adjusted for mood and anxiety comorbidity predicted lifetime SUD diagnosis (odds ratio = 2.38; 95% confidence interval = [1.15, 4.94]). CONCLUSION: Our results provide further evidence on the association of drug dependence and ADHD symptoms, and their overrepresentation among prison inmates.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 843,
                "text": "PTSD"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 551,
                "text": "CAGEr"
            }
        },
        {
            "context": "Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. The human melanocortin-1 receptor gene (MC1R) encodes a G-protein coupled receptor that is primarily expressed on melanocytes, where it plays a key role in pigmentation regulation. Variant alleles are associated with red hair colour and fair skin, known as the RHC phenotype, as well as skin cancer risk. The R151C, R160W and D294H alleles, designated 'R', are strongly associated with the RHC phenotype and have been proposed to result in loss of function receptors due to impaired G-protein coupling. We recently provided evidence that the R151C and R160W variants can efficiently couple to G-proteins in response to alpha-melanocyte stimulating hormone. The possibility that altered cellular localization of the R151C and R160W variant receptors could underlie their association with RHC was therefore considered. Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors. In additional exogenous expression studies, the R variant D84E and the rare I155T variant, also demonstrated a significant reduction in plasma membrane receptor numbers. The V60L, V92M and R163Q weakly associated RHC alleles, designated 'r', were expressed with normal or intermediate cell surface receptor levels. These results indicate that reduced receptor coupling activity may not be the only contributing factor to the genetic association between the MC1R variants and the RHC phenotype, with MC1R polymorphisms now linked to a change in receptor localization.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 41,
                "text": "MC1R"
            }
        },
        {
            "context": "The Cajal body. The Cajal body, originally identified over 100 years ago as a nucleolar accessory body in neurons, has come to be identified with nucleoplasmic structures, often quite tiny, that contain coiled threads of the marker protein, coilin. The interaction of coilin with other proteins appears to increase the efficiency of several nuclear processes by concentrating their components in the Cajal body. The best-known of these processes is the modification and assembly of U snRNPs, some of which eventually form the RNA splicing machinery, or spliceosome. Over the last 10 years, research into the function of Cajal bodies has been greatly stimulated by the discovery that SMN, the protein deficient in the inherited neuromuscular disease, spinal muscular atrophy, is a Cajal body component and has an essential role in the assembly of spliceosomal U snRNPs in the cytoplasm and their delivery to the Cajal body in the nucleus.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 241,
                "text": "coilin"
            }
        },
        {
            "context": "Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1-/+;Trp53-/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1-/-;Trp53-/- astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor-stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 379,
                "text": "NF1"
            }
        },
        {
            "context": "Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma. Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour - medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 161,
                "text": "cancer"
            }
        },
        {
            "context": "Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 409,
                "text": "PLN"
            }
        },
        {
            "context": "Deciphering transcription dysregulation in FSH muscular dystrophy. DUX4, a homeobox-containing gene present in a tandem array, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant autosomal disease. New findings about DUX4 have raised as many fundamental questions about the molecular pathology of this unique disease as they have answered. This review discusses recent studies addressing the question of whether there is extensive FSHD-related transcription dysregulation in adult-derived myoblasts and myotubes, the precursors for muscle repair. Two models for the role of DUX4 in FSHD are presented. One involves transient pathogenic expression of DUX4 in many cells in the muscle lineage before the myoblast stage resulting in a persistent, disease-related transcription profile ('Majority Rules'), which might be enhanced by subsequent oscillatory expression of DUX4. The other model emphasizes the toxic effects of inappropriate expression of DUX4 in only an extremely small percentage of FSHD myoblasts or myotube nuclei ('Minority Rules'). The currently favored Minority Rules model is not supported by recent studies of transcription dysregulation in FSHD myoblasts and myotubes. It also presents other difficulties, for example, explaining the expression of full-length DUX4 transcripts in FSHD fibroblasts. The Majority Rules model is the simpler explanation of findings about FSHD-associated gene expression and the DUX4-encoded homeodomain-type protein.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 184,
                "text": "FSHD"
            }
        },
        {
            "context": "Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, <20% represent C-->T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 267,
                "text": "NF1"
            }
        },
        {
            "context": "Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients. Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes. Compared to other methods, the protein truncation test (PTT) provides improved efficiency in detecting NF1 mutations which are dispersed throughout the gene which spans 350 kilobases of genomic DNA. We have applied the PTT and subsequent sequence analysis of cloned cDNA to identify mutations in NF1 patients. We report here the identification of two novel (W336X and Q315X), and one recurrent (R304X) mutation located in exon 7 and show that all three premature termination codons lead to skipping of exon 7 in a proportion of the transcripts derived from the mutated allele. Possible mutation-induced alterations of the RNA secondary structure and their impact on skipping of exon 7 of the NF1 gene are explored and discussed.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 237,
                "text": "NF1"
            }
        },
        {
            "context": "Role of fusaric acid in the development of 'Fusarium wilt' symptoms in tomato: Physiological, biochemical and proteomic perspectives. Fusarium wilt is one of the most prevalent and damaging diseases of tomato. Among various toxins secreted by the Fusarium oxysporum f. sp. lycopersici (causal agent of Fusarium wilt of tomato), fusaric acid (FA) is suspected to be a potent pathogenicity factor in tomato wilt disease development. With this rationale the present study was carried out with physiological, biochemical and proteomic perspectives. Treatment of FA was given to the leaves of tomato directly through infiltration to show the characteristic features of Fusarium wilt of tomato. The phytotoxic effect of FA was assessed in the form of cell death in tomato leaves which was observed by increased uptake of Evans blue stain. The measurement of electrolyte leakage was used as an indicator of the extent of cell death. The influence of FA on the leaf photosynthesis of tomato plant was investigated and it was found that FA strongly reduced the photosynthetic pigment contents of tomato leaves resulting to heavy suppression of leaf photosynthesis processes, which therefore affected leaf physiology finally leading to leaf wilting and necrosis. This cell death inducer (FA) produced an enormous oxidative burst during which large quantities of reactive oxygen species (ROS) like HO was generated in the treated leaf tissues of tomato plants which was evident from enhancement in lipid peroxidation. To assess the involvement of proteolysis in the cell death cascade induced by FA treatment, total protease activity was measured in the leaf tissues and it was found that the total protease activity increased with the treatment and leading to cell death. Furthermore, proteomic study was used as a powerful tool to understand the alterations in cellular protein expression in response to FA exposure. Differential expression in several proteins was observed in the present study. Proteomic analyses, thus, clearly indicate that proteins belonging to different functional classes are significantly affected in the plant leaf tissues after FA exposure leading to deterioration of structure and metabolism of cells. Thus, it is concluded that FA plays an important role in fungal pathogenicity by decreasing cell viability.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 319,
                "text": "tomato"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "Comparison of TVT and TOT on urethral mobility and surgical outcomes in stress urinary incontinence with hypermobile urethra. OBJECTIVE: To compare the change of urethral mobility after midurethral sling procedures in stress urinary incontinence with hypermobile urethra and assess these findings with surgical outcomes. STUDY DESIGN: 141 women who agreed to undergo midurethral sling operations due to stress urinary incontinence with hypermobile urethra were enrolled in this non-randomized prospective observational study. Preoperatively, urethral mobility was measured by Q tip test. All women were asked to complete Urogenital Distress Inventory Short Form (UDI-6) and Incontinence Impact Questionnaire Short Form (IIQ-7) to assess the quality of life. Six months postoperatively, Q tip test and quality of life assessment were repeated. The primary surgical outcomes were classified as cure, improvement and failure. Transient urinary obstruction, de novo urgency, voiding dysfunction were secondary surgical outcomes. RESULTS: Of 141 women, 50 (35. 5%) women underwent TOT, 91 (64.5%) underwent TVT. In both TOT and TVT groups, postoperative Q tip test values, IIQ-7 and UDI-6 scores were statistically reduced when compared with preoperative values. Postoperative Q tip test value in TVT group was significantly smaller than in TOT group [25°(15-45°) and 20° (15-45°), respectively]. When we compared the Q-tip test value, IIQ-7 and UDI-6 scores changes, there were no statistically significant changes between the groups. Postoperative urethral mobility was more frequent in TOT group than in TVT group (40% vs 23.1%, respectively). Postoperative primary and secondary outcomes were similar in both groups. CONCLUSIONS: Although midurethral slings decrease the urethtal hypermobility, postoperative mobility status of urethra does not effect surgical outcomes of midurethral slings in women with preoperative urethral hypermobility.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 403,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies. Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.",
            "question": "Which is the most common gene signature in Rheumatoid Arthritis patients?",
            "answers": {
                "answer_start": 1041,
                "text": "interferon signature"
            }
        },
        {
            "context": "Human XIST yeast artificial chromosome transgenes show partial X inactivation center function in mouse embryonic stem cells. Initiation of X chromosome inactivation requires the presence, in cis, of the X inactivation center (XIC). The Xist gene, which lies within the XIC region in both human and mouse and has the unique property of being expressed only from the inactive X chromosome in female somatic cells, is known to be essential for X inactivation based on targeted deletions in the mouse. Although our understanding of the developmental regulation and function of the mouse Xist gene has progressed rapidly, less is known about its human homolog. To address this and to assess the cross-species conservation of X inactivation, a 480-kb yeast artificial chromosome containing the human XIST gene was introduced into mouse embryonic stem (ES) cells. The human XIST transcript was expressed and could coat the mouse autosome from which it was transcribed, indicating that the factors required for cis association are conserved in mouse ES cells. Cis inactivation as a result of human XIST expression was found in only a proportion of differentiated cells, suggesting that the events downstream of XIST RNA coating that culminate in stable inactivation may require species-specific factors. Human XIST RNA appears to coat mouse autosomes in ES cells before in vitro differentiation, in contrast to the behavior of the mouse Xist gene in undifferentiated ES cells, where an unstable transcript and no chromosome coating are found. This may not only reflect important species differences in Xist regulation but also provides evidence that factors implicated in Xist RNA chromosome coating may already be present in undifferentiated ES cells.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 236,
                "text": "Xist"
            }
        },
        {
            "context": "Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells. Telomerase is required for the unlimited lifespan of cancer cells. The vast majority of pancreatic adenocarcinomas overexpress telomerase activity and blocking telomerase could limit their lifespan. GRN163L (Imetelstat) is a lipid-conjugated N3'→P5' thio-phosphoramidate oligonucleotide that blocks the template region of telomerase. The aim of this study was to define the effects of long-term GRN163L exposure on the maintenance of telomeres and lifespan of pancreatic cancer cells. Telomere size, telomerase activity, and telomerase inhibition response to GRN163L were measured in a panel of 10 pancreatic cancer cell lines. The cell lines exhibited large differences in levels of telomerase activity (46-fold variation), but most lines had very short telomeres (2-3 kb in size). GRN163L inhibited telomerase in all 10 pancreatic cancer cell lines, with IC50 ranging from 50 nM to 200 nM. Continuous GRN163L exposure of CAPAN1 (IC50 = 75 nM) and CD18 cells (IC50 = 204 nM) resulted in an initial rapid shortening of the telomeres followed by the maintenance of extremely short but stable telomeres. Continuous exposure to the drug eventually led to crisis and to a complete loss of viability after 47 (CAPAN1) and 69 (CD18) doublings. Crisis In these cells was accompanied by activation of a DNA damage response (γ-H2AX) and evidence of both senescence (SA-β-galactosidase activity) and apoptosis (sub-G1 DNA content, PARP cleavage). Removal of the drug after long-term GRN163L exposure led to a reactivation of telomerase and re-elongation of telomeres in the third week of cultivation without GRN163L. These findings show that the lifespan of pancreatic cancer cells can be limited by continuous telomerase inhibition. These results should facilitate the design of future clinical trials of GRN163L in patients with pancreatic cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 0,
                "text": "Telomerase"
            }
        },
        {
            "context": "Chronic myelogenous leukemia with the e6a2 BCR-ABL and lacking imatinib response: presentation of two cases. The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur. The current report describes two e6a2 CML patients with imatinib treatment failure and unusual disease progression. One patient was Philadelphia chromosome positive and one was Philadelphia chromosome negative with an atypical BCR-ABL rearrangement, ins (22;9).",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 113,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 674,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 601,
                "text": "Hsp90"
            }
        },
        {
            "context": "Fibrillin gene (FBN1) mutations in Japanese patients with Marfan syndrome. Marfan syndrome (MFS; MIM #154700) is a connective tissue disorder characterized by cardiovascular, skeletal, and ocular abnormalities. The fibrillin-1 gene (FBN1; MIM no. 134797) on chromosome 15 was revealed to be the cause of Marfan syndrome. To date over 137 types of FBN1 mutations have been reported. In this study, two novel mutations and a recurrent de-novo mutation were identified in patients with MFS by means of single-strand conformational polymorphism (SSCP) analysis. The two novel mutations are a 4-bp deletion at nucleotide 2820-2823 and a G-to-T transversion at nucleotide 1421 (C474F), located on exon 23 and exon 11, respectively. A previously reported mutation at the splicing donor site of intron 2 (IVS2 G + 1A), which is predicted to cause exon skipping, was identified in a sporadic patient with classical MFS.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 16,
                "text": "FBN1"
            }
        },
        {
            "context": "High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. BACKGROUND AND OBJECTIVES: Iron depletion is common in regular blood donors. The objective of the study was to investigate the frequency and severity of iron depletion in regular blood donors and whether IV iron is more effective than oral to avoid iron depletion and symptoms thereof, especially restless legs syndrome (RLS). METHOD: One hundred and twenty blood donors with at least five previous whole blood donations were randomized to receive either IV iron sucrose (Venofer(®), RenaPharma/Vifor, Uppsala, Sweden), 200 mg, or to 20×100 mg of oral iron sulphate (Duroferon(®), GlaxoSmithKline, Stockholm, Sweden), after each blood donation during 1 year. Iron status and RLS incidence and severity were investigated. RESULTS: Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). The IV iron group increased storage iron to a greater extent than the oral iron group after 12 months (P=0·0043). Female donors were more responsive to IV iron sucrose compared to oral iron sulphate, particularly female donors below 50 years of age. RLS severity scores were significantly lower in the IV iron group. The two treatments were safe. CONCLUSION: Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. IV iron sucrose substitutes iron loss in blood donors more efficiently compared with oral iron sulphate, especially in women. Iron substitution to blood donors should be individualized and based on P-ferritin monitoring.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1485,
                "text": "iron"
            }
        },
        {
            "context": "Phenotypic and molecular analyses of X-linked dystonia-parkinsonism (\"lubag\") in women. BACKGROUND: X-linked dystonia-parkinsonism (XDP) or \"lubag\" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 37,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Glivec and CML: a lucky date. Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 762,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Quantification of UCP1 function in human brown adipose tissue. Brown adipose tissue (BAT) mitochondria are distinct from their counterparts in other tissues in that ATP production is not their primary physiologic role. BAT mitochondria are equipped with a specialized protein known as uncoupling protein 1 (UCP1). UCP1 short-circuits the electron transport chain, allowing mitochondrial membrane potential to be transduced to heat, making BAT a tissue capable of altering energy expenditure and fuel metabolism in mammals without increasing physical activity. The recent discovery that adult humans have metabolically active BAT has rekindled an interest in this intriguing tissue, with the overarching aim of manipulating BAT function to augment energy expenditure as a countermeasure for obesity and the metabolic abnormalities it incurs. Subsequently, there has been heightened interest in quantifying BAT function and more specifically, determining UCP1-mediated thermogenesis in BAT specimens - including in those obtained from humans. In this article, BAT mitochondrial bioenergetics will be described and compared with more conventional mitochondria in other tissues. The biochemical methods typically used to quantify BAT mitochondrial function will also be discussed in terms of their specificity for assaying UCP1 mediated thermogenesis. Finally, recent data concerning BAT UCP1 function in humans will be described and discussed.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 285,
                "text": "uncoupling protein 1"
            }
        },
        {
            "context": "Severe pulmonary congestion in a near miss at the first seizure: further evidence for respiratory dysfunction in sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy (SUDEP) is the most important direct seizure-related cause of death, and most cases usually occur in patients with intractable, longstanding epilepsy. Suspected mechanisms for SUDEP include central and obstructive apnea, cardiac arrhythmia, postictal respiratory arrest, and primary cessation of brain activity. We report a patient who experienced a near SUDEP following his first prolonged tonic-clonic seizure requiring intubation. Chest X-ray examination showed severe bilateral congestion of the middle and superior pulmonary fields and an enlarged heart. Observations of pulmonary compromise in near-miss patients are extremely rare. Our patient showed marked cyanosis and respiratory distress after the index seizure, in agreement with the view that respiratory distress was the primary etiology in this case. Moreover, this observation confirms that SUDEP is not exclusively an issue for patients with chronic, uncontrolled epilepsy.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 150,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. BACKGROUND: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms. METHODS: PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene-gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence. RESULTS: A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On the background of the BDNF Val66Val genotype, DTS score increased significantly with the addition of a DRD2 Taq1A A1 allele. However, on the BDNF Met66 allele background, the addition of an A1 allele was found to reduce total DTS score. CONCLUSIONS: This study provides preliminary evidence for an epistatic interaction between BDNF Val66Met and DRD2 Taq1A polymorphisms on the severity of PTSD symptoms, where both too little and too much dopamine can result in increased PTSD symptom severity.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 545,
                "text": "PTSD"
            }
        },
        {
            "context": "Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review. BACKGROUND: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene. CASE PRESENTATION: We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data. CONCLUSIONS: Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 75,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 690,
                "text": "ADAR"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 158,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "The role of amino-terminal sequences in cellular localization and antiviral activity of APOBEC3B. Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δvif, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δvif, and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1Δvif packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1Δvif, while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1Δvif by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 917,
                "text": " nuclear"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 0,
                "text": "GBshape"
            }
        },
        {
            "context": "Expression and function of Noxo1gamma, an alternative splicing form of the NADPH oxidase organizer 1. Activation of the superoxide-producing NADPH oxidase Nox1 requires both the organizer protein Noxo1 and the activator protein Noxa1. Here we describe an alternative splicing form of Noxo1, Noxo1gamma, which is expressed in the testis and fetal brain. The Noxo1gamma protein contains an additional five amino acids in the N-terminal PX domain, a phosphoinositide-binding module; the domain plays an essential role in supporting superoxide production by NADPH oxidase (Nox) family oxidases including Nox1, gp91(phox)/Nox2, and Nox3, as shown in this study. The PX domain isolated from Noxo1gamma shows a lower affinity for phosphoinositides than that from the classical splicing form Noxo1beta. Consistent with this, in resting cells, Noxo1gamma is poorly localized to the membrane, and thus less effective in activating Nox1 than Noxo1beta, which is constitutively present at the membrane. On the other hand, cell stimulation with phorbol 12-myristate 13-acetate (PMA), an activator of Nox1-3, facilitates membrane translocation of Noxo1gamma; as a result, Noxo1gamma is equivalent to Noxo1beta in Nox1 activation in PMA-stimulated cells. The effect of the five-amino-acid insertion in the Noxo1 PX domain appears to depend on the type of Nox; in activation of gp91(phox)/Nox2, Noxo1gamma is less active than Noxo1beta even in the presence of PMA, whereas Noxo1gamma and Noxo1beta support the superoxide-producing activity of Nox3 to the same extent in a manner independent of cell stimulation.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 155,
                "text": "Nox1"
            }
        },
        {
            "context": "Effect of dural detachment on long-term tumor control for meningiomas treated using Simpson grade IV resection. OBJECT: Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrence-free survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection. METHODS: This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth. RESULTS: A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm(3) or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41-45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18-218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm(3) or more was not a statistically significant risk factor. CONCLUSIONS: Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long-term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high-risk meningiomas not amenable to gross-total resection.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 58,
                "text": "meningioma"
            }
        },
        {
            "context": "New synthetic antithrombotic agents for venous thromboembolism: pentasaccharides, direct thrombin inhibitors, direct Xa inhibitors. Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 829,
                "text": "xa"
            }
        },
        {
            "context": "JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4(+) T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 734,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 131,
                "text": "Stroke"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L.) 11. Molecular cloning and expression of alfalfa isoflavone reductase, a key enzyme of isoflavonoid phytoalexin biosynthesis. The major phytoalexin in alfalfa is the isoflavonoid (-)-medicarpin (or 6aR, 11aR)-medicarpin. Isoflavone reductase (IFR), the penultimate enzyme in medicarpin biosynthesis, is responsible for introducing one of two chiral centers in (-)-medicarpin. We have isolated a 1.18 kb alfalfa cDNA (pIFRalf1) which, when expressed in Escherichia coli, converts 2'-hydroxyformononetin stereospecifically to (3R)-vestitone, as would be predicted for IFR from alfalfa. The calculated molecular weight of the polypeptide (35,400) derived from the 954 bp open reading frame compares favorably to estimated Mrs determined for IFR proteins purified from other legumes. The transcript (1.4 kb) is highly induced in elicited alfalfa cell cultures. The kinetics of induction are consistent with the appearance of IFR activity, the accumulation of medicarpin, and the observed induction of other enzymes in the pathway. Low levels of IFR transcripts were found in healthy plant parts (roots and nodules) which accumulate low levels of a medicarpin glucoside. IFR appears to be encoded by a single gene in alfalfa. The cloning of IFR opens up the possibility of genetic manipulation of phytoalexin biosynthesis in alfalfa by altering isoflavonoid stereochemistry.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 231,
                "text": "medicarpin"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 596,
                "text": "xa"
            }
        },
        {
            "context": "Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.",
            "question": "When was empagliflozin FDA approved?",
            "answers": {
                "answer_start": 228,
                "text": "2014"
            }
        },
        {
            "context": "Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 170,
                "text": "FBN1"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 128,
                "text": "CD38"
            }
        },
        {
            "context": "Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors. Dopa decarboxylase (DDC), a pyridoxal 5'-phosphate (PLP) enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD). PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide) is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide) are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a) to use virtual screening to identify potential human DDC inhibitors and (b) to evaluate the reliability of our virtual-screening (VS) protocol by experimentally testing the \"in vitro\" activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with K(i) values > 10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with K(i) values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a K(i) value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 395,
                "text": "L-Dopa"
            }
        },
        {
            "context": "Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. McLeod syndrome is an X-linked multisystem disorder characterized by abnormalities in the neuromuscular and hematopoietic systems. We have assembled a cosmid contig of 360 kb that encompasses the McLeod gene locus. A 50 kb deletion was detected by screening DNA from patients with radiolabeled whole cosmids, and two transcription units were identified within this deletion. The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype. XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins. Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites. These findings provide direct evidence that XK is responsible for McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 524,
                "text": "XK"
            }
        },
        {
            "context": "LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.",
            "question": "Which R / bioconductor package is used for enrichment analysis of genomic regions?",
            "answers": {
                "answer_start": 0,
                "text": "LOLA"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 794,
                "text": "xa"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1637,
                "text": "factor Xa"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 297,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P-bodies. Argonaute proteins are effectors of RNA interference that function in the context of cytoplasmic ribonucleoprotein complexes to regulate gene expression. Processing bodies (PBs) and stress granules (SGs) are the two main types of ribonucleoprotein complexes with which Argonautes are associated. Targeting of Argonautes to these structures seems to be regulated by different factors. In the present study, we show that heat-shock protein (Hsp) 90 activity is required for efficient targeting of hAgo2 to PBs and SGs. Furthermore, pharmacological inhibition of Hsp90 was associated with reduced microRNA- and short interfering RNA-dependent gene silencing. Neither Dicer nor its cofactor TAR RNA binding protein (TRBP) associates with PBs or SGs, but interestingly, protein activator of the double-stranded RNA-activated protein kinase (PACT), another Dicer cofactor, is recruited to SGs. Formation of PBs and recruitment of hAgo2 to SGs were not dependent upon PACT (or TRBP) expression. Together, our data suggest that Hsp90 is a critical modulator of Argonaute function. Moreover, we propose that Ago2 and PACT form a complex that functions at the level of SGs.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 0,
                "text": "Hsp90"
            }
        },
        {
            "context": "Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Although the most common form of the disease is the classical infantile form (Krabbe disease), later-onset forms also have been described. We have analyzed the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD and in 1 patient with classical Krabbe disease. Half of the patients were heterozygous for the large gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that result in deficient galactocerebrosidase activity were also identified in these patients. They include the missense mutations R63H, G95S, M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-nt insertion in the RNA, caused by the aberrant splicing of intron 6. All of these genetic defects are clustered in the first 10 exons of the galactocerebrosidase gene and therefore affect the 50-kD subunit of the mature enzyme. Studies on the distribution and enzymatic activity of the polymorphic alleles 1637T/C (I546/T546) provided support for previous data that had indicated the existence of two galactocerebrosidase forms with different catalytic activities in the general population. Our data also indicate that the mutations occur preferentially in the \"low activity\" 1637C allele.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 183,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Transcription-coupled DNA repair in prokaryotes. Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) that acts specifically on lesions in the transcribed strand of expressed genes. First reported in mammalian cells, TCR was then documented in Escherichia coli. In this organism, an RNA polymerase arrested at a lesion is displaced by the transcription repair coupling factor, Mfd. This protein recruits the NER lesion-recognition factor UvrA, and then dissociates from the DNA. UvrA binds UvrB, and the assembled UvrAB* complex initiates repair. In mutants lacking active Mfd, TCR is absent. A gene transcribed by the bacteriophage T7 RNA polymerase in E. coli also requires Mfd for TCR. The CSB protein (missing or defective in cells of patients with Cockayne syndrome, complementation group B) is essential for TCR in humans. CSB and its homologs in higher eukaryotes are likely functional equivalents of Mfd.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 173,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation. The Ski-interacting protein SKIP/SNW1 associates with the P-TEFb/CDK9 elongation factor and coactivates inducible genes, including HIV-1. We show here that SKIP also associates with c-Myc and Menin, a subunit of the MLL1 histone methyltransferase (H3K4me3) complex and that HIV-1 Tat transactivation requires c-Myc and Menin, but not MLL1 or H3K4me3. RNAi-ChIP experiments reveal that SKIP acts downstream of Tat:P-TEFb to recruit c-Myc and its partner TRRAP, a scaffold for histone acetyltransferases, to the HIV-1 promoter. By contrast, SKIP is recruited by the RNF20 H2B ubiquitin ligase to the basal HIV-1 promoter in a step that is bypassed by Tat and downregulated by c-Myc. Of interest, we find that SKIP and P-TEFb are dispensable for UV stress-induced HIV-1 transcription, which is strongly upregulated by treating cells with the CDK9 inhibitor flavopiridol. Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an elongation step that is bypassed under stress.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 322,
                "text": "H3K4"
            }
        },
        {
            "context": "Non-A, non-B viral hepatitis in Egypt. A study was carried out on 200 patients of ages 20-40 years suffering from acute viral hepatitis. Sera were tested for markers of hepatitis B (HBsAg, and IgM anti-HBc) and hepatitis A (IgM-anti-HAV) by the ELISA technique. Sera negative for the markers of both viruses: Hepatitis A (HAV) and Hepatitis B (HBV) were subsequently tested for IGM Heterophil antibodies against Epstein-Barr virus (EBV) by the Monospot slide test to diagnose acute infectious mononucleosis and tested for anti-CMV (IgM) by ELISA technique for the diagnosis of acute Cytomegalovirus (CMV) infection. Non-A, non-B hepatitis (NANB) was diagnosed by exclusion. The results of the study showed that 133 (66.5%) patients had evidence of HBV infection, while only 9(4.5%) were diagnosed as HAV infection. EBV and CMV were the possible etiological agents of acute viral hepatitis in (3.5%) and 1%) respectively. Accordingly the Non-A, non-B hepatitis in this study amounts to (24.5%) of the acute viral hepatitis.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 412,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.",
            "question": "Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?",
            "answers": {
                "answer_start": 573,
                "text": "TBC1D7"
            }
        },
        {
            "context": "A nutritional perspective on UCP1-dependent thermogenesis. Uncoupling protein 1 (UCP1) is the hallmark protein responsible for cold- and diet-induced thermogenesis in brown adipose tissue (BAT). UCP1 activity is protective against body fat accumulation. UCP1 has re-gained researchers' attention in the context of obesity following the realization that BAT is present and can be activated in adult humans and of inducible UCP1-expressing cells in white fat depots. UCP1-mediated thermogenesis is activated by specific food compounds, which function by stimulating sympathetic nervous system activity to adipose tissues and/or by acting on the adipose cells directly or indirectly, through humoral factors released upon their intake. The impact, functional consequences and potential mechanism of action of macronutrients, micronutrients and bioactive compounds impinging on UCP1 expression/activity is discussed, as well as emerging links between human genetic variation and differential responses to potential thermogenic food ingredients. Advances in this field can help dietary recommendations and strategies for long-term weight loss/maintenance and improved metabolic health.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 59,
                "text": "Uncoupling protein 1"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2889,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Molecular and cellular bases of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients. Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis. Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet. CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML. However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML. In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors. A critical issue to resolve this problem is to fully understand the biology of LSCs, and to identify key genes that play significant roles in survival and self-renewal of LSCs. In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 823,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Negative Q-tip test as a risk factor for failed incontinence surgery in women. Fifteen women with a clinical and urodynamic diagnosis of stress urinary incontinence had a negative Q-tip test (greater than or equal to 30 degrees Q-tip angle change on straining). All 15 had retropubic surgical procedures for stress incontinence in the form of a revised Pereyra procedure (n = 6) or Burch retropubic urethropexy (n = 9). Five of the nine patients undergoing the Burch procedure (55%) and three of the six undergoing the Peyreya procedure (50%) failed the procedure, for an overall failure rate of 53%. This rate was five times higher than that among women with stress urinary incontinence and a positive Q-tip test who underwent the same procedures (P less than .01). We conclude that women with stress urinary incontinence and no anatomic defect in the support of the urethrovesical junction should not undergo retropubic procedures because of their high failure rate. Other occlusive procedures, such as sling operations, should be considered for this group.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 137,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "CSEQ-SIMULATOR: A DATA SIMULATOR FOR CLIP-SEQ EXPERIMENTS. CLIP-Seq protocols such as PAR-CLIP, HITS-CLIP or iCLIP allow a genome-wide analysis of protein-RNA interactions. For the processing of the resulting short read data, various tools are utilized. Some of these tools were specifically developed for CLIP-Seq data, whereas others were designed for the analysis of RNA-Seq data. To this date, however, it has not been assessed which of the available tools are most appropriate for the analysis of CLIP-Seq data. This is because an experimental gold standard dataset on which methods can be accessed and compared, is still not available. To address this lack of a gold-standard dataset, we here present Cseq-Simulator, a simulator for PAR-CLIP, HITS-CLIP and iCLIP-data. This simulator can be applied to generate realistic datasets that can serve as surrogates for experimental gold standard dataset. In this work, we also show how Cseq-Simulator can be used to perform a comparison of steps of typical CLIP-Seq analysis pipelines, such as the read alignment or the peak calling. These comparisons show which tools are useful in different settings and also allow identifying pitfalls in the data analysis.",
            "question": "Which data simulator is available for CLIP-SEQ experiments?",
            "answers": {
                "answer_start": 707,
                "text": "Cseq-Simulator"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 152,
                "text": "orexin"
            }
        },
        {
            "context": "Low alpha-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease. Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 88,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy. Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 346,
                "text": "FSHD"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 101,
                "text": "CO2"
            }
        },
        {
            "context": "[Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer]. OBJECTIVE: To study the effects of siltuximab on the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) signaling pathway in ovarian epithelial carcinoma. METHODS: (1) Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. (2) Expression of phosphorylation Stat3 (pStat3) protein in siltuximab and IL-6 treated SKOV3 cell lines was determined by western blot, and expression levels of Stat3-induced bcl-XL, MCL-1, survivin, in siltuximab treated SKOV3/TR and CAOV3/TR cells lines were also determined by western blot. (3) Real-time image analysis was used to study the nuclear translocation of pEGFP-Stat3 fusion protein in ovarian cancer cell line SKOV3-pEGFP-Stat3 treated with siltuximab and IL-6. (4) Paclitaxel sensitivity in siltuximab treated SKOV3/TR and CAOV3/TR cell lines were assessed using the methyl thiazolyl tetrazolium (MTT). The 50% inhibiting concentration (IC(50)) was defined as the paclitaxel concentration required to decrease the A(490) value to 50%. RESULTS: (1) There were significantly difference in IL-6 staining density and the positive rate of IL-6 protein stained among the metastatic, and drug-resistant recurrent tumors, and matched primary tumors [69% (18/26)] vs. 77% (20/26) vs. 23% (6/26), P < 0.05]. (2)A clear increase in Stat3 phosphorylation levels was observed in the IL-6-treated SKOV3 cell lines as compared to the SKOV3 cell lines. When the IL-6-treated SKOV3 cells were incubated with siltuximab with a range of concentrations of 0.001, 0.01, 0.1, 1.0 and 10 µg/ml, there were trends toward reduced pStat3 expression in the treated cell lines. Compared without treatment with siltuximab, the expression of the anti-apoptotic proteins MCL-1, bcl-XL and survivin in SKOV3/TR and CAOV3/TR cell lines were significantly decreased after treated with siltuximab. (3) In resting cells, the majority of pEGFP-Stat3 was cytoplasmic until the addition of human IL-6, which promptly induced the translocation of fluorescent Stat3 molecules to the nucleus. Exposure of cells to siltuximab with a range of concentrations of 0.001, 0.01, 0.1, 1.0 and 10 µg/ml, followed by an incubation in IL-6 significantly reduced pEGFP-Stat3 nucleocytoplasmic translocation. (4) MTT cytotoxicity assay demonstrated that siltuximab increased paclitaxel-induced cell death and partially overcame paclitaxel resistance. Treated with siltuximab (1 and 10 µg/ml), the paclitaxel IC(50) value of siltuximab in SKOV3/TR (0.49, 0.19 µg/ml) and CAOV3/TR (0.0010, 0.0008 µg/ml) cells were significantly lower than those in untreated cells (0.71, 0.0021 µg/ml; all P < 0.05). CONCLUSIONS: These results demonstrated that siltuximab effectively block the IL-6 signaling pathways, which. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 141,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Protective effect of peptide GV1001 against renal ischemia-reperfusion injury in mice. BACKGROUND: Ischemia reperfusion injury (IRI) is a common complication after kidney transplantation. Peptide GV1001 is a peptide vaccine representing a 16-amino acid human telomerase reverse transcriptase sequence, which has been reported to possess potential antineoplastic and anti-inflammatory activity. This study aimed to investigate the potential effects of peptide GV1001 on renal IRI. METHODS: Peptide GV1001 was subcutaneously administered to C57BL6/J mice 30 minutes before and 12 hours after bilateral IRI. Sham operation and phosphate-buffered saline (PBS) injection were used as controls. Blood and renal tissues were harvested at 1 day after IRI. RESULTS: Peptide GV1001 treatment significantly attenuated renal functional deterioration after IRI (peptide GV1001 group vs PBS group; blood urea nitrogen, P < .05; creatinine, P < .05). Peptide GV1001 treatment also attenuated renal tissue injury (tubular injury score; the peptide GV1001 group vs PBS group; P < .001). Renal apoptosis was also lower in the peptide GV1001 group. Immunohistochemical studies showed that IRI increased perirenal infiltration of both neutrophils and macrophages, and that peptide GV1001 significantly attenuated this process. Expression of interleukin-6 and monocyte chemotactic protein-1 was significantly reduced by peptide GV1001 treatment. CONCLUSIONS: Peptide GV1001 ameliorates acute renal IRI by reducing inflammation and apoptosis; therefore, it is promising as a potential therapeutic agent for renal IRI. The mechanisms of protection should be explored in further studies.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 253,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 62,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. BACKGROUND: Plasma kallikrein plays a major role in the contact (kallikrein-kinin) cascade producing bradykinin. Bradykinin is a vasodilator, which increases vascular permeability, activates inflammation and produces pain. Plasma kallikrein is also crosslinked to the coagulation system and the complement cascade. OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. Ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor. It was identified through phage display technology. METHODS: The search terms 'ecallantide', 'DX-88' and 'hereditary angioedema' were entered into Pubmed/Medline, ClinicalTrials and Google. RESULTS/CONCLUSION: At present, the drug is being studied for two major indications. First, the results for the treatment of hereditary angioedema are promising. Second, a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 488,
                "text": "Ecallantide"
            }
        },
        {
            "context": "In vivo ultraviolet and dimethyl sulfate footprinting of the 5' region of the expressed and silent Xist alleles. The Xist (X inactive specific transcript) gene plays an essential role in X chromosome inactivation. To elucidate the mechanisms controlling Xist expression and X inactivation, we examined in vivo DNA-protein interactions in the Xist promoter region in a female mouse cell line (BMSL2), which has distinguishable Xist alleles. In vivo footprinting was accomplished by treatment of cells with dimethyl sulfate or ultraviolet light, followed by ligation-mediated polymerase chain reaction of purified DNA. The expressed allele on the inactive X chromosome and the silent allele on the active X chromosome were separated by the use of a restriction fragment length polymorphism prior to ligation-mediated polymerase chain reaction. The chromatin structure of the Xist promoter was found to be consistent with the activity state of the Xist gene. The silent allele (on the active X chromosome) showed no footprints, while the expressed allele (on the inactive X chromosome) showed footprints at a consensus sequence for a CCAAT box, two weak Sp1 sites, and a weak TATA box.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 117,
                "text": "Xist"
            }
        },
        {
            "context": "Spontaneous brachial pseudo-aneurysm in a 12-year-old with kyphoscoliosis-type Ehlers-Danlos Syndrome. The Ehlers-Danlos Syndrome (EDS) is a rare connective tissue disorder characterised by fragility of the soft connective tissues and widespread manifestations in skin, ligaments, joints, blood vessels and internal organs. We report a case of a 12-year-old boy, previously diagnosed with kyphoscoliosis-type EDS (type VI), presenting with a left brachial artery pseudo-aneursym with history of multiple spontaneous and post-traumatic arterial ruptures. Surgical management of this patient was performed successfully by primary repair of brachial artery lesion.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 212,
                "text": "connective tissue"
            }
        },
        {
            "context": "Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the \"Mowat-Wilson\" syndrome. ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway. ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 174,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Melanocortin receptors, red hair, and skin cancer. Cutaneous pigmentation is a major determinant of the cutaneous response to ultraviolet radiation, and consequently of the risk of developing skin cancer. Over the past 10 years, several genes involved in melanogenesis have been identified, including the melanocortin 1 receptor gene. Recent work on the melanocortin 1 receptor suggests that it is a key player in determining whether eumelanin or pheomelanin is predominantly produced both in vitro and in vivo. In the mouse, variants of this receptor, which differ in their ability to activate adenylyl cyclase, are associated with different coat colors. In humans, melanocortin 1 receptor variants are associated with red hair and fair skin, and work in progress from our laboratory suggests that certain melanocortin 1 receptor variants may preferentially be associated with hair color rather than skin type. In addition, melanocortin 1 receptor variants are a risk factor, possibly independent of skin type, for melanoma susceptibility.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 667,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [(3)H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [(3)H]S107 per RyR1 tetramer with EC(50) ∼52 µM and Hillslope ∼2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 µM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 536,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review. INTRODUCTION: Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. AREAS COVERED: SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1471,
                "text": "xa"
            }
        },
        {
            "context": "The association of calcaneal spur length and clinical and functional parameters in plantar fasciitis. INTRODUCTION: Plantar fasciitis (PF)is the most common cause of plantar heel pain. Despite many treatment alternatives for heel spur, the association of calcaneal spur size with clinical and functional parameters is inconclusive. The objective of this study to investigate the correlation of calcaneal spur length with clinical findings and functional status documented with Foot Function Index in patients with plantar fasciitis. METHODS: We performed power analysis for the sample size estimation. 87 patients with PF were scrutinized to reach the estimated patient number 75. Computer-aided linear measurements were done for spur length from tip to base in milimeters. Perceived pain intensity was evaluated by visual analog scale (VAS). Patients were asked to rate the pain experienced on a 10-cm VAS. Foot function index was applied to the patients to evaluate pain, disability and activity limitation of the patients. RESULTS: Of the 75 participants, 24 were males (32%) and 51 were females (68%). The mean age was 47 ± 10 years (range 30-65 years). The mean calcaneal spur length was 3.86 ± 3.36 mm (range between 0 and 12.2). Calcaneal spur length was significantly correlated with age (p = 0.003), BMI (p = 0.029), symptom duration, (p = 0.001) VAS (p = 0.003), and FFI total score (p < 0.001). DISCUSSION: Our study demonstrated that length of the calcaneal spur is significantly correlated with age, BMI, symptom duration, perceived pain, FFI pain and disability subscores, and FFI total scores. CONCLUSION: The size of the calcaneal spur is an important parameter correlated with pain and functional scores in PF.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 174,
                "text": "heel pain"
            }
        },
        {
            "context": "Two regions within the amino-terminal half of APOBEC3G cooperate to determine cytoplasmic localization. APOBEC3G limits the replication of human immunodeficiency virus type 1, other retroviruses, and retrotransposons. It localizes predominantly to the cytoplasm of cells, which is consistent with a model wherein cytosolic APOBEC3G packages into assembling virions, where it exerts its antiviral effect by deaminating viral cDNA cytosines during reverse transcription. To define the domains of APOBEC3G that determine cytoplasmic localization, comparisons were made with APOBEC3B, which is predominantly nuclear. APOBEC3G/APOBEC3B chimeric proteins mapped a primary subcellular localization determinant to a region within the first 60 residues of each protein. A panel of 25 APOBEC3G mutants, each with a residue replaced by the corresponding amino acid of APOBEC3B, revealed that several positions within this region were particularly important, with Y19D showing the largest effect. The mislocalization phenotype of these mutants was only apparent in the context of the amino-terminal half of APOBEC3G and not the full-length protein, suggesting the existence of an additional localization determinant. Indeed, a panel of five single amino acid substitutions within the region from amino acids 113 to 128 had little effect by themselves but, in combination with Y19D, two substitutions-F126S and W127A-caused full-length APOBEC3G to redistribute throughout the cell. The critical localization-determining residues were predicted to cluster on a common solvent-exposed surface, suggesting a model in which these two regions of APOBEC3G combine to mediate an intermolecular interaction that controls subcellular localization.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 603,
                "text": " nuclear"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 1343,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "The p47phox- and NADPH oxidase organiser 1 (NOXO1)-dependent activation of NADPH oxidase 1 (NOX1) mediates endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction in a streptozotocin-induced murine model of diabetes. AIMS/HYPOTHESIS: We have previously shown that NADPH oxidase (NOX) lies upstream of uncoupled endothelial nitric oxide synthase (eNOS), which is known to occur in diabetic endothelium. However, it remains unclear which specific NOX isoform(s) is responsible for eNOS uncoupling and endothelial dysfunction in diabetic mouse models. The aim of the present study was to test the hypothesis that one or more NOX isoform(s) mediate(s) diabetic uncoupling of eNOS, which has been shown to occur in patients with diabetes to contribute to endothelial dysfunction. METHODS: Diabetes was induced by streptozotocin administration. The N (ω)-nitro-L-arginine methyl ester (L-NAME)-sensitive superoxide production of aortic segments, reflective of eNOS uncoupling activity, was determined by electron spin resonance. RESULTS: The L-NAME-sensitive superoxide production was more than doubled in wild-type diabetic mice, implicating uncoupling of eNOS. This was abolished in diabetic p47 ( phox-/-) (also known as Ncf1 (-/-)) mice, but preserved in Nox2 (-/y) (also known as Cybb (-/-)) mice made diabetic. The eNOS uncoupling activity was markedly attenuated in diabetic mice transfected with Nox1 or Nox1 organiser 1 (Noxo1) short interfering RNA (siRNA), and abolished in Nox1 (-/y) diabetic mice. Diabetes-induced impairment in endothelium-dependent vasorelaxation was also significantly attenuated in the Nox1 (-/y) mice made diabetic. By contrast, Nox4 siRNA, or inhibition of mitochondrial complex I or III with rotenone or siRNA, respectively, had no effect on diabetic uncoupling of eNOS. Overexpression of Dhfr, or oral administration of folic acid to improve dihydrofolate reductase (DHFR) function, recoupled eNOS in diabetes to improve endothelial function. CONCLUSIONS/INTERPRETATION: Our data demonstrate for the first time that the p47(phox) and NOXO1-dependent activation of NOX1, but not that of NOX2, NOX4 or mitochondrion, mediates diabetic uncoupling of eNOS. NOX1-null mice are protected from diabetic endothelial dysfunction. Novel approaches to inhibit NOX1 and/or improve DHFR function, may prove to have therapeutic potential for diabetic endothelial dysfunction.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 75,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease. Taliglucerase alfa is a plant cell-expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n=6) or 60U/kg (n=5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 88,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Transcriptional regulation by MAP kinases. Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 2082,
                "text": "Jnk"
            }
        },
        {
            "context": "Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels > 3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.",
            "question": "Which disease is treated with semaglutide?",
            "answers": {
                "answer_start": 257,
                "text": "type 2 diabetes"
            }
        },
        {
            "context": "[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 551,
                "text": "xa"
            }
        },
        {
            "context": "X-inactivation: quantitative predictions of protein interactions in the Xist network. The transcriptional silencing of one of the female X-chromosomes is a finely regulated process that requires accumulation in cis of the long non-coding RNA X-inactive-specific transcript (Xist) followed by a series of epigenetic modifications. Little is known about the molecular machinery regulating initiation and maintenance of chromosomal silencing. Here, we introduce a new version of our algorithm catRAPID to investigate Xist associations with a number of proteins involved in epigenetic regulation, nuclear scaffolding, transcription and splicing processes. Our method correctly identifies binding regions and affinities of protein interactions, providing a powerful theoretical framework for the study of X-chromosome inactivation and other events mediated by ribonucleoprotein associations.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 274,
                "text": "Xist"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 719,
                "text": "webSDA"
            }
        },
        {
            "context": "The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P =.043) and 12.5% of the HEM-AP + CE patients (P =.007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P =.19) and 8% of HEM-AP + CE patients (P <.001). With mean follow-up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE patients, compared with rates of 31% for HEM-AP patients and 69% for HEM-AP + CE patients (P =.0004). After 1 year, 100% of AP-CE patients were still alive, compared with 85% of HEM-AP patients and 67.5% of HEM-AP + CE patients (P =.01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 367,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Species identification by analysis of bone collagen using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. Species identification of fragmentary bone, such as in rendered meat and bone meal or from archaeological sites, is often difficult in the absence of clear morphological markers. Here we present a robust method of analysing genus-specific collagen peptides by mass spectrometry simply by using solid-phase extraction (a C18 ZipTip) for peptide purification, rather than liquid chromatography/mass spectrometry (LC/MS). Analysis of the collagen from 32 different mammal species identified a total of 92 peptide markers that could be used for species identification, for example, in processed food and animal feed. A set of ancient (>100 ka@10 degrees C) bone samples was also analysed to show that the proposed method has applications to archaeological bone identification.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 43,
                "text": "collagen"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 130,
                "text": "FSHD"
            }
        },
        {
            "context": "Pharmacokinetic Interactions and Safety of Coadministration of Glecaprevir and Pibrentasvir in Healthy Volunteers. BACKGROUND AND OBJECTIVE: Glecaprevir and pibrentasvir are pangenotypic direct-acting antiviral agents for the treatment of chronic hepatitis C virus infection. The aim of the present study was to evaluate the drug-drug interaction and safety of glecaprevir and pibrentasvir coadministration in healthy volunteers. METHODS: In this open-label, randomized, multiple-dose, Phase 1 study in 72 subjects, glecaprevir (100-1200 mg once daily) and pibrentasvir (40-200 mg once daily) were administered alone for 7 days and then in combination for another 7 days. Intensive blood sampling was performed on Days 1, 7, 8, and 14, and pharmacokinetic interactions were assessed using a repeated measures analysis of glecaprevir and pibrentasvir maximum plasma concentration (C ) and area under the curve (AUC). RESULTS: Coadministration of glecaprevir 400 mg increased pibrentasvir 120 and 40 mg steady-state C  and AUC values to 2.9-6.3-fold, and coadministration of glecaprevir 700 mg increased pibrentasvir 160 mg steady-state C  and AUC values to up to sevenfold of the values when pibrentasvir was administered alone. Glecaprevir C  and AUC values during coadministration were less than 1.5-fold of the values when glecaprevir was administered alone. The combination of glecaprevir and pibrentasvir at doses up to 400 mg was well tolerated by the healthy subjects in this study. High glecaprevir exposures at 700 and 1200 mg were associated with grade 2/3 elevations in alanine aminotransferase, aspartate aminotransferase, and/or bilirubin. CONCLUSIONS: Coadministration of pibrentasvir 120 mg with glecaprevir doses up to 400 mg resulted in increases in pibrentasvir exposures without significant changes in glecaprevir exposures in the absence of any clinically significant laboratory abnormalities.",
            "question": "Glecaprevir and Pibrentasvir are used for tratment of which disease?",
            "answers": {
                "answer_start": 247,
                "text": "hepatitis C virus infection"
            }
        },
        {
            "context": "TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules. Summary: The molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton. Contact: luis.sanchez-pulido@igmm.ed.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "What is the function of the TMEM132 genes?",
            "answers": {
                "answer_start": 864,
                "text": "cellular adhesion function"
            }
        },
        {
            "context": "Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient diamond-Blackfan anemia improves following RPS19 gene transfer. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 1001,
                "text": "DBA"
            }
        },
        {
            "context": "Anterograde amnesia in triazolam overdose despite flumazenil treatment: a case report. Anterograde amnesia, possibly accompanied by acute brain syndrome, is a potential side-effect of certain benzodiazepines, particularly triazolam. Flumazenil is a benzodiazepine antagonist that is highly effective in reversing the central nervous system effects of benzodiazepine overdose. We report a case of triazolam overdose resulting in anterograde amnesia after flumazenil administration had restored clear consciousness. The defect in memory may have been due to too little flumazenil being given or failure of memory consolidation affected by the character of triazolam during the induced lucent period. We feel that physicians should be aware of the potential occurrence of acute brain syndrome in patients with benzodiazepine overdose despite treatment with flumazenil.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 233,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Dinutuximab: first global approval. United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 634,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 606,
                "text": "xa"
            }
        },
        {
            "context": "Ehlers-Danlos syndrome(s) mimicking child abuse: Is there an impact on clinical practice? Ehlers-Danlos syndrome is a heterogeneous group of heritable connective tissue disorders characterized by increased fragility of various non-ossified tissues. It is usually ascertained due to abnormal skin texture, scarring complications, vascular fragility, or chronic symptoms, such as fatigue and musculoskeletal pain. Sometimes, Ehlers-Danlos syndrome remains undetected until the patient, usually in the pediatric age, shows extensive or severe mucocutaneous injuries after only minor traumas. In this scenario, the misdiagnosis of Ehlers-Danlos syndrome with child abuse is a possibility, as occasionally reported in the literature. Recently, more attention was posed by lay people between the possible association of Ehlers-Danlos syndrome and bone fragility. Literature and personal experience show a strong association between Ehlers-Danlos syndrome, generalized joint hypermobility and reduced bone mass density in older children and adults, especially fertile women. The existence of a true increased risk of fracture in Ehlers-Danlos syndrome is still a matter of debate in children and adults with little and conflicting evidence. In case of suspected child abuse, Ehlers-Danlos syndrome is certainly on the differential for bruising, especially in EDS types with marked cutaneous and capillary involvement. In suspected child abuse cases, careful examination of the index case and her/his extended family is routine, as well as exclusion of other disorders such as osteogenesis imperfecta. The hypothesis of Ehlers-Danlos syndrome as an alternative explanation for infantile fractures remains speculative.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 151,
                "text": "connective tissue"
            }
        },
        {
            "context": "Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 323,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Peroxiredoxin 2 and peroxide metabolism in the erythrocyte. Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that uses cysteine residues to decompose peroxides. Prx2 is the third most abundant protein in erythrocytes, and competes effectively with catalase and glutathione peroxidase to scavenge low levels of hydrogen peroxide, including that derived from hemoglobin autoxidation. Low thioredoxin reductase activity in the erythrocyte is able to keep up with this basal oxidation and maintain the Prx2 in its reduced form, but exposure to exogenous hydrogen peroxide causes accumulation of the disulfide-linked dimer. The high cellular concentration means that although turnover is slow, erythrocyte Prx2 can act as a noncatalytic scavenger of hydrogen peroxide and a sink for hydrogen peroxide before turnover becomes limiting. The consequences of Prx2 oxidation for the erythrocyte are not well characterized, but mice deficient in this protein develop severe hemolytic anemia associated with Heinz body formation. Prx2, also known as calpromotin, regulates ion transport by associating with the membrane and activating the Gárdos channel. How Prx2 redox transformations are linked to membrane association and channel activation is yet to be established. In this review, we discuss the functional properties of Prx2 and its role as a major component of the erythrocyte antioxidant system.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 89,
                "text": "antioxidant"
            }
        },
        {
            "context": "Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats. Cellular inflammatory response plays an important role in ischemic brain injury and anti-inflammatory treatments in stroke are beneficial. Dietary supplementation with docosahexaenoic acid (DHA) shows anti-inflammatory and neuroprotective effects against ischemic stroke. However, its effectiveness and its precise modes of neuroprotective action remain incompletely understood. This study provides evidence of an alternative target for DHA and sheds light on the mechanism of its physiological benefits. We report a global inhibitory effect of 3 consecutive days of DHA preadministration on circulating and intracerebral cellular inflammatory responses in a rat model of permanent cerebral ischemia. DHA exhibited a neuroprotective effect against ischemic deficits by reduction of behavioral disturbance, brain infarction, edema and blood-brain barrier disruption. The results of enzymatic assay, Western blot, real-time reverse transcriptase polymerase chain reaction and flow cytometric analysis revealed that DHA reduced central macrophages/microglia activation, leukocyte infiltration and pro-inflammatory cytokine expression and peripheral leukocyte activation after cerebral ischemia. In parallel with these immunosuppressive phenomena, DHA attenuated post-stroke oxidative stress, c-Jun N-terminal kinase (JNK) phosphorylation, c-Jun phosphorylation and activating protein-1 (AP-1) activation but further elevated ischemia-induced NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) expression. DHA treatment also had an immunosuppressive effect in lipopolysaccharide/interferon-γ-stimulated glial cultures by attenuating JNK phosphorylation, c-Jun phosphorylation and AP-1 activation and augmenting Nrf2 and HO-1 expression. In summary, we have shown that DHA exhibited neuroprotective and anti-inflammatory effects against ischemic brain injury and these effects were accompanied by decreased oxidative stress and JNK/AP-1 signaling as well as enhanced Nrf2/HO-1 expression.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1427,
                "text": "JNK"
            }
        },
        {
            "context": "[Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer]. OBJECTIVE: To study the effects of siltuximab on the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) signaling pathway in ovarian epithelial carcinoma. METHODS: (1) Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. (2) Expression of phosphorylation Stat3 (pStat3) protein in siltuximab and IL-6 treated SKOV3 cell lines was determined by western blot, and expression levels of Stat3-induced bcl-XL, MCL-1, survivin, in siltuximab treated SKOV3/TR and CAOV3/TR cells lines were also determined by western blot. (3) Real-time image analysis was used to study the nuclear translocation of pEGFP-Stat3 fusion protein in ovarian cancer cell line SKOV3-pEGFP-Stat3 treated with siltuximab and IL-6. (4) Paclitaxel sensitivity in siltuximab treated SKOV3/TR and CAOV3/TR cell lines were assessed using the methyl thiazolyl tetrazolium (MTT). The 50% inhibiting concentration (IC(50)) was defined as the paclitaxel concentration required to decrease the A(490) value to 50%. RESULTS: (1) There were significantly difference in IL-6 staining density and the positive rate of IL-6 protein stained among the metastatic, and drug-resistant recurrent tumors, and matched primary tumors [69% (18/26)] vs. 77% (20/26) vs. 23% (6/26), P < 0.05]. (2)A clear increase in Stat3 phosphorylation levels was observed in the IL-6-treated SKOV3 cell lines as compared to the SKOV3 cell lines. When the IL-6-treated SKOV3 cells were incubated with siltuximab with a range of concentrations of 0.001, 0.01, 0.1, 1.0 and 10 µg/ml, there were trends toward reduced pStat3 expression in the treated cell lines. Compared without treatment with siltuximab, the expression of the anti-apoptotic proteins MCL-1, bcl-XL and survivin in SKOV3/TR and CAOV3/TR cell lines were significantly decreased after treated with siltuximab. (3) In resting cells, the majority of pEGFP-Stat3 was cytoplasmic until the addition of human IL-6, which promptly induced the translocation of fluorescent Stat3 molecules to the nucleus. Exposure of cells to siltuximab with a range of concentrations of 0.001, 0.01, 0.1, 1.0 and 10 µg/ml, followed by an incubation in IL-6 significantly reduced pEGFP-Stat3 nucleocytoplasmic translocation. (4) MTT cytotoxicity assay demonstrated that siltuximab increased paclitaxel-induced cell death and partially overcame paclitaxel resistance. Treated with siltuximab (1 and 10 µg/ml), the paclitaxel IC(50) value of siltuximab in SKOV3/TR (0.49, 0.19 µg/ml) and CAOV3/TR (0.0010, 0.0008 µg/ml) cells were significantly lower than those in untreated cells (0.71, 0.0021 µg/ml; all P < 0.05). CONCLUSIONS: These results demonstrated that siltuximab effectively block the IL-6 signaling pathways, which. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 30,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. Specific outcomes upon activation of the c-Jun N-terminal kinase (JNK) pathway critically depend on the intensity and duration of signal transmission. Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. It has been shown that M3/6 itself is phosphorylated by JNK upon stimulation with arsenite, but the role of this phosphorylation has not been investigated. In this study, we mapped JNK-induced phosphorylation sites on M3/6 using mass spectrometry. Phosphorylated residues Ser 515, Thr 518 and Ser 520 were identified and site-directed mutagenesis was employed to investigate their role. Upon arsenite stimulation, M3/6 mutated at these sites exhibited decreased phosphorylation compared to the wild-type protein. No difference was observed in terms of the enzyme's in vitro phosphatase activity, its substrate specificity towards JNK isoforms, its interactions with JNK and the scaffold family of JNK-interacting proteins (JIPs), its stability or its subcellular localization. Interestingly, expression of M3/6 phosphorylation mutants delayed the time-course of JNK phosphorylation and activation by arsenite. We propose that phosphorylation of the M3/6 phosphatase by JNK in response to stress stimuli results in attenuation of phosphatase activity and acceleration of JNK activation.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 361,
                "text": "JNK"
            }
        },
        {
            "context": "Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development. BACKGROUND: zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies. MATERIALS AND METHODS: We identified a patient with Mowat-Wilson syndrome who also developed cholestasis and histopathologic features consistent with biliary atresia, suggesting that mutations involving zfhz1b may lead to biliary developmental anomalies or injury to the biliary tract. We used the zebrafish model system to determine whether zfhx1b has a role in vertebrate biliary development. RESULTS: Using zebrafish we determined that zfhx1b was expressed in the developing liver during biliary growth and remodeling, and that morpholino antisense oligonucleotide-mediated knockdown of zfhx1b led to defects in biliary development. These findings were associated with decreased expression of vhnf1, a transcription factor known to be important in biliary development in zebrafish and in mammals. CONCLUSIONS: Our studies underscore the importance of genetic contributions in the etiology of infantile hepatobiliary disorders, including biliary atresia.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 120,
                "text": "zfhx1b"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 483,
                "text": "xa"
            }
        },
        {
            "context": "Molecular basis of congenital hypopigmentary disorders in humans: a review. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 1770,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 163,
                "text": "Nox1"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 117,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Archaeal cell cycle progress. The discovery of multiple chromosome replication origins in Sulfolobus species has added yet another eukaryotic trait to the archaea, and brought new levels of complexity to the cell cycle in terms of initiation of chromosome replication, replication termination and chromosome decatenation. Conserved repeated DNA elements--origin recognition boxes--have been identified in the origins of replication, and shown to bind the Orc1/Cdc6 proteins involved in cell cycle control. The origin recognition boxes aid in the identification and characterization of new origins, and their conservation suggests that most archaea have a similar replication initiation mechanism. Cell-cycle-dependent variation in Orc1/Cdc6 levels has been demonstrated, reminiscent of variations in cyclin levels during the eukaryotic cell cycle. Information about archaeal chromosome segregation is also accumulating, including the identification of a protein that binds to short regularly spaced repeats that might constitute centromere-like elements. In addition, studies of cell-cycle-specific gene expression have potential to reveal, in the near future, missing components in crenarchaeal chromosome replication, genome segregation and cell division. Together with an increased number of physiological and cytological investigations of the overall organization of the cell cycle, rapid progress of the archaeal cell cycle field is evident, and archaea, in particular Sulfolobus species, are emerging as simple and powerful models for the eukaryotic cell cycle.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 47,
                "text": "multiple"
            }
        },
        {
            "context": "Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6-month extension study, long-term ( < 8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term ( < 2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for > 2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB.",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 310,
                "text": "tuberculosis"
            }
        },
        {
            "context": "The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. PURPOSE: An extensive body of literature regarding p53 has accumulated during the last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, whereas its clinical usefulness in the management of bladder cancer remains controversial. We outline the basic constitutive functions of p53 and summarize its current role in the management of transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We conducted a MEDLINE based literature review concerning the fundamental mechanisms of p53 and its role in the management of bladder cancer. RESULTS: The p53 gene is a tumor suppressor gene that acts as \"guardian of the genome.\" Many diverse cellular events, including DNA damage and hypoxia, activate the p53 gene. The p53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death. Loss of p53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations select for certain critical features of malignancy. Alteration of P53 is the most common mutation in human cancer. Roughly half of all human malignancies, including many urological cancers, exhibit p53 mutations. In bladder cancer p53 mutations have been associated with higher tumor grade and advanced stage, as well as progression of superficial disease to muscle invasion. Moreover, p53 nuclear over expression appears to be an independent predictor of disease progression and decreased survival after cystectomy. CONCLUSIONS: The importance of p53 mutation in tumor cell biology is irrefutable. Wild-type p53 mediates imperative functions such as regulation of the cell cycle and programmed cell death. Deficiency of p53 function by mutation or inactivation abrogates normal cell cycle checkpoints and apoptosis, generating a favorable milieu for genomic instability and carcinogenesis. However, despite the manifest importance of p53 in human malignancy, its current role in the management of bladder cancer appears somewhat limited. A multitude of retrospective studies have associated p53 mutations with adverse outcomes in superficial and muscle invasive disease. Nonetheless, randomized prospective studies are needed to determine the potential clinical implications of p53 in bladder cancer.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 698,
                "text": "p53"
            }
        },
        {
            "context": "Chromosome-Specific Centromere Sequences Provide an Estimate of the Ancestral Chromosome 2 Fusion Event in Hominin Genomes. Human chromosome 2 is a product of a telomere fusion of two ancestral chromosomes and loss/degeneration of one of the two original centromeres. Genomic signatures of this event are limited to inverted telomeric repeats at the precise site of chromosomal fusion and to the small amount of relic centromeric sequences that remain on 2q21.2. Unlike the site of fusion, which is enriched for sequences that are shared elsewhere in the human genome, the region of the nonfunctioning and degenerate ancestral centromere appears to share limited similarity with other sites in the human genome, thereby providing an opportunity to study this genomic arrangement in short, fragmented ancient DNA genomic datasets. Here, chromosome-assigned satellite DNAs are used to study shared centromere sequence organization in Denisovan and Neandertal genomes. By doing so, one is able to provide evidence for the presence of both active and degenerate centromeric satellite profiles on chromosome 2 in these archaic genomes, supporting the hypothesis that the chromosomal fusion event took place prior to our last common ancestor with Denisovan and Neandertal hominins and presenting a genomic reference for predicting karyotype in ancient genomic datasets.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 141,
                "text": "2"
            }
        },
        {
            "context": "RNA editing in P transposable element read-through transcripts in Drosophila melanogaster. RNA editing is proposed as a modulator of transcriptomes, but its biological impact has not been fully elucidated. In particular, its importance for transposable elements is controversial. We found RNA editing on antisense read-through transcripts of KP elements, one of the deletion derivatives of P transposable elements in Drosophila melanogaster. Three kinds of RNA editing were detected at 20 sites around the terminal inverted repeats (TIR); 15 A-to-G, four U-to-C, and one C-to-U conversions. A-to-G conversions are suggested to be attributed to A-to-I RNA editing on KP element RNAs, because inosine (I) in RNA is recognized as G by reverse transcriptase. TIRs were deduced to form dsRNAs as a putative target of ADAR. This is the first report of RNA editing on mobile elements of Drosophila.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 812,
                "text": "ADAR"
            }
        },
        {
            "context": "PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. BACKGROUND: Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. METHODS: The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. RESULTS: The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. CONCLUSIONS: PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 194,
                "text": "PARP"
            }
        },
        {
            "context": "Human peripheral blood lymphocytes and fibroblasts as Notch3 expression models. Notch3 is a single pass transmembrane protein belonging to the Notch receptor family. Notch proteins are involved in a very conserved signaling system (Notch signaling) with a broad spectrum of functions, from cell proliferation and differentiation to apoptosis. Mutations in Notch3 gene are linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder characterized by stroke and dementia in young adults. Studies evaluating Notch3 expression in human differentiated cells and adult tissues have shown high Notch3 levels only in vascular smooth muscle cells (VSMC). However, it has been hypothesized that Notch3 is ubiquitously expressed in adult human tissues. Our aim was to evaluate Notch3 expression in human peripheral blood lymphocytes (PBLs) and fibroblasts from normal healthy subjects. In both cell types, we examined the expression of Notch3 by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, we assessed Notch3 protein expression by Western blot analysis. RT-PCR and qRT-PCR analysis showed the presence of Notch3 mRNA in both cell types. Western blot analysis confirmed Notch3 protein expression in PBLs and fibroblasts though showing different profiles. Our data support the expression of Notch3 in adult human cell types, and suggests that PBLs and fibroblasts could provide readily available cells for the study of the role of Notch3 expression in the pathogenetic mechanisms leading to different human disease.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 356,
                "text": "Notch3 gene"
            }
        },
        {
            "context": "Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab). OBJECTIVE: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. METHODS: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. RESULTS: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. CONCLUSION: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 954,
                "text": "PD-L1"
            }
        },
        {
            "context": "Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 162,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Gender differences in Latin-American patients with rheumatoid arthritis. BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a large population with unique characteristics, including high admixture. OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in LAC. METHODS: This was a 2-phase study. First we conducted a cross-sectional and analytical study in which 1128 consecutive Colombian patients with RA were assessed. Second, a systematic review of the literature was done to evaluate the effect of gender in LAC patients with RA. RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man. Colombian women with RA are more at risk of having an early age at onset and developing polyautoimmunity and abdominal obesity, and they perform more household duties than their male counterparts. However, male gender was associated with the presence of extra-articular manifestations. Of a total of 641 potentially relevant articles, 38 were considered for final analysis, in which several factors and outcomes related to gender were identified. CONCLUSIONS: RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 1447,
                "text": "women"
            }
        },
        {
            "context": "The regulatory domain stabilizes the p53 tetramer by intersubunit contacts with the DNA binding domain. The tumor suppressor protein p53 is often referred to as the guardian of the genome. In the past, controversial findings have been presented for the role of the C-terminal regulatory domain (RD) of p53 as both a negative regulator and a positive regulator of p53 activity. However, the underlying mechanism remained enigmatic. To understand the function of the RD and of a dominant phosphorylation site within the RD, we analyzed p53 variants in vivo and in vitro. Our experiments revealed, surprisingly, that the p53 RD of one subunit interacts with the DNA binding domain of an adjacent subunit in the tetramer. This leads to the formation of intersubunit contacts that stabilize the tetrameric state of p53 and enhance its transcriptional activity in a cooperative manner. These effects are further modulated by phosphorylation of a conserved serine within the RD.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 133,
                "text": "p53"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 57,
                "text": "xa"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 339,
                "text": "webSDA"
            }
        },
        {
            "context": "Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak-Higashi syndrome of cattle. An inheritable bleeding disorder with light coat color caused by an autosomal recessive gene has been reported in a population of Japanese black cattle. The disease has been diagnosed as Chediak-Higashi Syndrome (CHS) of cattle which correspond to a human inheritable disorder caused by mutation in LYST gene. To characterize the molecular lesion causing CHS in cattle, cDNAs encoding bovine LYST were isolated from a bovine brain cDNA library. The nucleotide and deduced amino acid sequences of bovine LYST had 89.6 and 90.2% identity with those of the human LYST gene, respectively. In order to identify the mutation within the LYST gene causing CHS in cattle, cDNA fragments of the LYST gene were amplified from an affected animal by RT-PCR and their nucleotide sequences were completely determined. Notably, a nucleotide substitution of A to G transition, resulting in an amino acid substitution of histidine to arginine (H2015R) was identified in the affected animal. The presence of the substitution was completely corresponding with the occurrence of the CHS phenotype among 105 members of pedigrees of the Japanese black cattle and no cattle of other populations had this substitution. These findings strongly suggested that H2015R is the causative mutation in CHS of Japanese black cattle.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 86,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson's disease. A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 360,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1063,
                "text": "7"
            }
        },
        {
            "context": "Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes, both of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GM02063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1, whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 112,
                "text": "repressor"
            }
        },
        {
            "context": "Glivec and CML: a lucky date. Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 475,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Red hair--a desirable mutation? Red hair is one of the most striking variants of human hair coloration and has historically been of profound social importance. Red hair in man is due to certain loss of function mutations of one of the peptide products of the pro-opiomelanocortin (POMC) gene, the melanocortin-1 receptor (MC1R, MIM 155555). Such functional mutations enable the melanocyte to produce red-yellow pheomelanin in preference to the default, black-brown eumelanin. This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 638,
                "text": "MC1R"
            }
        },
        {
            "context": "A case of Mowat-Wilson syndrome caused by a truncating mutation within exon 8 of the ZEB2 gene. Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. The cause of MWS is a de novo mutation in the ZEB2 gene. This report describes a Turkish boy who was clinically diagnosed with MWS and had his diagnosis confirmed by molecular analysis of the ZEB2 gene. The investigation identified a heterozygous complex rearrangement in exon 8 of ZEB2, specifically a 48-nucleotide deletion and a 44-nucleotide insertion that caused a frameshift. MWS is a relatively newly identified disorder, and even MWS patients without Hirschsprung disease can be diagnosed easily based on clinical findings alone.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 361,
                "text": "ZEB2"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 405,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 344,
                "text": "Transcription Factor EB (TFEB)"
            }
        },
        {
            "context": "The role of amino-terminal sequences in cellular localization and antiviral activity of APOBEC3B. Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δvif, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δvif, and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1Δvif packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1Δvif, while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1Δvif by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 248,
                "text": " nuclear"
            }
        },
        {
            "context": "Chronic myeloid leukemia: a historical perspective. Patients with splenomegaly and abnormally high leukocyte counts were first recognized in France, Germany, and Scotland in the 1840s. The only well-documented therapy in the 19th century was use of arsenic in one or other form, which did undoubtedly reduce the leukocyte count but probably did little or nothing to prolong life. These early cases were probably examples of chronic myeloid leukemia (CML) (then called chronic granulocytic leukemia). In the 20th century important steps in unraveling the pathogenesis of CML were the discovery of the Philadelphia chromosome in 1960, and of the (9;22) translocation in 1973. There followed definition of the breakpoint cluster region on chromosome 22 in 1984 and the demonstration of the BCR-ABL transcript in CML in 1985. In the first half of the 20th century patients were treated predominantly with radiotherapy, and later on with busulfan, hydroxycarbamide, or interferon-alfa (IFN-α). From 1980 onwards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. The era of tyrosine kinase inhibitors (TKI) began in 1998 and today the use of the original TKI, imatinib, has replaced SCT as initial therapy for patients who present with CML in chronic phase.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 787,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress. BACKGROUND AND PURPOSE: Cardiovascular risk factors are associated with an increased risk of dementia. Treatment of hypertension and hypercholesterolemia is associated with a decrease in incident dementia. Whether interventions aimed at cardiovascular risk factors in late life also reduce dementia risk is unknown. Here, we report the outline of a pragmatic study that will attempt to answer this question and we describe the prevalence of cardiovascular risk factors in the target population. METHODS: We designed a large cluster-randomized trial with a 6-year follow-up in 3700 elderly subjects (70 to 78 y) to assess whether nurse-led intensive vascular care in primary care decreases the incidence of dementia and reduces disability. Secondary outcome parameters are mortality, incidence of vascular events, and cognitive functioning. Intensive vascular care comprises treatment of hypertension, hypercholesterolemia, diabetes and reducing overweight, smoking cessation, and stimulating physical exercise. RESULTS: Baseline data of 1004 subjects show that 87% of the subjects have 1 or more cardiovascular risk factors and 44% have even 2 or more risk factors amenable to treatment. Seventy-nine percent of the subjects receiving antihypertensive medication still have a systolic pressure of >140 mm Hg. CONCLUSIONS: In this older age group, the very high percentage of elderly subjects with cardiovascular risk factors illustrates the large window of opportunity for therapies directed to lower the cardiovascular risk and potentially also the risk for dementia.",
            "question": "What is the preDIVA clinical trial?",
            "answers": {
                "answer_start": 0,
                "text": "Prevention of dementia by intensive vascular care"
            }
        },
        {
            "context": "Comparison of ampicillin/sulbactam and amoxicillin/clavulanic acid for detection of borderline oxacillin-resistant Staphylococcus aureus. Borderline oxacillin-resistant Staphylococcus aureus (BORSA) may be misidentified as intrinsically methicillin-resistant Staphylococcus aureus (MRSA) in the clinical laboratory. Under disk diffusion testing conditions designed to maximize detection of MRSA (incubation at 32 degrees C, pre-induction with methicillin, or plating on 4% NaCl-supplemented agar), BORSA strains also tend to appear resistant to semisynthetic penicillins. Under these conditions, ampicillin/sulbactam appears to be more accurate than amoxicillin/clavulanic acid for differentiating BORSA from MRSA.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 84,
                "text": "borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus. In a patient suffering from X-linked chronic granulomatous disease (X-CGD)--a disorder of phagocytesuperoxide generation--and McLeod syndrome, characterized by the absence of the red cell Kell antigen, we identified a deletion of the entire X-CGD gene by means of DNA hybridization with a cDNA probe. Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 103,
                "text": "Xk"
            }
        },
        {
            "context": "Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. We previously identified a mammalian Set1A complex analogous to the yeast Set1/COMPASS histone H3-Lys4 methyltransferase complex (Lee, J.-H., and Skalnik, D. G. (2005) J. Biol. Chem. 280, 41725-41731). Data base analysis indicates that human Set1A protein shares 39% identity with an uncharacterized SET domain protein, KIAA1076, hereafter denoted Set1B. Immunoprecipitation and mass spectrometry reveal that Set1B associates with a approximately 450 kDa complex that contains all five non-catalytic components of the Set1A complex, including CFP1, Rbbp5, Ash2, Wdr5, and Wdr82. These data reveal two human protein complexes that differ only in the identity of the catalytic histone methyltransferase. In vitro assays demonstrate that the Set1B complex is a histone methyltransferase that produces trimethylated histone H3 at Lys(4). Both Set1A and Set1B are widely expressed. Inducible expression of the carboxyl terminus of either Set1A or Set1B decreases steady-state levels of both endogenous Set1A and Set1B protein, but does not alter the expression of the non-catalytic components of the Set1 complexes. A 123-amino acid fragment upstream of the Set1A SET domain is necessary for interaction with CFP1, Ash2, Rbbp5, and Wdr5. This protein domain is also required to mediate feedback inhibition of Set1A and Set1B expression, which is a consequence of reduced Set1A and Set1B stability when not associated with the methyltransferase complex. Confocal microscopy reveals that Set1A and Set1B each localize to a largely non-overlapping set of euchromatic nuclear speckles, suggesting that Set1A and Set1B each bind to a unique set of target genes and thus make non-redundant contributions to the epigenetic control of chromatin structure and gene expression.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 398,
                "text": "SET domain"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 307,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys. (S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the \"ON\" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 949,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor. OBJECTIVE: The present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. METHODS: Four monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. RESULTS: Opicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ∼76-84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. CONCLUSIONS: Opicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 270,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 154,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and > 10 years) and baseline mobility testing passing level (pass at > 125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 10 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.",
            "question": "Which retinal dystrophy related gene is targeted by the AAV2-hRPE65v2 drug?",
            "answers": {
                "answer_start": 78,
                "text": "RPE65"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 469,
                "text": "thyroid"
            }
        },
        {
            "context": "Cryptococcal meningitis in Rio de Janeiro State, Brazil, 1994-2004. The objective of this article was to evaluate the epidemiology of cryptococcal meningitis in Rio de Janeiro State, Brazil, from 1994 to 2004. Six hundred and ninety-six cases of cryptococcal meningitis were reported, with a mean incidence of 0.45 per 100,000 inhabitants. Patients were predominantly male; mean age was 35.9 years; AIDS was practically the only underlying disease, reported in 61.2% of cases; case-fatality was 51.8%. No decline in incidence was observed during the study period. AIDS is the main predisposing condition for cryptococcal meningitis, and thus the profile of most patients mirrors that of HIV infection. Missing information prevented the evaluation of other underlying diseases.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 687,
                "text": "HIV infection"
            }
        },
        {
            "context": "Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Aβ) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with Aβ and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, Aβ and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and Aβ, conferring protection to neurons from toxic insults of excessive Drp1, Aβ and/or phosphorylated tau.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 33,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Characterization of 6-hexadecanoylamino-4-methylumbelliferyl-beta-D- galactopyranoside as fluorogenic substrate of galactocerebrosidase for the diagnosis of Krabbe disease. 6-Hexadecanoylamino-4-methylumbelliferyl-beta-D-galactopyranoside (HMGal) has been shown to be a specific fluorogenic substrate of galactocerebrosidase and to facilitate the simple enzymatic diagnosis of Krabbe disease in human patients and in twitcher mice. HMGal hydrolysis at pH 4.5 is optimally stimulated by sodium taurocholate (0.25%) and oleic acid (0.05%) with a Km of 0.150, 0.04 and 0.03 mM, respectively for control mouse kidney, human fibroblasts and leukocytes. In control samples, the specific activity (nmol/mg prot./h) for HMGal is higher than for the natural substrate, galactocerebroside, and is severely deficient in the twitcher mouse and in patients with Krabbe disease. Comparative investigation of galactocerebrosidase activity in fibroblasts, leukocytes and brain with radioactive and fluorogenic substrates reveals a good agreement between the results of the two methods. Galactocerebroside (Gal-Cer) is a competitive inhibitor of HMGal hydrolysis in mouse kidney homogenates while GM1-ganglioside has no inhibitory effect in the same assay system. The sensitivity and specificity of this fluorogenic substrate for galactocerebrosidase provides a simple and rapid method for the diagnosis of Krabbe disease, and for the purification of this enzyme from normal tissues.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 304,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "The genetic basis of long QT and short QT syndromes: a mutation update. Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS- and SQTS-associated mutations.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 843,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 993,
                "text": "chromDraw"
            }
        },
        {
            "context": "Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 204,
                "text": "7"
            }
        },
        {
            "context": "Study of the effects of proteasome inhibitors on ribosomal protein S19 (RPS19) mutants, identified in patients with Diamond-Blackfan anemia. BACKGROUND: Mutations in the ribosomal protein S19 gene (RPS19) have been found in 25% of patients with Diamond-Blackfan anemia, a rare syndrome of congenital bone marrow failure characterized by erythroblastopenia and various malformations. Mechanistic understanding of the role of RPS19 in normal erythropoiesis and in the Diamond-Blackfan anemia defect is still poor. However, defective ribosome biogenesis and, in particular, impaired 18S ribosomal RNA maturation have been documented in association with various identified RPS19 mutations. Recently, new genes, all encoding ribosomal proteins, have been found to be mutated in Diamond-Blackfan anemia, adding further support to the concept that ribosome biogenesis plays an important role in regulating erythropoiesis. We previously showed variability in the levels of expression and subcellular localization of a subset of RPS19 mutant proteins. DESIGN AND METHODS: To define the mechanistic basis for this variability better, we studied a large number of mutant proteins and characterized both RPS19 expression level using a specific antibody against RPS19 and RPS19 subcellular localization after transfection of Cos-7 cells with various green fluorescent protein-RPS19 mutants. To investigate the role of the proteasome in RPS19 degradation, we examined the effect of various proteasome inhibitors, namely lactacystin, MG132, and bortezomib on RPS19 expression and subcellular localization RESULTS: We found two distinct classes of RPS19 protein defects in Diamond-Blackfan anemia based on the stability of the mutant proteins: (i) slightly decreased to normal levels of expression and normal nucleolar localization and (ii) markedly deficient expression and failure to localize to the nucleolus. All the proteasome inhibitors tested were able to restore the expression levels and normal subcellular localization of several unstable mutant proteins. CONCLUSIONS: Our findings demonstrate an important role for the proteasomal degradation pathway in regulating the expression levels and nucleolar localization of certain mutant RPS19 proteins in Diamond-Blackfan anemia.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 245,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "Endoplasmic reticulum-specific BH3-only protein BNIP1 induces mitochondrial fragmentation in a Bcl-2- and Drp1-dependent manner. Bcl-2/adenovirus E1B 19-kDa interacting protein 1 (BNIP1), which is predominantly localized to the endoplasmic reticulum (ER), is a pro-apoptotic Bcl-2 homology domain 3 (BH3)-only protein. Here, we show that the expression of BNIP1 induced not only a highly interconnected ER network but also mitochondrial fragmentation in a BH3 domain-dependent manner. Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission. Both BNIP1-induced mitochondrial fission and the translocation of Drp1 were abrogated by Bcl-2 overexpression. These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 661,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 113,
                "text": "MITF"
            }
        },
        {
            "context": "Davidson Trauma Scale (DTS): normative scores in the general population and effect sizes in placebo-controlled SSRI trials. The Davidson Trauma Scale (DTS) was developed as a self-rating for use in diagnosing and measuring symptom severity and treatment outcome in post-traumatic stress disorder (PTSD); 630 subjects were identified by random digit dialing and evaluated for a history of trauma. Prevalence rates of PTSD and subthreshold PTSD with impairment were 2.2 and 4.1%, respectively. In this general population sample, 438 subjects endorsed at least one trauma, and four groups were generated: A) threshold PTSD (n = 13), B) subthreshold PTSD with impairment (n = 26), C) subthreshold PTSD without impairment (n = 78), and D) no PTSD (n = 321). Mean (SD) DTS score in the entire population was 11.0 +/- 18.1. Differences were found in four of the five pairwise between-group contrasts. In a second sample of 447 clinical trial participants from three SSRI vs. placebo studies, we assessed treatment effect size according to different measures. In all three clinical trials, effect size with the DTS was equal to, or better than, those found for the Impact of Event Scale (IES), Clinician Administered PTSD Scale (CAPS), and Structured Interview for PTSD (SIP). These results further affirm the utility of the DTS as a self-rating measure of PTSD symptom severity and in evaluating treatment response.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 297,
                "text": "PTSD"
            }
        },
        {
            "context": "Identification of botulinum toxin type in clinical samples and foods in Iran. BACKGROUND: Botulism is a serious neuroparalytic disease caused by toxins of Clostridium botulinum. Botulinum toxin is produced under anaerobic conditions and is one of the most dangerous toxin in the world. Rapid diagnosis of botulism is very essential for successful therapy. In this study, we reviewed data of cases of botulism in Iran from April 2004 through March 2010. MATHERIALS AND METHODS: From a total of 1140 samples of suspected botulism samples, 477 serum, 294 stool, 111 gastric secretions, and 258 food samples were collected from 21 provinces. These samples belonged to 432 distinct patients. All samples were tested for botulism by mouse bioassay, a gold standard method for detection of botulism. RESULTS: From 1140 received samples, 64 (5.6 %) positive samples of botulism were identified. Of these, 14 (21.8 %) cases had toxin type A, seven (11 %) cases had toxin type B, 22 (34.3 %) cases had toxin type E, and seven (11 %) cases had toxin type AB. The toxin type could not been identified in 14 (21.8 %) cases. The highest positive results were in Gilan, Tehran, Golestan, and Hamedan provinces. Seafoods and locally- made cheese were the most implicated foods in type E and type A botulism, respectively. CONCLUSION: Accurate and rapid diagnosis of botulism is very important because every case of botulism can be a public health emergency. During the study period, the median number of positive cases per year was 2.7 (range: one to18). Therefore, it is suggested that all clinicians are required to submit the collected samples from patients with botulism symptoms to the botulism reference laboratory for specific diagnosis and confirmation of botulism.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 155,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression. Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 989,
                "text": "Ecm22"
            }
        },
        {
            "context": "[Isradipine in arterial hypertension in motor vehicle drivers]. The study covered influence of Isradipine (2.5 mg administered twice daily during 6 weeks) on blood circulation in the heart and occupationally important functions and traits among 30 drivers having mild and moderate arterial hypertension (AH). Systolic and diastolic pressure demonstrate reliable decrease in all the examinees with mild AH and in 93.8% of the examinees with moderate AH. Isradipine proved to influence positively decrease of hypertensive reactions and subclinical myocardial ischemia. Isradipine presented statistically significant improvement of the studied psychophysiologic parameters (quickness of latent and motor visual reaction, number of errors in color choice, exactness in following the mobile object). Thus, all above enables to recommend Isradipine (Lomir) as effective and safe method correcting arterial hypertension in drivers.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 24,
                "text": "hypertension"
            }
        },
        {
            "context": "Functional analysis of the N- and C-terminus of mammalian G9a histone H3 methyltransferase. Methylation of lysine 9 (K9) in the N-terminus tail of histone H3 (H3) in chromatin is associated with transcriptionally silenced genes and is mediated by histone methyltransferases. Murine G9a is a 1263 amino acid H3-K9 methyltransferase that possesses characteristic SET domain and ANK repeats. In this paper, we have used a series of green fluorescent protein-tagged deletion constructs to identify two nuclear localization signals (NLS), the first NLS embedded between amino acids 24 and 109 and the second between amino acids 394 and 401 of murine G9a. Our data show that both long and short G9a isoforms were capable of entering the nucleus to methylate chromatin. Full-length or N-terminus-deleted G9a isoforms were also catalytically active enzymes that methylated recombinant H3 or synthetic peptides representing the N-terminus tail of H3. In vitro methylation reactions using N-terminus tail peptides resulted in tri-methylation of K9 that remained processive, even in G9a enzymes that lacked an N-terminus region by deletion. Co-expression of G9a and H3 resulted in di- and tri-methylation of H3-K9, while siRNA-mediated knockdown of G9a in HeLa cells resulted in reduction of global H3-K9 di- and tri-methylation. A recombinant deletion mutant enzyme fused with maltose-binding protein (MBP-G9aDelta634) was used for steady-state kinetic analysis with various substrates and was compared with full-length G9a (G9aFL). Turnover numbers of MBP-G9aDelta634 for various substrates was approximately 3-fold less compared with G9aFL, while their Michaelis constants (K(m)) for recombinant H3 were similar. The K(AdoMet)m for MBP-G9aDelta634 was approximately 2.3-2.65 microM with various substrates. Catalytic efficiencies (kcat/K(m)) for both MBP-G9aDelta634 and G9aFL were similar, suggesting that the N-terminus is not essential for catalysis. Furthermore, mutation of conserved amino acids R1097A, W1103A, Y1120A, Y1138A and R1162A, or the metal binding C1168A in the catalytic region, resulted in catalytically impaired enzymes, thereby confirming the involvement of the C-terminus of G9a in catalysis. Thus, distinct domains modulate nuclear targeting and catalytic functions of G9a.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 361,
                "text": "SET domain"
            }
        },
        {
            "context": "Effect of hydroxyurea and normal plasma on DNA synthesis in lymphocytes from Fanconi anemia patients. Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited. Deoxyribonucleotides are needed in both semiconservative and repair DNA synthesis. To investigate the involvement of deoxyribonucleotide pools in the inhibition of DNA synthesis in FA, we evaluated the effect on FA lymphocytes of hydroxyurea (HU), an inhibitor of ribonucleotide reductase which is known to alter the intracellular levels of deoxyribonucleotides. To achieve this goal, lymphocyte cultures of 4 FA patients and 4 normal individuals were used. Cultures were treated with HU and/or mitomycin C and normal human plasma. All cultures were processed to detect the number of DNA synthesizing nuclei by autoradiography. Scoring of 2000 nuclei for each kind of culture every 6 h in the last 24 h of incubation showed that, in long incubation periods, DNA synthesis in FA is largely inhibited by HU and this hypersensitivity may be partially decreased by addition of normal human plasma. It is known that recovery from damage induced by HU involves several enzymes such as flavin oxido-reductase, superoxide dismutase and catalase which are involved in the production or scavenging of O2 radicals; FA cells are deficient in the detoxification of oxygen and this could explain the response of FA cells to HU.",
            "question": "What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?",
            "answers": {
                "answer_start": 102,
                "text": "Fanconi anemia"
            }
        },
        {
            "context": "iLIR database: A web resource for LIR motif-containing proteins in eukaryotes. Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.",
            "question": "Which web resource for LIR motif-containing proteins in eukaryotes has been developed?",
            "answers": {
                "answer_start": 1491,
                "text": "the iLIR database"
            }
        },
        {
            "context": "The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster. RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar(5G1) null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar(5G1) mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar(5G1) null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 4,
                "text": "ADAR"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 178,
                "text": "TFIIS"
            }
        },
        {
            "context": "Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 46,
                "text": "orexin"
            }
        },
        {
            "context": "Association between psychiatric disorders and Marfan's syndrome in a large Sardinian family with a high prevalence of cardiac abnormalities. BACKGROUND: Marfan's syndrome is an inherited disorder of connective tissue associated with characteristic abnormalities of the skeletal, ocular, and cardiovascular systems. Marked clinical variability and age dependency of all manifestations of Marfan's syndrome may render the unequivocal diagnosis difficult in mildly affected, young subjects. HYPOTHESIS: The study and care of a 32-year-old woman with evidence of Marfan's syndrome, several cardiac abnormalities, and paranoid schizophrenia led to an investigation of her consenting relatives to verify the penetrance of Marfan's syndrome and the degree of comorbidity between the disease and psychiatric disorders. METHODS: The patient and 12 subjects belonging to three generations of her family underwent cardiovascular, skeletal, ophthalmologic, and psychiatric examinations. Two-dimensional and Doppler echocardiography were performed. RESULTS: One female index patient and six of her first-degree relatives were found to be affected by Marfan's syndrome. All seven patients were found to have mitral valve prolapse associated with other cardiac abnormalities. Four of these patients were affected by the following psychiatric disorders: generalized anxiety disorder, major depressive disorder, paranoid schizophrenia (two cases). Six more relatives without Marfan's syndrome showed mitral valve prolapse in association with other echocardiographic features. Two of these were found to be affected by a major depressive disorder. CONCLUSIONS: The present data support the hypothesis that a psychiatric condition, associated with a significantly high frequency of cardiac involvement, may be part of the phenotype of Marfan's syndrome.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 199,
                "text": "connective tissue"
            }
        },
        {
            "context": "Self-association of coilin reveals a common theme in nuclear body localization. We have found that coilin, the marker protein for Cajal bodies (coiled bodies, CBs), is a self-interacting protein, and we have mapped the domain responsible for this activity to the amino-terminus. Together with a nuclear localization signal, the self-interaction domain is necessary and sufficient for localization to CBs. Overexpression of various wild-type and mutant coilin constructs in HeLa cells results in disruption of both CBs and survival motor neurons (SMN) gems. Additionally, we have identified a cryptic nucleolar localization signal (NoLS), within the coilin protein, which may be exposed in specific coilin phospho-isoforms. The implications of these findings are discussed in light of the fact that other proteins known to localize within nuclear bodies (e. g., PML, SMN and Sam68) can also self-associate. Thus protein self-interaction appears to be a general feature of nuclear body marker proteins.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 99,
                "text": "coilin"
            }
        },
        {
            "context": "Jamaican vomiting sickness: a study of two adult cases. An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. Analyses of serum and urine samples were performed to compare the patterns of organic acidaemia and aciduria with those reported from childhood cases. The main conclusion from the comparison is that the toxic ackee constitutent, hypoglycin, produces essentially the same metabolic effects in adults as in children.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 148,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 83,
                "text": "PD-L1"
            }
        },
        {
            "context": "The tyrosinase gene in gorillas and the albinism of 'Snowflake'. The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla ('Snowflake'). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in 'Snowflake', indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 611,
                "text": "TYR"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 544,
                "text": "early"
            }
        },
        {
            "context": "Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. Thyroid hormone is a pleiotropic hormone with widespread biological actions. For instance, adequate levels of thyroid hormone are critical for the development of different tissues such as the central nervous system, but are also essential for the regulation of metabolic processes throughout life. The biological activity of thyroid hormone depends not only on serum thyroid hormone levels, but is also regulated at the tissue level by the expression and activity of deiodinases, which activate thyroid hormone or mediate its degradation. In addition, thyroid hormone transporters are necessary for the uptake of thyroid hormone into target tissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a specific thyroid hormone transporter and the finding that mutations in this transporter lead to a syndrome of severe psychomotor retardation and elevated serum 3,3',5-tri-iodothyronine levels known as the Allan-Herndon-Dudley syndrome, the interest in this area of research has greatly increased. In this review, we will focus on the molecular aspects of thyroid hormone transporters, including MCT8, MCT10, organic anion transporting polypeptides, and the effects of genetic variation in these transporters.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 868,
                "text": "thyroid"
            }
        },
        {
            "context": "Identification of Coilin Mutants in a Screen for Enhanced Expression of an Alternatively Spliced GFP Reporter Gene in Arabidopsis thaliana. Coilin is a marker protein for subnuclear organelles known as Cajal bodies, which are sites of various RNA metabolic processes including the biogenesis of spliceosomal small nuclear ribonucleoprotein particles. Through self-associations and interactions with other proteins and RNA, coilin provides a structural scaffold for Cajal body formation. However, despite a conspicuous presence in Cajal bodies, most coilin is dispersed in the nucleoplasm and expressed in cell types that lack these organelles. The molecular function of coilin, particularly of the substantial nucleoplasmic fraction, remains uncertain. We identified coilin loss-of-function mutations in a genetic screen for mutants showing either reduced or enhanced expression of an alternatively spliced GFP reporter gene in Arabidopsis thaliana The coilin mutants feature enhanced GFP fluorescence and diminished Cajal bodies compared with wild-type plants. The amount of GFP protein is several-fold higher in the coilin mutants owing to elevated GFP transcript levels and more efficient splicing to produce a translatable GFP mRNA. Genome-wide RNA-sequencing data from two distinct coilin mutants revealed a small, shared subset of differentially expressed genes, many encoding stress-related proteins, and, unexpectedly, a trend toward increased splicing efficiency. These results suggest that coilin attenuates splicing and modulates transcription of a select group of genes. The transcriptional and splicing changes observed in coilin mutants are not accompanied by gross phenotypic abnormalities or dramatically altered stress responses, supporting a role for coilin in fine tuning gene expression. Our GFP reporter gene provides a sensitive monitor of coilin activity that will facilitate further investigations into the functions of this enigmatic protein.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 140,
                "text": "Coilin"
            }
        },
        {
            "context": "Upregulation of uc.189 in patients with esophageal squamous cell carcinoma and its clinicopathologic value. Ultraconserved elements (UCEs) encoding noncoding RNAs serve as important regulators in cancer biology. Until now, the role of the UCE uc.189 in human cancers remains undefined and the clinical significance of uc.189 in esophageal cancers remains unknown. This study was to identify the prognostic value of uc.189 expression in esophageal squamous cell carcinomas (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of uc.189 in matched cancerous tissues and adjacent noncancerous tissues from 152 patients with ESCC. The correlation of uc.189 with clinicopathological features and prognosis were also analyzed. The expression of uc.189 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (122/152, 80.3%, p<0.01), and the high level of uc.189 expression was significantly correlated with invasion of the tumor (p=0.009), advanced clinical stage (p=0.000), lymph node metastasis (p=0.000), and poor prognosis. High expression of uc.189 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Uc.189 might be considered as a novel molecule involved in ESCC progression, which provides a potential prognostic biomarker and therapeutic target.",
            "question": "For which type of cancer can uc.189 be used as a potential prognostic biomarker?",
            "answers": {
                "answer_start": 436,
                "text": "esophageal squamous cell carcinomas (ESCC)"
            }
        },
        {
            "context": "Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations. Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1367,
                "text": "Xa"
            }
        },
        {
            "context": "NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 233,
                "text": "thyroid transcription factor 1"
            }
        },
        {
            "context": "A novel assay to quantitate MASP-2/ficolin-3 complexes in serum. Ficolin-1, -2 and -3 are recognition molecules in the lectin complement pathway and form complexes with serine proteases named MASP-1, -2 and -3 and two nonenzymatic proteins. MASP-2 is the main initiator of lectin pathway activation, while ficolin-3 is the most abundant ficolin molecule in the circulation. The significance of lectin pathway complexes in the circulation is unknown. Thus, we established an assay for the measurement of circulating MASP-2/ficolin-3 complexes. A quantitative sandwich ELISA was developed for the measurement of the MASP-2/ficolin-3 complexes in serum based on monoclonal antibodies against MASP-2 for coating and anti-ficolin-3 for detection. In addition, we assessed the serum concentrations of ficolin-3 and MASP-2 and the extent of ficolin-3 mediated C4 deposition on acetylated BSA in samples from 97 healthy donors. The median concentration of MASP-2/ficolin-3 complexes was found to be 119.7 AU/ml (range: 2.9-615.5 AU/ml). Significant correlations were found between the level of MASP-2/ficolin-3 complexes and the concentration of ficolin-3 (Spearman r=0.2532, p=0.0124), and MASP-2 (Spearman r=0.4505, p<0.0001), as well as the degree of C4 deposition (Spearman r=0.671, p<0.0001). When ficolin-3 deficient (homozygous for the rs28357092 polymorphism) and MASP-2 deficient (homozygous for the rs72550870 polymorphism) sera were incubated together, complex formation was induced between MASP-2 and ficolin-3. The complex formation disappeared in the presence of EDTA. An assay allowing quantitative measurement exclusively of MASP-2/ficolin-3 complexes in serum is described. This method may add further insight into the pathophysiology of disorders associated with the deficiency or abnormal activities of MASP-2 and ficolin-3.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 119,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "What would be the properties of an ideal SERM? Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 47,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 985,
                "text": "xa"
            }
        },
        {
            "context": "Two cases of Sotos syndrome with novel mutations of the NSD1 gene. Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome. Fluorescent in situ hybridization analysis (FISH), MLPA or multiplex quantitative PCR allow detection of total/partial NSD1 deletions and direct sequencing allows detection of NSD1 mutations. We describe two boys with Sotos syndrome in whom PCR amplification and direct sequencing of the NSD1 gene identified two novel mutations not previously described: c.4736dupG in exon 12 and c.3938_3939insT in exon 7. In addition to the cardinal and major features of the syndrome (abnormal facial appearance, overgrowth, cardiac anomalies, renal anomalies, hypotonia, neonatal jaundice, seizures and brain MRI abnormalities) in both patients, one boy also had cryptorchidism and vertebral anomalies, features considered not common. Despite the wide range of possible combinations of phenotypic features, molecular analysis can correctly identify Sotos syndrome.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 98,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 1460,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "Impact of training for healthcare professionals on how to manage an opioid overdose with naloxone: effective, but dissemination is challenging. BACKGROUND: Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). Training in these skills has been successfully trialled internationally with opioid users themselves. Healthcare professionals working in substance misuse are in a prime position to deliver overdose prevention training to drug users and may themselves witness opioid overdoses. The best method of training dissemination has not been identified. The study assessed post-training change in clinician knowledge for managing an opioid overdose and administering naloxone, evaluated the 'cascade method' for disseminating training, and identified barriers to implementation. METHODS: A repeated-measures design evaluated knowledge pre-and-post training. A sub-set of clinicians were interviewed to identify barriers to implementation. Clinicians from addiction services across England received training. Participants self-completed a structured questionnaire recording overdose knowledge, confidence and barriers to implementation. RESULTS: One hundred clinicians were trained initially, who trained a further 119 clinicians (n=219) and thereafter trained 239 drug users. The mean composite score for opioid overdose risk signs and actions to be taken was 18.3/26 (±3.8) which increased to 21.2/26 (±4.1) after training, demonstrating a significant improvement in knowledge (Z=9.2, p<0.001). The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation. CONCLUSIONS: Training clinicians how to manage an opioid overdose and administer naloxone was effective. However the 'cascade method' was only modestly successful for disseminating training to a large clinician workforce, with a range of clinician and service perceived obstacles. Drug policy changes and improvements to educational programmes for drug services would be important to ensure successful implementation of overdose training internationally.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 1903,
                "text": "naloxone"
            }
        },
        {
            "context": "Does the STOP-Bang, an obstructive sleep apnea screening tool, predict difficult intubation? OBJECTIVE: A close relationship between obstructive sleep apnea (OSA) and difficult intubation has been suggested. We hypothesized that the STOP-Bang questionnaire, a screening tool for obstructive sleep apnea (OSA), can predict difficult intubation. PATIENTS AND METHODS: In this prospective cohort study, 200 adult surgical patients undergoing surgery under general anesthesia were studied to evaluate the usefulness of the STOP-Bang questionnaire for predicting difficult intubation. STOP-Bang questionnaire results, Mallampati score and tonsil size, as well as demographic data, were recorded preoperatively. Cormack & Lehane grading and difficulty of intubation (Cormack & Lehane grade III or IV, need of an intubation aid, or need of three or more intubation attempts) were also evaluated. RESULTS: Eighty-three out of 200 patients had a high risk of OSA based on the STOP-Bang questionnaire. The occurrence of difficult intubation was higher in the patients at a high risk of OSA (i.e., a STOP-Bang score of > 3) than in the patients at a low risk (13.3% vs. 2.6%) (p = 0.004). Higher age, greater weight, higher body mass index, greater neck circumference, male gender, presence of comorbidities, lower preoperative SpO2, longer extubation times, higher Mallampati score, higher Cormack & Lehane grading, tonsil size and difficult intubation were significantly correlated with a high risk of OSA (p < 0.001). Fourteen out of 200 patients had difficulty in intubation. A STOP-Bang score of > 3 was seen more frequently in the difficult intubation patients (78.6% vs. 38.7%) (p = 0.009). Greater weight, greater neck circumference, greater Mallampati score, a STOP-Bang score > 3 and male gender were significantly correlated with difficult intubation (p < 0.05). CONCLUSIONS: A STOP-Bang score of > 3 was a predictor for difficult intubation.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 279,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1986,
                "text": "CD38"
            }
        },
        {
            "context": "Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.",
            "question": "Which is the cellular localization of the protein Opa1?",
            "answers": {
                "answer_start": 136,
                "text": "mitochondrial intermembrane space"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 307,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 569,
                "text": "miR-7"
            }
        },
        {
            "context": "Quantification of UCP1 function in human brown adipose tissue. Brown adipose tissue (BAT) mitochondria are distinct from their counterparts in other tissues in that ATP production is not their primary physiologic role. BAT mitochondria are equipped with a specialized protein known as uncoupling protein 1 (UCP1). UCP1 short-circuits the electron transport chain, allowing mitochondrial membrane potential to be transduced to heat, making BAT a tissue capable of altering energy expenditure and fuel metabolism in mammals without increasing physical activity. The recent discovery that adult humans have metabolically active BAT has rekindled an interest in this intriguing tissue, with the overarching aim of manipulating BAT function to augment energy expenditure as a countermeasure for obesity and the metabolic abnormalities it incurs. Subsequently, there has been heightened interest in quantifying BAT function and more specifically, determining UCP1-mediated thermogenesis in BAT specimens - including in those obtained from humans. In this article, BAT mitochondrial bioenergetics will be described and compared with more conventional mitochondria in other tissues. The biochemical methods typically used to quantify BAT mitochondrial function will also be discussed in terms of their specificity for assaying UCP1 mediated thermogenesis. Finally, recent data concerning BAT UCP1 function in humans will be described and discussed.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 314,
                "text": "UCP1"
            }
        },
        {
            "context": "Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) mice. We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-alpha). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-alpha from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters.The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 82,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new? Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3 months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients.",
            "question": "What is inhibited by a drug rilotumumab?",
            "answers": {
                "answer_start": 1247,
                "text": "hepatocyte growth factor"
            }
        },
        {
            "context": "Ecm22 and Upc2 regulate yeast mating through control of expression of the mating genes PRM1 and PRM4. Budding yeast mating is an excellent model for receptor-activated cell differentiation. Here we identify the related transcription factors Ecm22 and Upc2 as novel regulators of mating. Cells lacking both ECM22 and UPC2 display strong mating defects whereas deletion of either gene has no effect. Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4. These genes are strongly induced in response to mating pheromone, which is also largely dependent on ECM22 and UPC2. We further show that deletion of PRM4 like PRM1 results in markedly reduced mating efficiency. Expression of PRM1 but not of PRM4 is also regulated by Ste12, a key transcription factor for mating. STE12 deletion lowers basal PRM1 expression, whereas STE12 overexpression strongly increases PRM1 levels. This regulation of PRM1 transcription is mediated through three Ste12-binding sites in the PRM1 promoter. Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways. In summary, we propose a novel mechanism for budding yeast mating. We suggest that Ecm22 and Upc2 regulate mating through the induction of the mating genes PRM1 and PRM4.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 398,
                "text": "Ecm22"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 29,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Critical roles of the mitochondrial complex II in oocyst formation of rodent malaria parasite Plasmodium berghei. It is generally accepted that the mitochondria play central roles in energy production of most eukaryotes. In contrast, it has been thought that Plasmodium spp., the causative agent of malaria, rely mainly on cytosolic glycolysis but not mitochondrial oxidative phosphorylation for energy production during blood stages. However, Plasmodium spp. possesses all genes necessary for the tricarboxylic acid (TCA) cycle and most of the genes for electron transport chain (ETC) enzymes. Therefore, it remains elusive whether oxidative phosphorylation is essential for the parasite survival. To elucidate the role of TCA metabolism and ETC in malaria parasites, we deleted the gene for flavoprotein (Fp) subunit, Pbsdha, one of four components of complex II, a catalytic subunit for succinate dehydrogenase activity. The Pbsdha(-) parasite grew normally at blood stages in mouse. In contrast, ookinete formation of Pbsdha(-) parasites in the mosquito stage was severely impaired. Finally, Pbsdha(-) ookinetes failed in oocyst formation, leading to complete malaria transmission blockade. These results suggest that malaria parasite may switch the energy metabolism from glycolysis to oxidative phosphorylation to adapt to the insect vector where glucose is not readily available for ATP production.",
            "question": "Which is the causative agent of malaria?",
            "answers": {
                "answer_start": 259,
                "text": "Plasmodium spp."
            }
        },
        {
            "context": "Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 835,
                "text": "MC1R"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 379,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Cost analysis of an outbreak of Clostridium difficile infection ribotype 027 in a Dutch tertiary care centre. BACKGROUND: The economic impact of Clostridium difficile infection (CDI) on the healthcare system is significant. From May 2013 to May 2014, an outbreak of C. difficile ribotype 027 occurred in a Dutch tertiary care hospital, involving 72 patients. The primary aim of this study was to provide insight into the financial burden that this CDI outbreak brought upon this hospital. METHODS: A retrospective analysis was performed to estimate the costs of a one-year-long C. difficile ribotype 027 outbreak. Medical charts were reviewed for patient data. In addition, all costs associated with the outbreak control measures were collected. FINDINGS: The attributable costs of the whole outbreak were estimated to be €1,222,376. The main contributing factor was missed revenue due to increased length of stay of CDI patients and closure of beds to enable contact isolation of CDI patients (36%). A second important cost component was extra surveillance and activities of the Department of Medical Microbiology and Infection Control (25%). CONCLUSION: To the authors' knowledge, this is the first study to provide insight into the attributable costs of CDI in an outbreak setting, and to delineate the major cost items. It is clear that the economic consequences of CDI are significant. The high costs associated with a CDI outbreak should help to justify the use of additional resources for CDI prevention and control.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 279,
                "text": "ribotype 027"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 132,
                "text": "OikoBase"
            }
        },
        {
            "context": "Partially functional Cenpa-GFP fusion protein causes increased chromosome missegregation and apoptosis during mouse embryogenesis. CENP-A is an essential histone H3-like protein that localizes to the centromeric region of eukaryotic chromosomes. Heterozygous and homozygous Cenpa-GFP fusion-protein mouse mutants, generated through targeted insertion of the green fluorescent protein (GFP) gene into the mouse Cenpa gene locus, show specific localized fluorescence at all the centromeres. Heterozygous mice are healthy and fertile. Cenpa-GFP homozygotes (Cenpag/g) undergo many cell divisions, giving rise to up to one million cells that show relatively accurate differentiation into distinct mouse embryonic tissues until day 10.5 when significant levels of chromosome missegregation, aneuploidy and apoptosis result in death. Cenpag/g embryos assemble functional kinetochores that bind to a host of centromere-specific structural and mitotic spindle checkpoint proteins (Cenpc, BubR1, Mad2 and Zw10). Examination of the nucleosomal phasing of centromeric minor and pericentromeric major satellite sequences indicates that the formation of Cenpag/g homotypic nucleosomes is not accompanied by any overt alteration to the overall size of the monomeric nucleosomal structure or the spacing of these structures. This study provides the first example of an essential centromeric protein gene variant in which subtle perturbation at the centromeric nucleosomal/chromatin level manifests in a significantly delayed lethality when compared with Cenpa null mice.",
            "question": "Where is the histone variant CENPA preferentially localized?",
            "answers": {
                "answer_start": 476,
                "text": "centromeres"
            }
        },
        {
            "context": "Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1040,
                "text": "flumazenil"
            }
        },
        {
            "context": "A revised six-kingdom system of life. A revised six-kingdom system of life is presented, down to the level of infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi, Plantae and Chromista. Intermediate high level categories (superkingdom, subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are extensively used to avoid splitting organisms into an excessive number of kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms, Protozoa and Animalia, are subject to the International Code of Zoological Nomenclature, the kingdom Bacteria to the International Code of Bacteriological Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to the International Code of Botanical Nomenclature. Circumscriptions of the kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20 classes; fungal classification at the rank of subclass and above is comprehensively revised. The kingdoms Protozoa and Animalia are modified in the light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not Protozoa, and that mesozoans are related to bilaterian animals. Animalia are divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa, Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other phyla). Several new higher level groupings are made in the animal kingdom including three new phyla: Acanthognatha (rotifers, acanthocephalans, gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not as a separate kingdom. The recently revised phylum Rhizopoda is modified further by adding more flagellates and removing some 'rhizopods' and is therefore renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa and Archamoebae (both now infraphyla) as a new subphylum Conosa within the phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the (formerly microsporidian) metchnikovellids are now both placed within the phylum Sporozoa. These changes make a total of only 13 currently recognized protozoan phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is modified in circumscription by adding the Discicristata, a new infrakingdom comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in relation to the principles of megasystematics, here defined as systematics that concentrates on the higher levels of classes, phyla, and kingdoms. These principles also make it desirable to rank Archaebacteria as an infrakingdom of the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising all bacteria bounded by a single membrane. The bacterial subkingdom Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides in the outer leaflet of the outer membrane and phospholipids in its inner leaflet. (ABSTRACT TRUNCATED)",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1123,
                "text": "Fungi"
            }
        },
        {
            "context": "Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 323,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Nerve safety of tanezumab, a nerve growth factor inhibitor for pain treatment. OBJECTIVE: To evaluate peripheral nerve safety and clinical efficacy of tanezumab in patients with painful osteoarthritis. METHODS: Patients received intravenous tanezumab 5mg, tanezumab 10mg, or placebo every 8 weeks for 24 weeks. Neurological safety was evaluated via a composite score (nerve conduction attributes and heart rate variability with deep breathing; Σ5NC + HRdb), intraepidermal nerve fiber (IENF) density, and clinical assessments. Efficacy and general safety were also evaluated. RESULTS: The study was stopped prematurely by an FDA partial clinical hold (joint safety issues in other studies). Differences in change from baseline to Week 24 in Σ5NC + HRdb were not significant. Tanezumab 5mg vs placebo exceeded the prespecified clinically important difference using last observation carried forward imputation, but not with observed data or when patients with evidence of neuropathy at baseline were excluded. No significant differences were found in individual nerve conduction measures. No treatment exceeded the prespecified clinically important decrease in IENF. Tanezumab resulted in significant improvement in pain, physical function, and Patient's Global Assessment. Safety was similar to previous tanezumab clinical trials. CONCLUSIONS: Tanezumab has a modulating effect on pain, does not appear to increase neurological safety signals, and offers a potentially promising, novel approach in treatment of pain.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 29,
                "text": "nerve growth factor"
            }
        },
        {
            "context": "Subunit contributions to histone methyltransferase activities of fly and worm polycomb group complexes. The ESC-E(Z) complex of Drosophila melanogaster Polycomb group (PcG) repressors is a histone H3 methyltransferase (HMTase). This complex silences fly Hox genes, and related HMTases control germ line development in worms, flowering in plants, and X inactivation in mammals. The fly complex contains a catalytic SET domain subunit, E(Z), plus three noncatalytic subunits, SU(Z)12, ESC, and NURF-55. The four-subunit complex is >1,000-fold more active than E(Z) alone. Here we show that ESC and SU(Z)12 play key roles in potentiating E(Z) HMTase activity. We also show that loss of ESC disrupts global methylation of histone H3-lysine 27 in fly embryos. Subunit mutations identify domains required for catalytic activity and/or binding to specific partners. We describe missense mutations in surface loops of ESC, in the CXC domain of E(Z), and in the conserved VEFS domain of SU(Z)12, which each disrupt HMTase activity but preserve complex assembly. Thus, the E(Z) SET domain requires multiple partner inputs to produce active HMTase. We also find that a recombinant worm complex containing the E(Z) homolog, MES-2, has robust HMTase activity, which depends upon both MES-6, an ESC homolog, and MES-3, a pioneer protein. Thus, although the fly and mammalian PcG complexes absolutely require SU(Z)12, the worm complex generates HMTase activity from a distinct partner set.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 414,
                "text": "SET domain"
            }
        },
        {
            "context": "[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1986,
                "text": "CD38"
            }
        },
        {
            "context": "Selexipag for the treatment of pulmonary arterial hypertension. INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 31,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. DESIGN: A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. SETTING: An 800-bed, teaching, university-affiliated hospital. PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant \"waking\" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 3511,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1203,
                "text": "PD-L1"
            }
        },
        {
            "context": "CADASIL and migraine: A narrative review. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke, cognitive decline, psychiatric disturbances and migraine. The prevalence of migraine in CADASIL is slightly higher than in the general population, and the proportion of migraine with aura is much higher. The pathophysiological mechanism that leads to increased aura prevalence in CADASIL is unknown. Possible mechanisms of the excess of migraine with aura are an increased susceptibility to cortical spreading depression (CSD) or a different expression of CSD. It is also possible that the brainstem migraine area is involved in CADASIL. Last, it is possible that the NOTCH3 mutation acts as a migraine aura susceptibility gene by itself. In this narrative review we summarize the literature about migraine in CADASIL, with a special focus on what CADASIL might teach us about the pathophysiology of migraine.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 173,
                "text": "NOTCH3 gene"
            }
        },
        {
            "context": "Friedreich's ataxia: clinical aspects and pathogenesis. Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 159,
                "text": "frataxin"
            }
        },
        {
            "context": "Finkelstein's test: a biomechanical analysis. PURPOSE: Finkelstein's test is the classic diagnostic test for de Quervain's disease. Finkelstein hypothesized that the entry of the muscle bellies of the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons into the first extensor compartment was responsible for the findings observed in his now eponymous test. We agree with Finkelstein's hypothesis and further hypothesize that this position would induce measurable bulk (muscle mass within the retinaculum) and tethering (stretching of synovial tissue) effects within the compartment. To test this latter hypothesis we measured the excursion and gliding resistance of the EPB and APL tendons within the first compartment. METHODS: Fifteen fresh-frozen cadavers were used. Gliding resistance and excursion were measured in 4 different wrist positions, including the wrist position of Finkelstein's test (30 degrees ulnar deviation). The bulk and tethering effect was calculated based on the mean gliding resistance over the tendon proximal/distal excursion cycle and the gliding resistance at the terminal distal excursion. RESULTS: The EPB tendon excursion was significantly more distal in 30 degrees ulnar deviation than in 60 degrees extension. Additionally the bulk and tethering resistance was significantly greater in 30 degrees ulnar deviation compared with 60 degrees extension. For the APL tendon there was no significant difference in either the tendon excursion or the bulk and tethering resistance between 30 degrees ulnar deviation and 60 degrees extension. CONCLUSIONS: We showed that in the position of Finkelstein's test the EPB tendon is significantly more distal and has significantly greater bulk and tethering effect compared with the other EPB positions. This is not the case for the APL tendon in the position of Finkelstein's test. These results suggest that an abnormal Finkelstein's test reflects differences of the EPB more than it does the APL.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 109,
                "text": "de Quervain's disease"
            }
        },
        {
            "context": "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 522,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 999,
                "text": "factor Xa"
            }
        },
        {
            "context": "Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases. Rigel Pharmaceuticals Inc is developing fostamatinib, a prodrug of the spleen tyrosine kinase (Syk) inhibitor R-406, for the potential treatment of autoimmune diseases such as rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and B-cell lymphomas. Syk is a key mediator of Fc and B-cell receptor signaling in inflammatory cells, such as B-cells, mast cells, macrophages and neutrophils. Preclinical studies of R-406 or fostamatinib demonstrated a significant reduction in major inflammatory mediators such as TNFalpha, IL-1, IL-6 and IL-18, leading to reduced inflammation and bone degradation in models of RA. In a phase II clinical trial, fostamatinib treatment effectively improved American College of Rheumatology response rates in patients with RA. Preclinical studies and phase II trials also suggested the potential of using fostamatinib for the treatment of ITP and B-cell lymphomas, by increasing platelet counts and inducing response rates, respectively. Fostamatinib is orally bioavailable and was well tolerated in phase I and II trials, with the most common side effect being gastrointestinal symptoms. At the time of publication, phase II trials for fostamatinib were ongoing in patients with RA, ITP and B-cell lymphomas. The Syk inhibitor appears to be a promising therapeutic for immunological diseases, but further data are required to establish the efficacy and long-term safety of the drug in humans.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 153,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. INTRODUCTION: In the last few years, several tyrosine kinase inhibitors (TKIs) have been synthesized and become available for preclinical studies and clinical trials. This article summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity, as well as the emerging role of TKIs in lymphoid malignancies, allergic diseases, and autoimmune disorders. AREAS COVERED: A literature review was conducted of the MEDLINE database PubMed for articles in English. Publications from 2000 through January 2012 were scrutinized. The search terms used were Bruton's tyrosine kinase (Btk) inhibitors, PCI-32765, GDC-0834, LFM-A13, AVL-101, AVL-292, spleen tyrosine kinase (Syk) inhibitors, R343, R406, R112, R788, fostamatinib, BAY-61-3606, C-61, piceatannol, Lyn, imatinib, nilotinib, bafetinib, dasatinib, GDC-0834, PP2, SU6656 in conjunction with lymphoid malignancy, NHL, CLL, autoimmune disease, allergic disease, asthma, and rheumatoid arthritis. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION: The use of TKIs, especially inhibitors of Btk, Syk, and Lyn, is a promising new strategy for targeted treatment of B-cell lymphoid malignancies, autoimmune disorders and allergic diseases. However, definitive data from ongoing and future clinical trials will aid in better defining the status of TKIs in the treatment of these disorders.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 801,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Modulation of rabbit muscle sarcoplasmic reticulum Ca(2+)-ATPase activity by novel quercetin derivatives. Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is the pump crucial for calcium homeostasis and its impairment results in pathologies such as myopathy, heart failure or diabetes. Modulation of SERCA activity may represent an approach to the therapy of diseases with SERCA impairment involvment. Quercetin is flavonoid known to modulate SERCA activity. We examined the effect of nine novel quercetin derivatives on the activity of the pump. We found that 5-morpholinohydroxypoxyquercetin, di(prenylferuoyl)quercetin, di(diacetylcaffeoyl)-mono-(monoacetylcaffeoyl)quercetin and monoacetylferuloylquercetin stimulated the activity of SERCA. On the contrary, monochloropivaloylquercetin, tri(chloropivaloyl)quercetin, pentaacetylquercetin, tri(trimethylgalloyl)quercetin and diquercetin inhibited the activity of the pump. To identify compounds with a potential to protect SERCA against free radicals, we assessed the free radical scavenging activity of quercetin derivatives. We also related lipophilicity, an index of the ability to incorporate into the membrane of sarcoplasmic reticulum, to the modulatury effect of quercetin derivatives on SERCA activity. In addition to its ability to stimulate SERCA, di(prenylferuloyl)quercetin showed excellent radical scavenging activity.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 106,
                "text": "Sarcoplasmic reticulum Ca(2+)-ATPase"
            }
        },
        {
            "context": "Non-viral reprogramming of fibroblasts into induced pluripotent stem cells by Sleeping Beauty and piggyBac transposons. The generation of induced pluripotent stem (iPS) cells represents a promising approach for innovative cell therapies. The original method requires viral transduction of several reprogramming factors, which may be associated with an increased risk of tumorigenicity. Transposition of reprogramming cassettes represents a recent alternative to viral approaches. Since binary transposons can be produced as common plasmids they provide a safe and cost-efficient alternative to viral delivery methods. Here, we compared the efficiency of two different transposon systems, Sleeping Beauty (SB) and piggyBac (PB), for the generation of murine iPS. Murine fibroblasts derived from an inbred BL/6 mouse line carrying a pluripotency reporter, Oct4-EGFP, and fibroblasts derived from outbred NMRI mice were employed for reprogramming. Both transposon systems resulted in the successful isolation of murine iPS cell lines. The reduction of the core reprogramming factors to omit the proto-oncogene c-Myc was compatible with iPS cell line derivation, albeit with reduced reprogramming efficiencies. The transposon-derived iPS cells featured typical hallmarks of pluripotency, including teratoma growth in immunodeficient mice. Thus SB and PB transposons represent a promising non-viral approach for iPS cell derivation.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 713,
                "text": "piggyBac"
            }
        },
        {
            "context": "[SENSITIVITY OF THE NEW SKIN TEST DIASKINTEST® FOR THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN CHILDREN AND ADOLESCENTS]. In Russia, an intradermal Diaskintest® drug has been designed, which is a recombinant tuberculosis allergen based on M. tuberculosis-- specific proteins: ESAT-6 and CFP-10 produced by a genetically modified Escherichia coli culture. Diaskintest® test and Mantoux test with 2TE PPD-L were concurrently carried out in 300 children and adolescents with tuberculosis and followed up in risk groups at a tuberculosis dispensary to determine the sensitivity of the new skin test in active tuberculosis infection. Diaskintest® showed a high sensitivity not only in active tuberculosis, but also in occult, the so-called latent, tuberculosis infection. This is suggested by the following evidence. The high percentage (83.8%) of positive responses to Diaskintest® is noted in children and adolescents with tuberculosis, receiving an intensive course of chemotherapy. Negative tests were observed only in minor forms at the resolution stage. In the children who had completed treatment, positive tests were seen in 78.3%, moreover in those with prior tuberculosis of intrathoracic lymph nodes; negative tests were observed not earlier than 18 months after start of treatment. The highest sensitivity of Diaskintest® was shown in children with early primary tuberculosis infection and through family contact with bacteria-excreting subjects (91.7%). These children may be judged with the highest assurance to have latent tuberculosis infection, the population of which is in an active state at the moment of the study. The children with early primary tuberculosis infection, but in no family contact with bacteria-excreting individuals, showed a lower percentage of positive responses to Diaskintest® both before (37.5%) and after (10%) treatment, which suggests that there must be a lower bacterial burden in the child. A high percentage of positive responses to Diaskintest® (76.2%) were found in subjects with hyperergic reactions to tuberculin. These were in only 16.7% in the group of patients receiving preventive therapy. In children and adolescents with a persistent positive Mantoux test (for more than 3 years), the response to Diaskintest® was negative in most cases since in early infection when mycobacteria propagated, the reaction to the drug was positive, but as 3 years pass the probability of the infection transition to the persistence stage is high--at that time the response to Diaskintest® becomes negative. Diaskintest® induces no delayed hypersensitivity associated with BCG vaccination, suggesting its high specificity. There were no positive reactions in patients with nonspecific lung diseases.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 604,
                "text": "tuberculosis"
            }
        },
        {
            "context": "[Ehlers-Danlos syndrome--20 years experience with diagnosis and classification at the university skin clinic of Heidelberg]. BACKGROUND: The Ehlers-Danlos syndrome encompasses a group of hereditary disorders of the connective tissue, characterized by hyperextensible skin, joint hypermobility; and varying degrees of vessel and tissue fragility. The main forms are classical, hypermobile, vascular, kyphoscoliotic A/B, arthrochalasis A/B and dermatosparaxis types. PATIENTS AND METHODS: We report our experience in diagnosis and classification of Ehlers-Danlos-syndrome, especially with the combination of clinical and morphological criteria, at the Department of Dermatology of the University of Heidelberg with more than 600 patients between 1984 and 2004. RESULTS: We classified those types of EDS which are characterized by regular and characteristic ultrastructural changes in the dermal components, primarily collagen, including the classical, hypermobile and vascular types as well as the less-common arthrochalasis and dermatosparaxis types. The combination of clinical and morphologic features facilitates the selection of candidate genes for molecular genetic investigation. CONCLUSIONS: Besides the skin, skeleton and vessels, many other organ systems such as eyes and intestine, can be affected in Ehlers-Danlos syndrome. Accordingly, interdisciplinary cooperation (pediatrics, surgery, orthopedics, rheumatology, neurology, genetics) is necessary. As the connective tissue of the skin is accessible for biopsy and diagnostic investigation, dermatologists should be trained in the diagnostic approach and classification of this syndrome.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 215,
                "text": "connective tissue"
            }
        },
        {
            "context": "Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations. We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. The hypoglycemia is deemed to be due to cortisol deficiency. This report represents the second published case of cortisol deficiency in the CS. A brief review of the endocrine disturbances in the syndrome is provided. We highlight the need for careful endocrinological evaluation of individuals with CS.",
            "question": "Which hormone deficiency is implicated in the Costello syndrome ?",
            "answers": {
                "answer_start": 23,
                "text": "growth hormone deficiency"
            }
        },
        {
            "context": "Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. OBJECTIVE: To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States. DATA SOURCES: Summary statements were obtained from each pharmaceutical company regarding their agent. STUDY SELECTION: Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials. RESULTS: Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points. CONCLUSIONS: The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 1094,
                "text": "ecallantide"
            }
        },
        {
            "context": "The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene. Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 572,
                "text": "7"
            }
        },
        {
            "context": "High frequency oscillations mirror disease activity in patients with focal cortical dysplasia. PURPOSE: The study analyzes the occurrence of high frequency oscillations in different types of focal cortical dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. METHODS: High frequency oscillations (80-450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal cortical dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b. KEY FINDINGS: Patients with focal cortical dysplasia type 2 had significantly more seizures than those with type 1 (p < 0.001). Rates of high frequency oscillations were significantly higher in patients with focal cortical dysplasia type 2 versus type 1 (p < 0.001). In addition, it could be confirmed that rates of high frequency oscillations were significantly higher in presumed epileptogenic areas than outside (p < 0.001). SIGNIFICANCE: Activity of high frequency oscillations mirrors the higher epileptogenicity of focal cortical dysplasia type 2 lesions compared to type 1 lesions. Therefore, rates of high frequency oscillations can reflect disease activity of a lesion. This has implications for the use of high frequency oscillations as biomarkers for epileptogenic areas, because a detailed analysis of their rates may be necessary to use high frequency oscillations as a predictive tool in epilepsy surgery.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 765,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Machado-Joseph disease/spinocerebellar ataxia type 3. Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 769,
                "text": "ataxin-3"
            }
        },
        {
            "context": "In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first 'outside to in' signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of interleukin 17 (IL-17) and interferon γ production and proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA animal model using SCID mice implanted with synovium and cartilage from patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice and also reduced synovial inflammation and invasion into the implanted cartilage. A phase 2 double-blind study using tofacitinib was carried out in Japanese patients with active RA and inadequate response to methotrexate (MTX). A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1417,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Striatal glutamate release in L-DOPA-induced dyskinetic animals. L-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-l-alanine (l-DOPA) in Parkinson's disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local L-DOPA application in the striatum. In addition, effects from the 5-HT(1A) receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OHDPAT; 1 mg/kg) was assessed on glutamate release and on dyskinetic behavior. The results revealed a bilateral = 30% reduction of basal extracellular glutamate concentration and attenuated potassium-evoked glutamate release after a unilateral dopamine-depletion in L-DOPA naïve animals. In dyskinetic subjects, basal glutamate concentration was comparable to normal controls, although potassium-evoked glutamate release was reduced to similar levels as in drug naïve dopamine-lesioned animals. Furthermore, acute striatal L-DOPA administration attenuated glutamate release in all groups, except in the dopamine-lesioned striatum of dyskinetic animals. Co-administration of 8-OHDPAT and L-DOPA decreased dyskinesia in dopamine-lesioned animals, but did not affect potassium-evoked glutamate release, which was seen in normal animals. These findings indicate altered glutamate transmission upon dopamine-depletion and dyskinesia.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 511,
                "text": "l-DOPA"
            }
        },
        {
            "context": "Willis-Ekbom Disease or Restless Legs Syndrome? BACKGROUND: Restless Legs Syndrome (RLS) or Willis-Ekbom Disease (WED) is highly prevalent, but patients and healthcare providers alike know little about it. Furthermore, controversy persists as to the best way of diagnosing this nosological entity. OBJECTIVE: To verify whether the term used to refer to this disease entity (Restless Legs Syndrome or Willis-Ekbom Disease) affects the prevalence of self-diagnosed RLS/WED in a sample of newly graduated physicians. METHODS: Newly graduated physicians were asked to self-evaluate for the presence of RLS/WED. Briefly, participants were allocated randomly across two groups. One was asked to self-assess for RLS, while the other was asked to self-assess for WED. The evaluation form given to one group asked 'Do you have Restless Legs Syndrome?' whereas the form given to participants in the other group asked 'Do you have Willis-Ekbom Disease?'. Both forms also contained the four criteria for diagnosing RLS proposed by the International Restless Legs Syndrome Study Group (IRLSSG) and instructions for self-diagnosis according to these criteria. RESULTS: The study sample comprised 1413 newly graduated physicians. Of the 708 participants who were given the form that used the term RLS, 87 (12.28%) diagnosed themselves with the condition. Conversely, of 705 physicians given the form with the term WED, 13 (1.84%) diagnosed themselves with the condition (p <0.0001). CONCLUSION: A greater proportion of newly graduated physicians diagnosed themselves with RLS/WED when presented with the term Restless Legs Syndrome than when presented with the term Willis-Ekbom Disease. This suggests that the term Restless Legs Syndrome may not be the most appropriate term to denote this nosological entity.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 24,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 593,
                "text": "SERCA"
            }
        },
        {
            "context": "Modifications of the bladder wall (organ damage) in patients with bladder outlet obstruction: ultrasound parameters. INTRODUCTION: Progressive changes in the bladder wall are observed in men with lower urinary tract obstruction secondary to benign prostatic enlargement (BPE). The high pressure voiding causes initially an increase in the proportion of smooth muscle (hyperplasia/hypertrophy of the detrusor) that develops to major changes in the advanced stages of bladder decompensationi (fibrosis), hyperactivity and decreased functional capacity. Early identification of bladder changes by noninvasive transabdominal ultrasound can suggest therapeutic choices that can prevent further organ damage in the bladder wall. Aim of our study is to review ultrasound (US) parameters, that could be considered reliable and reproducible, in order to demonstrate the damage of the bladder wall. METHODS: We performed a literature review to detect reported US parameters according to our aims. Our clinical experience was evaluated in retrospective manner to detect feasibility and limitations of the evaluation of these parameters in men with different degrees of bladder damage secondary to BPE. RESULTS: Measurement of the bladder wall thickness (BWT) or detrusor wall thickness (DWT) by US is reliable, with at least 3 measurements of the anterior bladder wall taken at a filling volume of 250 ml. In particular, the DWT [thickness of the hypoechoic muscle between two hyperechoic layers corresponding to serosa and mucosa] is considered the best diagnostic tool to measure detrusor hypertrophy using cut-off value > 2.9 mm in men. US derived measurements of bladder weight (Estimated Bladder Weight, EBW) is another noninvasive tool for assessing bladder modifications in patients with bladder outlet obstruction (BOO) with a cut-off value of 35 gr. Technique for measuring the BWT and EBW relies on conventional US 7.5-4 MHz using the automatic system of computation (BVM 6500 3.7 MHz). The variability of intra-operator (4.6 to 5.1%) and interoperator measurements (12.3%) is acceptable. Also conventional US detects established signs of bladder damage: diverticulosis, trabecolations in the bladder wall (pseudo-diverticula), calculi and post-void residual urine (PVR) (> 50 cc). Furthermore the Intravescical Prostate Protrusion (IPP), easy measured by transabdominal ultrasound, is strongly correlated to obstruction in men with BPE (cut-off 12 mm). Measurement, scoring and monitoring of the cervico-urethral obstruction in men with symptomatic BPE is possible by the non-invasive US of the bladder wall. Early identification by measuring DWTand EBW in addition to established US paremeters has the advantage of suggest the adoption of therapeutic measures sufficient to prevent progression of bladder damage. CONCLUSIONS: US derived measurements of DWT and EBW are reproducible and reliable. Transabdominal US also detect established bladder damage such as diverticula, stones and PVR, while IPP measurement seems to be correlated to BOO. US bladder parameters are considered potential noninvasive clinical tools for baseline assessment of patients with BOO. In particular noninvasive US parameters could be useful for longitudinal studies monitoring men with lower urinary tract obstruction secondary to BPE.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 94,
                "text": "ultrasound"
            }
        },
        {
            "context": "Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I. The classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown. We investigated whether cEDS affected the protein synthesis rate in skin and tendon, and whether this could be stimulated in tendon tissue with insulin-like growth factor-I (IGF-I). Five patients with cEDS and 10 healthy, matched controls (CTRL) were included. One patellar tendon of each participant was injected with 0.1 ml IGF-I (Increlex, Ipsen, 10 mg/ml) and the contralateral tendon with 0.1 ml isotonic saline as control. The injections were performed at both 24 and 6 h prior to tissue sampling. The fractional synthesis rate (FSR) of proteins in skin and tendon was measured with the stable isotope technique using a flood-primed continuous infusion over 6 h. After the infusion one skin biopsy and two tendon biopsies (one from each patellar tendon) were obtained. We found similar baseline FSR values in skin and tendon in the cEDS patients and controls [skin: 0.005 ± 0.002 (cEDS) and 0.007 ± 0.002 (CTRL); tendon: 0.008 ± 0.001 (cEDS) and 0.009 ± 0.002 (CTRL) %/h, mean ± SE]. IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0.007 ± 0.002, CTRL 0.001 ± 0.001%/h). In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 339,
                "text": "connective tissue"
            }
        },
        {
            "context": "Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM) cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 150,
                "text": "CD38"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 999,
                "text": "factor Xa"
            }
        },
        {
            "context": "C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin. We identified 2 cases with C9ORF72 repeat expansions. Both harbored phosphorylated TDP-43 and DPR inclusions. We show that DPR inclusions can incorporate or occur independently of ubiquilin. We also identified 1 case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 43,
                "text": "amyotrophic lateral sclerosis"
            }
        },
        {
            "context": "The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein. A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 447,
                "text": "TYR"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1219,
                "text": "dabigatran"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 0,
                "text": "Chromosome XII"
            }
        },
        {
            "context": "Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease. X-Linked Dystonia-Parkinsonism (XDP or \"Lubag\") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 56,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Asymmetric bidirectional transcription from the FSHD-causing D4Z4 array modulates DUX4 production. Facioscapulohumeral Disease (FSHD) is a dominantly inherited progressive myopathy associated with aberrant production of the transcription factor, Double Homeobox Protein 4 (DUX4). The expression of DUX4 depends on an open chromatin conformation of the D4Z4 macrosatellite array and a specific haplotype on chromosome 4. Even when these requirements are met, DUX4 transcripts and protein are only detectable in a subset of cells indicating that additional constraints govern DUX4 production. Since the direction of transcription, along with the production of non-coding antisense transcripts is an important regulatory feature of other macrosatellite repeats, we developed constructs that contain the non-coding region of a single D4Z4 unit flanked by genes that report transcriptional activity in the sense and antisense directions. We found that D4Z4 contains two promoters that initiate sense and antisense transcription within the array, and that antisense transcription predominates. Transcriptional start sites for the antisense transcripts, as well as D4Z4 regions that regulate the balance of sense and antisense transcripts were identified. We show that the choice of transcriptional direction is reversible but not mutually exclusive, since sense and antisense reporter activity was often present in the same cell and simultaneously upregulated during myotube formation. Similarly, levels of endogenous sense and antisense D4Z4 transcripts were upregulated in FSHD myotubes. These studies offer insight into the autonomous distribution of muscle weakness that is characteristic of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 128,
                "text": "FSHD"
            }
        },
        {
            "context": "Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. BACKGROUND: Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. METHODS: Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. RESULTS: NSD1 gene mutations were detected in 26 (72%) Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations (6 frameshift, 8 nonsense, 2 spice site, and 7 missense). Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. CONCLUSIONS: Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 12,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "E. coli DNA replication in the absence of free β clamps. During DNA replication, repetitive synthesis of discrete Okazaki fragments requires mechanisms that guarantee DNA polymerase, clamp, and primase proteins are present for every cycle. In Escherichia coli, this process proceeds through transfer of the lagging-strand polymerase from the β sliding clamp left at a completed Okazaki fragment to a clamp assembled on a new RNA primer. These lagging-strand clamps are thought to be bound by the replisome from solution and loaded a new for every fragment. Here, we discuss a surprising, alternative lagging-strand synthesis mechanism: efficient replication in the absence of any clamps other than those assembled with the replisome. Using single-molecule experiments, we show that replication complexes pre-assembled on DNA support synthesis of multiple Okazaki fragments in the absence of excess β clamps. The processivity of these replisomes, but not the number of synthesized Okazaki fragments, is dependent on the frequency of RNA-primer synthesis. These results broaden our understanding of lagging-strand synthesis and emphasize the stability of the replisome to continue synthesis without new clamps.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 64,
                "text": "DNA replication"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 0,
                "text": "MethPed"
            }
        },
        {
            "context": "Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 362,
                "text": "NOTCH3 gene"
            }
        },
        {
            "context": "The N370S mutation in the glucocerebrosidase gene of Portuguese type 1 Gaucher patients: linkage to the PvuII polymorphism. The mutation N370S accounts for 63% of the mutated glucocerebrosidase alleles of Portuguese type 1 Gaucher patients. It has been shown previously that this mutation is linked to the Pv1.1- form of the PvuII polymorphism and suggested that the N370S mutation in glucocerebrosidase alleles has an Ashkenazi Jewish origin. We have found that in Portuguese type 1 Gaucher patients this mutation is also invariably associated with the Pv1.1- haplotype, despite the fact that there is no evidence of Ashkenazi Jewish background in this population.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 175,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 293,
                "text": "SET domain"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 969,
                "text": "libFLASM"
            }
        },
        {
            "context": "Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Lung cancer is the leading cause of cancer related deaths in Canada with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 788,
                "text": "EGFR"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 1748,
                "text": "chromosome 2"
            }
        },
        {
            "context": "HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. Impaired remyelination due to degeneration of both postmitotic oligodendrocytes and oligodendrocyte progenitors (OPs) is the major hallmark of inflammatory demyelination in multiple sclerosis (MS) lesions and experimental autoimmune encephalomyelitis (EAE). Here, we have demonstrated the potential of lovastatin, a HMG-CoA reductase inhibitor, for the restoration of impaired remyelination mediated through enhanced survival and differentiation of OPs in the spinal cord of treated EAE animals. Lovastatin treatment significantly increased the level of myelin lipids in the spinal cord of treated EAE animals, coinciding with the attenuation of disease severity and inflammatory demyelination as compared with untreated EAE animals. The increased expression of myelin proteins and transcription factors associated with differentiating oligodendrocytes along with the increase in number of NG2+/BrdU- and NG2+/BrdU+ cells, and the expression of proliferating OP-specific proteins, demonstrated the restoration of remyelination in the spinal cord of lovastatin-treated EAE animals. Corresponding to this, in vitro studies further corroborated the increased survival and differentiation of OPs in lovastatin-treated activated mixed glial cells suggesting that lovastatin protects against the degeneration of OPs and enhances their differentiation through induction of a pro-remyelinating environment in the spinal cord of treated EAE animals. Together, these data demonstrate that lovastatin has the potential to augment remyelination in MS lesions and other neuroinflammatory diseases.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 345,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Multicenter evaluation of the Cepheid Xpert methicillin-resistant Staphylococcus aureus (MRSA) test as a rapid screening method for detection of MRSA in nares. The first U.S. multicenter clinical trial to assess the performance of the Cepheid Xpert MRSA assay (Xpert MRSA) was conducted. The assay is a qualitative test designed for the rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) directly from nares swabs. This novel test combines integrated nucleic acid extraction and automated real-time PCR for the detection of a MRSA-specific signature sequence. A total of 1,077 nares specimens were collected from seven geographically distinct health care sites across the United States with prevalence rates ranging from 5.2% to 44%. Nares specimens were tested by (i) the Xpert MRSA assay, (ii) direct culture on CHROMagar MRSA medium (direct CM culture), and (iii) broth-enriched culture (Trypticase soy broth with 6.5% sodium chloride) followed by plating onto CHROMagar MRSA medium (broth-enriched CM culture). When direct CM culture was designated the reference method, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA assay were 94.3%, 93.2%, 73.0%, and 98.8%, respectively. When broth-enriched CM culture was used as the reference method, the clinical sensitivity, specificity, PPV, and NPV of the Xpert MRSA assay were 86.3%, 94.9%, 80.5%, and 96.6%, respectively. The BD GeneOhm MRSA (BDGO) assay was performed as a comparative molecular method. No statistical performance differences were observed between the Xpert MRSA and BDGO assays when they were compared to culture methods. From this large-scale, multicenter clinical comparison, we conclude that the Xpert MRSA assay is a simple, rapid, and accurate method for performing active surveillance for MRSA in a variety of health care populations.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 89,
                "text": "MRSA"
            }
        },
        {
            "context": "Mutational analysis of the U12-dependent branch site consensus sequence. Highly conserved sequences at the 5' splice site and branch site of U12-dependent introns are important determinants for splicing by U12-dependent spliceosomes. This study investigates the in vivo splicing phenotypes of mutations in the branch site consensus sequence of the U12-dependent intron F from a human NOL1 (P120) minigene. Intron F contains a fully consensus branch site sequence (UUCCUUAAC). Mutations at each position were analyzed for their effects on U12-dependent splicing in vivo. Mutations at most positions resulted in a significant reduction of correct U12-dependent splicing. Defects observed included increased unspliced RNA levels, the activation of cryptic U2-dependent 5' and 3' splice sites, and the activation of cryptic U12-dependent branch/3' splice sites. A strong correlation was observed between the predicted thermodynamic stability of the branch site: U12 snRNA interaction and correct U12-dependent splicing. The lack of a polypyrimidine tract between the branch site and 3' splice site of U12-dependent introns and the observed reliance on base-pairing interactions for correct U12-dependent splicing emphasize the importance of RNA/RNA interactions during U12-dependent intron recognition and proper splice site selection.",
            "question": "Which is the branch site consensus sequence in U12-dependent introns?",
            "answers": {
                "answer_start": 464,
                "text": "UUCCUUAAC"
            }
        },
        {
            "context": "Alpha-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex. Alpha-synuclein (α-Syn) is the principal protein component of Lewy bodies, a pathological hallmark of Parkinson's disease (PD). This protein may regulate protein phosphatase 2A (PP2A) activity, although the molecular mechanisms for α-Syn-mediated regulation of PP2A and the potential neuroprotective actions of PP2A against PD-associated pathology remain largely unexplored. We found that α-Syn gene overexpression in SK-N-SH cells and primary neurons led to PP2A/C phosphorylation at Y307, a known target of Src kinase, and consequent phosphatase inhibition. In addition, phospho-activated Src (p-Y416 Src, pSrc) was higher in SK-N-SH cells and primary neurons overexpressing α-Syn. Thus, α-Syn may promote Src activation and PP2A inactivation, leading to hyperphosphorylation of proteins. Immunoprecipitation revealed higher calmodulin/Src complex formation in α-Syn-overexpressing cells and α-Syn transgenic mice. A TUNEL apoptosis assay and an MTT cell viability assay demonstrated that the PP2A activator C2-ceramide protected neurons against α-Syn-induced cell injury. Buffering the Ca(2+) elevations induced by α-Syn overexpression ameliorated the cytotoxicity of α-Syn. Our findings define a potential molecular mechanism for α-Syn-mediated regulation of PP2A through formation of the calmodulin/Src complex, activation of Src, and Src-mediated phospho-inhibition of PP2A. Overexpression of α-Syn may lead to neurodegeneration in PD in part by suppressing the endogenous neuroprotective activity of PP2A.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 120,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1136,
                "text": "telomerase"
            }
        },
        {
            "context": "The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy. Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p=0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot-Marie-Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot-Marie-Tooth Disease type 2.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 205,
                "text": "GAN gene"
            }
        },
        {
            "context": "Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 77,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 289,
                "text": "BRG1"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 76,
                "text": "P53-binding protein 1"
            }
        },
        {
            "context": "First trimester maternal serum PAPP-A and free β-HCG levels in hyperemesis gravidarum. OBJECTIVE: To evaluate whether hyperemesis gravidarum (HG) affects first-trimester maternal serum PAPP-A and free β-hCG levels. METHOD: An observational study was conducted in 115 cases of HG and 110 control pregnancies who attended the first-trimester prenatal screening program between January 2006 and July 2010. RESULTS: Maternal serum TSH levels were lower and free T4, and transaminases (ALT, AST) levels were higher in pregnancies complicated with HG compared with controls (p < 0.05 for all). In HG cases, median values of maternal serum PAPP-A were significantly higher with respect to normal pregnancies (1.2 vs 1.0 MoM; p = 0.009). Similarly, median values of free β-hCG were 1.3 MoM in HG pregnancies and 1.0 MoM in controls (p = 0.006). Multivariate analysis revealed that PAPP-A and hCG were independently associated with HG after controlling for TSH, free T4, AST, and ALT. CONCLUSION: HG is associated with elevated levels of PAPP-A and free β-hCG, and such changes are independent of serum indicators of thyroid and liver function.",
            "question": "Which protein is associated with hyperemesis gravidarum during pregrancy?",
            "answers": {
                "answer_start": 1047,
                "text": "hCG"
            }
        },
        {
            "context": "Solution structure of the spectrin repeat: a left-handed antiparallel triple-helical coiled-coil. Cytoskeletal proteins belonging to the spectrin family have an elongated structure composed of repetitive units. The three-dimensional solution structure of the 16th repeat from chicken brain alpha-spectrin (R16) has been determined by NMR spectroscopy and distance geometry-simulated annealing calculations. We used a total of 1035 distance restraints, which included 719 NOE-based values obtained by applying the ambiguous restraints for iterative assignment (ARIA) method. In addition, we performed a direct refinement against 1H-chemical shifts. The final ensemble of 20 structures shows an average RMSD of 1.52 A from the mean for the backbone atoms, excluding loops and N and C termini. R16 is made up of three antiparallel alpha-helices separated by two loops, and folds into a left-handed coiled-coil. The basic unit of spectrin is an antiparallel heterodimer composed of two homologous chains, beta and alpha. These assemble a tetramer via a mechanism that relies on the completion of a single repeat by association of the partial repeats located at the C terminus of the beta-chain (two helices) and at the N terminus of the alpha-chain (one helix). This tetramer is the assemblage able to cross-link actin filaments. Model building by homology of the \"tetramerization\" repeat from human erythrocyte spectrin illuminates the possible role of point mutations which cause hemolytic anemias.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 941,
                "text": "antiparallel"
            }
        },
        {
            "context": "Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 364,
                "text": "flumazenil"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 287,
                "text": "XK"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 832,
                "text": "factor Xa"
            }
        },
        {
            "context": "Insulin-like growth factor-binding protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes. Non-melanoma skin cancers (NMSC) are the most common malignancies in caucasians worldwide. Insulin-like growth factor-binding protein-7 (IGFBP7) was suggested to function as a tumor suppressor gene in several cancers, and to play a role in the proliferation of keratinocytes. A-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells. A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function. Two editing sites were identified within the IGFBP7 transcript. To evaluate the expression and editing of IGFBP7 mRNA in NMSC compared to normal epidermis. We examined the expression and mRNA editing level of IGFBP7 in 22 basal cell carcinoma (BCC), 15 squamous cell carcinoma (SCC), and 18 normal epidermis samples that were surgically removed from patients by the Mohs Micrographic Surgery procedure. We studied the effect of IGFBP7 editing on an immortalized HaCaT keratinocyte cell model. IGFBP7 mRNA is over expressed in BCC and SCC compared to normal epidermis. Moreover, the IGFBP7 transcript is highly edited in normal epidermis, but its editing is significantly reduced in BCC and SCC. The edited form of IGFBP7 can inhibit proliferation and induce senescence in cultured keratinocytes. This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 1513,
                "text": "A-to-I"
            }
        },
        {
            "context": "Current strategies for treatment of relapsed/refractory multiple myeloma. In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 885,
                "text": "orally"
            }
        },
        {
            "context": "The first case report of McLeod syndrome in a Chinese patient. We report the first case of McLeod syndrome (MLS) in a 47-year-old Chinese man who presented with progressive limb weakness, chorea of feet, red blood cell acanthocytosis, absence of Kx red blood cell antigen and weak expression of Kell antigens. The diagnosis of MLS was confirmed by genetic testing showing a hemizygous mutation of XK gene. We review literature on neuroacanthocytosis in the Chinese population.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 397,
                "text": "XK"
            }
        },
        {
            "context": "Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 814,
                "text": "orally"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 258,
                "text": "7"
            }
        },
        {
            "context": "The S-methylmethionine cycle in angiosperms: ubiquity, antiquity and activity. Angiosperms synthesize S-methylmethionine (SMM) from methionine (Met) and S-adenosylmethionine (AdoMet) in a unique reaction catalyzed by Met S-methyltransferase (MMT). SMM serves as methyl donor for Met synthesis from homocysteine, catalyzed by homocysteine S-methyltransferase (HMT). MMT and HMT together have been proposed to constitute a futile SMM cycle that stops the free Met pool from being depleted by an overshoot in AdoMet synthesis. Arabidopsis and maize have one MMT gene, and at least three HMT genes that belong to two anciently diverged classes and encode enzymes with distinct properties and expression patterns. SMM, and presumably its cycle, must therefore have originated before dicot and monocot lineages separated. Arabidopsis leaves, roots and developing seeds all express MMT and HMTs, and can metabolize [35S]Met to [35S]SMM and vice versa. The SMM cycle therefore operates throughout the plant. This appears to be a general feature of angiosperms, as digital gene expression profiles show that MMT and HMT are co-expressed in leaves, roots and reproductive tissues of maize and other species. An in silico model of the SMM cycle in mature Arabidopsis leaves was developed from radiotracer kinetic measurements and pool size data. This model indicates that the SMM cycle consumes half the AdoMet produced, and suggests that the cycle serves to stop accumulation of AdoMet, rather than to prevent depletion of free Met. Because plants lack the negative feedback loops that regulate AdoMet pool size in other eukaryotes, the SMM cycle may be the main mechanism whereby plants achieve short-term control of AdoMet level.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 175,
                "text": "AdoMet"
            }
        },
        {
            "context": "BCR-ABL gene amplification and overexpression in a patient with chronic myeloid leukemia treated with imatinib. Imatinib mesylate was designed as an inhibitor targeting the BCR-ABL tyrosine kinase, the molecular counterpart of the Philadelphia translocation t(9;22)(q34;q11). We report on a patient with chronic myeloid leukemia (CML) undergoing acceleration during imatinib treatment. Cytogenetic analysis revealed four different cell populations: 46,XX,t(9;22)(q34;q11),der(18)t(2;18)(p11;p11)[1]/47,idem,i(17)(q10),-der(18)t(2;18),+der(22)t(9;22)[1]/46,idem,-t(9;22),der(9)t(9;22),ider(22)t(9;22)[12]/ 47,idem,-t(9;22),der(9)t(9;22),+22,ider(22)t(9;22)x2[1]. FISH analysis confirmed the presence of these four clones. Moreover, 49% of the interphase nuclei contained either one or two clustered fusion signals, indicating a low-level amplification of the BCR-ABL fusion gene. With quantitative real-time RT-PCR, a BCR-ABL/G6PDH ratio of 0.8 was determined, which is comparable to that measured in the K562 cell line with a known BCR-ABL amplification and which is increased by more than about 60-fold compared to a CML at diagnosis with >80% Philadelphia-positive cells. We give further evidence that the genomic BCR-ABL amplification results in an increased level of BCR-ABL transcript linking two potent mechanisms of resistance against imatinib treatment.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 173,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Label-free MSE proteomic analysis of chronic myeloid leukemia bone marrow plasma: disclosing new insights from therapy resistance. Chronic myeloid leukemia (CML) is a pluripotent hematopoietic disorder that is currently considered incurable. The tyrosine kinase product of the Philadelphia chromosome, P210 BCR-ABL, provided a pathogenetic explanation for the initiation of the CML chronic phase and is the molecular therapeutic target for the disease. Imatinib mesylate, an orally available BCR-ABL kinase inhibitor, can induce haematologic and cytogenetic remission of CML. However, imatinib resistance occurs frequently, resulting in relapse. New treatment strategies are focusing on resistant CML stem cells and the bone marrow stroma. The identification of novel pathways and mechanisms in the bone marrow microenvironment could significantly contribute to the development of such strategies. In this work, we used a high-resolution label-free MS(E) proteomic approach to identify differential protein expression in the CML bone marrow plasma of responsive and resistant patients. Oxidative lipid metabolism and regulation of the switch from canonical to noncanonical WNT signaling may contribute to CML resistance in the bone marrow compartment.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 307,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Nardilysin regulates inflammation, metaplasia, and tumors in murine stomach. Chronic inflammation contributes to a wide variety of human disorders. In the stomach, longstanding gastritis often results in structural alterations in the gastric mucosa, including metaplastic changes and gastric cancers. Therefore, it is important to elucidate factors that are involved in gastric inflammation. Nardilysin (N-arginine dibasic convertase; Nrdc) is a metalloendopeptidase of the M16 family that promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of a disintegrin and metalloproteinase (ADAM) proteins. Here, we have demonstrated that Nrdc crucially regulates gastric inflammation caused by Helicobacter felis infection or forced expression of prostaglandin E in K19-C2mE mice. Metaplastic changes following gastric inflammation were suppressed by the deletion of Nrdc. Furthremore, the deletion of Nrdc significantly suppressed N-methyl-N-nitrosourea (MNU)-induced gastric tumorigenesis in the murine stomach. These data may lead to a global therapeutic approach against various gastric disorders by targeting Nrdc.",
            "question": "Which is the enzymatic activity of nardilysin?",
            "answers": {
                "answer_start": 392,
                "text": "Nardilysin (N-arginine dibasic convertase; Nrdc) is a metalloendopeptidase of the M16 family that promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of a disintegrin and metalloproteinase (ADAM) proteins."
            }
        },
        {
            "context": "Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca2+ overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca2+. Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 1073,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data?",
            "answers": {
                "answer_start": 0,
                "text": "diffloop"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 1628,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Clinical assessment of bortezomib for multiple myeloma in comparison with thalidomide. PURPOSE: We studied the efficacy and safety of bortezomib (BOR) for treatment of multiple myeloma in comparison with thalidomide (THAL) by reference to adverse events, and searched for laboratory markers that could be used for prognostication of patients. METHODS: Biochemical data of patients receiving BOR and THAL for treatment of multiple myeloma at the Japanese Red Cross Narita Hospital were investigated retrospectively, after obtaining Institutional Review Board approval. Judgment of curative effects complied with the effects criteria of the International Myeloma Working Group (IMWG). RESULTS: BOR showed a higher rate of effectiveness than THAL for refractory multiple myeloma, and its effects were rapid. BOR treatment prolonged the survival time of THAL-resistant patients. The efficacy of BOR was unrelated to patient age, the number of previous therapeutic regimens, or the disease period. After medication with BOR, patients in whom it had been effective tended to show an increase of the serum alkaline phosphatase (ALP) level. Thrombocytopenia (86.2%) and leucopenia (69.0%) were observed at high frequencies, but no previously unreported adverse events or fatalities were associated with BOR therapy. CONCLUSION: It is suggested that BOR has therapeutic efficacy for multiple myeloma as a first-line medical treatment and/or for patients with THAL resistance, and can improve prognosis and survival. Since serum ALP elevation was observed in many patients for whom BOR was effective, this may be a predictor of BOR efficacy.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 168,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 674,
                "text": "telomerase"
            }
        },
        {
            "context": "Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/kexin type 9: the available clinical evidence. INTRODUCTION: Despite the proven efficacy of statins, they are often reported to be inadequate to achieve low-density lipoprotein cholesterol (LDL-C) goals (especially in high-risk patients). Moreover, a large number of subjects cannot tolerate statins or full doses of these drugs. Thus, there is a need for additional effective LDL-C reducing agents. AREAS COVERED: Evolocumab (AMG145) is a monoclonal antibody inhibiting the proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL receptor and prevents it from normal recycling by targeting it for degradation. Phase I and II trials revealed that its subcutaneous injection, either alone or in combination with statins, is able to reduce LDL-C from 40 to 80%, apolipoprotein B100 from 30 to 59% and lipoprotein(a) from 18 to 36% in a dose-dependent manner. The incidence of side effects seems to be low and mainly limited to nasopharyngitis, injection site pain, arthralgia and back pain. EXPERT OPINION: Evolocumab is an innovative powerful lipid-lowering drug, additive to statins and with an apparently large therapeutic range associated to a low rate of mild adverse events. If available data will be confirmed in long-term trials with strong outcomes, Evolocumab will provide an essential tool to treat high-risk patients who need to reach ambitious LDL-C target.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 591,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 104,
                "text": "Facioscapulohumeral dystrophy"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 719,
                "text": "webSDA"
            }
        },
        {
            "context": "Enhancer Sharing Promotes Neighborhoods of Transcriptional Regulation Across Eukaryotes. Enhancers physically interact with transcriptional promoters, looping over distances that can span multiple regulatory elements. Given that enhancer-promoter (EP) interactions generally occur via common protein complexes, it is unclear whether EP pairing is predominantly deterministic or proximity guided. Here, we present cross-organismic evidence suggesting that most EP pairs are compatible, largely determined by physical proximity rather than specific interactions. By reanalyzing transcriptome datasets, we find that the transcription of gene neighbors is correlated over distances that scale with genome size. We experimentally show that nonspecific EP interactions can explain such correlation, and that EP distance acts as a scaling factor for the transcriptional influence of an enhancer. We propose that enhancer sharing is commonplace among eukaryotes, and that EP distance is an important layer of information in gene regulation.",
            "question": "Which effects create neighborhoods of transcriptional regulation in eukaryotes?",
            "answers": {
                "answer_start": 0,
                "text": "Enhancer Sharing"
            }
        },
        {
            "context": "Monoclonal antibodies - A new era in the treatment of multiple myeloma. Monoclonal antibodies (mAbs) are currently the most investigated therapeutic compounds in oncology, but there is no monoclonal antibody approved in the treatment of multiple myeloma (MM). Nevertheless several really promising molecules are under investigation in phase III clinical trials. Dominantly daratumumab (anti-CD38) and elotuzumab (anti-CS1) showed extraordinary effectiveness in phase I/II trials. The toxicity was acceptable which is important for their addition to standard anti-myeloma agents like proteasome inhibitors or immunomodulatory drugs. Monoclonal antibodies such as denosumab (anti-RANKL) or BHQ880 (anti-DKK-1) are investigated also in the management of myeloma bone disease. This review is focused on the most promising mAbs, their mechanisms of action and the rationale of use. Practically all available results have been described. If the ongoing trials confirm the efficacy and safety of mAbs, they would become an important part of MM treatment that would be translated in the further improvement of therapeutic outcomes.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 391,
                "text": "CD38"
            }
        },
        {
            "context": "Association of restless legs syndrome variants in Korean patients with restless legs syndrome. STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS. DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci. MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters. CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 255,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5'-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3' in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1188,
                "text": "FSHD"
            }
        },
        {
            "context": "Presentation and prevalence of PTSD in a bipolar disorder population: a STEP-BD examination. BACKGROUND: Co-occurring psychiatric diagnoses have a negative impact on quality of life and change the presentation and prognosis of bipolar disorder (BD). To date, comorbidity research on patients with BD has primarily focused on co-occurring anxiety disorders and trauma history; only recently has there been a specific focus on co-occurring PTSD and BD. Although rates of trauma and PTSD are higher in those with bipolar disorder than in the general population, little is known about differences across bipolar subtypes. METHODS: Using the NIMH STEP-BD dataset (N=3158), this study evaluated whether there were baseline differences in the prevalence of PTSD between participants with bipolar disorder I (BDI) and bipolar disorder II (BDII), using the MINI and the Davidson Trauma Scale. Differences in PTSD symptom clusters between patients with BDI and BDII were also evaluated. RESULTS: A significantly greater proportion of participants with BDI had co-occurring PTSD at time of study entry (Χ(2)(1)=12.6; p<.001). BDI and BDII subgroups did not significantly differ in re-experiencing, avoidance, or arousal symptoms. LIMITATIONS: The analysis may suggest a correlational relationship between PTSD and BD, not a causal one. Further, it is possible this population seeks treatment more often than individuals with PTSD alone. Finally, due to the episodic nature of BD and symptom overlap between the two disorders, misdiagnosis is possible. CONCLUSIONS: PTSD may be more prevalent in patients with BDI. However, the symptom presentation of PTSD appears similar across BD subtypes. Individuals should be thoroughly assessed for co-occurring diagnoses in an effort to provide appropriate treatment.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 480,
                "text": "PTSD"
            }
        },
        {
            "context": "IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins. Molluscum contagiosum virus (MCV) is a common, human poxvirus that causes small papular skin lesions that persist for long periods without signs of inflammation. Previous studies revealed that MCV encodes a family of proteins with homology to mammalian IL-18 binding proteins. IL-18 is a proinflammatory cytokine that induces synthesis of interferon gamma, activates NK cells, and is required for a T-lymphocyte helper type 1 response. We expressed and purified the proteins encoded by the MC53L and MC54L genes of MCV, as well as their human and murine homologs. All four recombinant proteins were able to bind with high affinity to human and murine IL-18 molecules and inhibited IL-18 mediated interferon gamma production in a dose-dependent manner. The pirating of IL-18 binding proteins by poxviruses and their use as decoy receptors is consistent with the critical role of IL-18 in defense against virus infections and provides a mechanism for evasion of the immune system by MCV.",
            "question": "Which virus type causes Molluscum contagiosum?",
            "answers": {
                "answer_start": 142,
                "text": "human poxvirus"
            }
        },
        {
            "context": "Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BACKGROUND: X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. RESULTS: We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. CONCLUSIONS: Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 182,
                "text": "X"
            }
        },
        {
            "context": "In vitro RNase and nucleic acid binding activities implicate coilin in U snRNA processing. Coilin is known as the marker protein for Cajal bodies (CBs), subnuclear domains important for the biogenesis of small nuclear ribonucleoproteins (snRNPs) which function in pre-mRNA splicing. CBs associate non-randomly with U1 and U2 gene loci, which produce the small nuclear RNA (snRNA) component of the respective snRNP. Despite recognition as the CB marker protein, coilin is primarily nucleoplasmic, and the function of this fraction is not fully characterized. Here we show that coilin binds double stranded DNA and has RNase activity in vitro. U1 and U2 snRNAs undergo a processing event of the primary transcript prior to incorporation in the snRNP. We find that coilin displays RNase activity within the CU region of the U2 snRNA primary transcript in vitro, and that coilin knockdown results in accumulation of the 3' pre-processed U1 and U2 snRNA. These findings present new characteristics of coilin in vitro, and suggest additional functions of the protein in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 91,
                "text": "Coilin"
            }
        },
        {
            "context": "Non-random X chromosome inactivation in mammalian cells. A salient feature of mammalian X dosage compensation is that X-inactivation occurs without regard to the parental origin of either active or inactive X. However, there are variations on the theme of random inactivation, namely paternal X inactivation in marsupials and in placental tissues of some mammals. Whether inactivation is random or paternal seems to depend on the time when this developmental program is initiated. As deletions of the X inactivation center (XIC/Xic) and/or the X inactive specific transcript (XIST/Xist) gene result in failure of cis X-inactivation, mutations in genes from this region might lead to preferential inactivation of one X chromosome or the other. The Xce locus in the murine Xic is considered a prototype for this model. Recent studies suggest that choice involves maintaining the activity of one X, while the other(s) by default is programmed to become inactive. Also, choice resides within the XIC, so that mutations elsewhere, although perhaps able to interfere with cis inactivation, are not likely to affect the X chromosome from only one parent. Mutations affecting the choice of active X will be more difficult to detect in humans than in inbred laboratory mice because of the greater allelic differences between maternal and paternal X chromosomes; some of these differences predispose to growth competition between the mosaic cell populations. I suggest that the skewing of inactivation patterns observed in human females most often occurs after random X inactivation, and is due mainly to cell selection favoring alleles that provide a relative growth advantage.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 581,
                "text": "Xist"
            }
        },
        {
            "context": "Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb. Epigenomic mapping of enhancer-associated chromatin modifications facilitates the genome-wide discovery of tissue-specific enhancers in vivo. However, reliance on single chromatin marks leads to high rates of false-positive predictions. More sophisticated, integrative methods have been described, but commonly suffer from limited accessibility to the resulting predictions and reduced biological interpretability. Here we present the Limb-Enhancer Genie (LEG), a collection of highly accurate, genome-wide predictions of enhancers in the developing limb, available through a user-friendly online interface. We predict limb enhancers using a combination of >50 published limb-specific datasets and clusters of evolutionarily conserved transcription factor binding sites, taking advantage of the patterns observed at previously in vivo validated elements. By combining different statistical models, our approach outperforms current state-of-the-art methods and provides interpretable measures of feature importance. Our results indicate that including a previously unappreciated score that quantifies tissue-specific nuclease accessibility significantly improves prediction performance. We demonstrate the utility of our approach through in vivo validation of newly predicted elements. Moreover, we describe general features that can guide the type of datasets to include when predicting tissue-specific enhancers genome-wide, while providing an accessible resource to the general biological community and facilitating the functional interpretation of genetic studies of limb malformations.",
            "question": "Which resource contains accurate enhancer predictions in the developing limb?",
            "answers": {
                "answer_start": 536,
                "text": "Limb-Enhancer Genie (LEG)"
            }
        },
        {
            "context": "Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 170,
                "text": "FBN1"
            }
        },
        {
            "context": "Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies. Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 122,
                "text": "Ataxin-3"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L). XXII. cDNA cloning and characterization of an elicitor-inducible isoflavone 7-O-methyltransferase. Medicarpin, the major phytoalexin in alfalfa, is synthesized via the isoflavonoid branch of phenylpropanoid metabolism. The methyl group at the 9 position of medicarpin is generally accepted to arise via the methylation of the 4' position (B-ring) of daidzein. Surprisingly, the isoflavone-O-methyltransferase (IOMT), which is induced along with other enzymes involved in medicarpin biosynthesis, methylates the A-ring 7-hydroxyl group of daidzein in vitro, a reaction that probably does not occur in vivo. Utilizing internal amino acid sequence information from purified alfalfa IOMT, we have isolated three full-length IOMT cDNA clones. A search of the protein databases revealed sequence similarities to O-methyltransferases from various sources. The highest match (50.5% identity) was found between IOMT8 and 6a-hydroxymaackiain 3-O-methyltransferase from Pisum sativum. The molecular weight of alfalfa IOMT expressed in Escherichia coli was similar to that of purified IOMT from alfalfa cell cultures (41 kDa by SDS-PAGE). The recombinant enzyme catalyzed the O-methylation of A-ring hydroxyl group(s) of isoflavones, and could also methylate the pterocarpan (+) 6a-hydroxymaackiain. Alfalfa contains multiple IOMT genes, and closely related sequences are present in the genomes of chickpea and cowpea, species that also produce B-ring methylated isoflavonoids in vivo. Northern blot analysis indicated that IOMT transcripts are rapidly induced following elicitation, prior to the increase in IOMT activity and medicarpin accumulation. The possible role of the isoflavone 7-OMT in the synthesis of formononetin in vivo is discussed.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 148,
                "text": "Medicarpin"
            }
        },
        {
            "context": "The Xist RNA A-repeat comprises a novel AUCG tetraloop fold and a platform for multimerization. X-chromosome inactivation (XCI) in female mammals depends on the noncoding RNA X inactivation specific transcript (Xist). The mechanism of chromosome-wide silencing by Xist is poorly understood. While it is established that the 5' region of Xist RNA, comprising the A-repeats and holding 7.5-8.5 copies of a conserved 26-mer sequence, is essential for Xist-mediated silencing, high-resolution structural information for the A-repeats is not available. Here, we report the three-dimensional solution structure of a 14-mer hairpin in the 5' region of a human A-repeat. This hairpin is remarkably stable and adopts a novel AUCG tetraloop fold, the integrity of which is required for silencing. We show that, contrary to previous predictions, the 3' region of single or tandem A-repeats mediates duplex formation in vitro. Significantly, mutations in this region disrupt the inter-repeat duplex formation in vitro and abrogate the silencing function of Xist A-repeats in vivo. Our data suggest that the complete A-repeat region may be stabilized by inter-repeat duplex formation and, as such, may provide a platform for multimerization and specific recognition of the AUCG tetraloops by trans-acting factors.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 211,
                "text": "Xist"
            }
        },
        {
            "context": "A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. STUDY OBJECTIVE: To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated. SETTING: Sixteen emergency departments in the United States. POPULATION: Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose. INTERVENTIONS: Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered. MEASUREMENTS AND MAIN RESULTS: Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ. CONCLUSION: Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1500,
                "text": "flumazenil"
            }
        },
        {
            "context": "Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly. Approximately 1% of human proteins harbor a prion-like domain (PrLD) of similar low complexity sequence and amino acid composition to domains that drive prionogenesis of yeast proteins like Sup35. PrLDs are over-represented in human RNA-binding proteins and mediate phase transitions underpinning RNP granule assembly. This modality renders PrLDs prone to misfold into conformers that accrue in pathological inclusions that characterize various fatal neurodegenerative diseases. For example, TDP-43 and FUS form cytoplasmic inclusions in amyotrophic lateral sclerosis (ALS) and mutations in TDP-43 and FUS can cause ALS. Here, we review our recent discovery of discrete missense mutations that alter a conserved gatekeeper aspartate residue in the PrLDs of hnRNPA2/B1 and hnRNPA1 and cause multisystem proteinopathy and ALS. The missense mutations generate potent steric zippers in the PrLDs, which enhance a natural propensity to form self-templating fibrils, promote recruitment to stress granules and drive cytoplasmic inclusion formation. PrLDs occur in ~250 human proteins and could contribute directly to the etiology of various degenerative disorders.",
            "question": "Which domain allowing self-association do exist in TDP-43 and FUS proteins?",
            "answers": {
                "answer_start": 186,
                "text": "prion-like domain"
            }
        },
        {
            "context": "Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 718,
                "text": "ibrutinib"
            }
        },
        {
            "context": "A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.",
            "question": "Mutation of which gene is associated with Achondroplasia?",
            "answers": {
                "answer_start": 463,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 4,
                "text": "poly(ADP-ribose) polymerase"
            }
        },
        {
            "context": "Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities. MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels.",
            "question": "Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome?",
            "answers": {
                "answer_start": 18,
                "text": "MCT8"
            }
        },
        {
            "context": "Identification of clusterin domain involved in NF-kappaB pathway regulation. Clusterin (CLU) is a ubiquitous protein that has been implicated in tumorigenesis, apoptosis, inflammation, and cell proliferation. We and others have previously shown that CLU is an inhibitor of the NF-kappaB pathway. However, the exact form of CLU and the region(s) of CLU involved in this effect were unknown. Using newly generated molecular constructs encoding for CLU and various regions of the molecule, we demonstrated that the presecretory form of CLU (psCLU) form bears the NF-kappaB regulatory activity. Sequence comparison analysis showed sequence motif identity between CLU and beta-transducin repeat-containing protein (beta-TrCP), a main E3 ubiquitin ligase involved in IkappaB-alpha degradation. These homologies were localized in the disulfide constraint region of CLU. We generated a specific molecular construct of this region, named DeltaCLU, and showed that it has the same NF-kappaB regulatory activity as CLU. Neither the alpha-chain nor the beta-chain of CLU had any NF-kappaB regulatory activity. Furthermore, we showed that following tumor necrosis factor-alpha stimulation of transfected cells, we could co-immunoprecipitate phospho-IkappaB-alpha with DeltaCLU. Moreover, we showed that DeltaCLU could localize both in the cytoplasm and in the nucleus. These results demonstrate the identification of a new CLU activity site involved in NF-kappaB pathway regulation.",
            "question": "Which is the E3 ubiquitin ligase which ubiquitinates IkB leading to its proteasomal degradation?",
            "answers": {
                "answer_start": 710,
                "text": "beta-TrCP"
            }
        },
        {
            "context": "Spatial variability in sulphur isotope values of archaeological and modern cod (Gadus morhua). RATIONALE: This study presents the first sulphur isotope data of modern and archaeological cod (Gadus morhua) bone collagen, undertaken to identify large-scale spatial variability of significance as both baseline values for studies of human diet and a potential variable in isotope-based studies of fish trading. METHODS: Collagen was extracted from modern and archaeological cod bones using a weak HCl solution and analysed for its sulphur isotopic composition by isotope ratio mass spectrometry (IRMS). RESULTS: The archaeological cod have sulphur isotope values ranging from +9.1‰ to +18.2‰, whereas values for modern specimens range from +14.8‰ to +18.3‰. The modern data show values implying less freshwater influence, consistent with their offshore catch locations, but also corroborate some of the regional variability evident from the archaeological evidence. CONCLUSIONS: The archaeological data have a large range of sulphur isotope values compared with the modern populations, probably indicating they were taken from a wide range of geographic locations, including both coastal and offshore locales. They show broad trends of regional difference that may relate to both the fish populations targeted (e.g. 'inshore' versus 'offshore') and the baseline values of the local ecosystem (e.g. degree of freshwater input from river systems).",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 417,
                "text": "Collagen"
            }
        },
        {
            "context": "Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. A single cell has the potential to kill an entire human being. Efforts to cure cancer are limited by survival of individual cancer cells despite immune surveillance and toxic therapies. Understanding the intricate network of pathways that maintain cellular homeostasis and mediate stress response or default into cell death is critical to the development of strategies to eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein response (UPR) are cellular pathways that degrade and recycle excess or damaged proteins to maintain cellular homeostasis and survival. This review will discuss autophagy and how it is integrated with proteasomal degradation and UPR to govern cell fate through restoration of cellular homeostasis or default into the apoptotic cell death pathway. The first response of autophagy is macroautophagy, which sequesters cytoplasm including organelles inside double-membraned autophagosome vesicles that fuse with lysosomes to degrade and recycle the contents. Ubiquitination patterns on proteins targeted for degradation determine whether adapter proteins will bring them to developing autophagosomes or to proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. These two processes and the lesser understood microautophagy, which involves direct engulfment of proteins into lysosomes, occur at basal and induced levels. Insufficient proteasome function or ER stress induction of UPR can induce autophagy, which can mitigate damage and stress. If this network is incapable of repairing the damage or overcoming continued stress, the default pathway of apoptosis is engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics has led to clinical trials investigating combinations of HCQ (hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. Further study of the complex integration of autophagy, proteasomal degradation, UPR and apoptosis is likely to provide additional targets for our fight against cancer. This article is part of a Special Issue entitled \"Apoptosis: Four Decades Later\".",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 1287,
                "text": "chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BACKGROUND: Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality. METHODS: Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of > 2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score  < IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study. DISCUSSION: APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.",
            "question": "What is the name of the RNAi investigational drug being developed against hereditary amyloidosis?",
            "answers": {
                "answer_start": 166,
                "text": "Patisiran"
            }
        },
        {
            "context": "High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. BACKGROUND AND OBJECTIVES: Iron depletion is common in regular blood donors. The objective of the study was to investigate the frequency and severity of iron depletion in regular blood donors and whether IV iron is more effective than oral to avoid iron depletion and symptoms thereof, especially restless legs syndrome (RLS). METHOD: One hundred and twenty blood donors with at least five previous whole blood donations were randomized to receive either IV iron sucrose (Venofer(®), RenaPharma/Vifor, Uppsala, Sweden), 200 mg, or to 20×100 mg of oral iron sulphate (Duroferon(®), GlaxoSmithKline, Stockholm, Sweden), after each blood donation during 1 year. Iron status and RLS incidence and severity were investigated. RESULTS: Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). The IV iron group increased storage iron to a greater extent than the oral iron group after 12 months (P=0·0043). Female donors were more responsive to IV iron sucrose compared to oral iron sulphate, particularly female donors below 50 years of age. RLS severity scores were significantly lower in the IV iron group. The two treatments were safe. CONCLUSION: Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. IV iron sucrose substitutes iron loss in blood donors more efficiently compared with oral iron sulphate, especially in women. Iron substitution to blood donors should be individualized and based on P-ferritin monitoring.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 994,
                "text": "iron"
            }
        },
        {
            "context": "ABL tyrosine kinases: evolution of function, regulation, and specificity. ABL-family proteins comprise one of the best conserved branches of the tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. This cassette is coupled to an actin-binding and -bundling domain, which makes ABL proteins capable of connecting phosphoregulation with actin-filament reorganization. Two vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain through which it mediates DNA damage-repair functions, whereas ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. Information on ABL regulatory mechanisms is being mined to provide new therapeutic strategies against hematopoietic malignancies caused by BCR-ABL1 and related leukemogenic proteins.",
            "question": "What kind of enzyme is encoded by the proto-oncogene ABL1?",
            "answers": {
                "answer_start": 332,
                "text": "nonreceptor tyrosine kinase"
            }
        },
        {
            "context": "Bach1-dependent and -independent regulation of heme oxygenase-1 in keratinocytes. Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H(2)O(2) led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H(2)O(2), indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H(2)O(2), Bach1 down-regulation did not attenuate the production of reactive oxygen species by H(2)O(2). In contrast, Bach1 overexpression abolished HO-1 induction by H(2)O(2), which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 308,
                "text": "repressor"
            }
        },
        {
            "context": "Amino acid delta13C analysis of hair proteins and bone collagen using liquid chromatography/isotope ratio mass spectrometry: paleodietary implications from intra-individual comparisons. We report a novel method for the chromatographic separation and measurement of stable carbon isotope ratios (delta(13)C) of individual amino acids in hair proteins and bone collagen using the LC-IsoLink system, which interfaces liquid chromatography (LC) with isotope ratio mass spectrometry (IRMS). This paper provides baseline separation of 15 and 13 of the 18 amino acids in bone collagen and hair proteins, respectively. We also describe an approach to analysing small hair samples for compound-specific analysis of segmental hair sections. The LC/IRMS method is applied in a historical context by the delta(13)C analysis of hair proteins and bone collagen recovered from six individuals from Uummannaq in Greenland. The analysis of hair and bone amino acids from the same individual, compared for the first time in this study, is of importance in palaeodietary reconstruction. If hair proteins can be used as a proxy for bone collagen at the amino acid level, this validates compound-specific isotope studies using hair as a model for palaeodietary reconstruction. Our results suggest that a small offset observed in the bulk delta(13)C values of the hair and bone samples may be attributed to two factors: (i) amino acid compositional differences between hair and bone proteins, and (ii) differential turnover rates of the tissues and the amino acid pools contributing to their synthesis. This application proposes that hair may be a useful complementary or alternative source of compound-specific paleodietary information.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 359,
                "text": "collagen"
            }
        },
        {
            "context": "Periovulatory expression of hydrogen peroxide-induced sulfiredoxin and peroxiredoxin 2 in the rat ovary: gonadotropin regulation and potential modification. Reactive oxygen species are involved in ovulation. The aim of this study was to examine gonadotropin regulation of antioxidant enzyme sulfiredoxin (Srx) and peroxiredoxin 2 (PRDX2) expressions and modification during the ovulatory process in rats. Administration of antioxidants in vivo reduced ovulation rate and cumulus expansion. LH treatment increased H(2)O(2) levels within 15 min, which, in turn, induced Srx gene expression in cultured preovulatory follicles. Treatment of preovulatory follicles with catalase suppressed the stimulatory effect of LH on Akt phosphorylation. LH- or H(2)O(2)-stimulated Srx mRNA levels were suppressed by inhibitors of antioxidant agents and MAPK kinase. An in vivo injection of equine chorionic gonadotropin-human chorionic gonadotropin (hCG) stimulated Srx mRNA within 1 h in granulosa but not thecal cells of preovulatory follicles. Srx protein levels were stimulated from 3 h post-hCG injection. Immunofluorescence analysis revealed that oocytes expressed the Srx protein. Furthermore, hCG treatment increased Srx expression in mural granulosa, theca and cumulus cells, but the Srx protein was not detected in corpora lutea. Gene expression of PRDX2, identified as an Srx-dependent modified enzyme, was stimulated by gonadotropins. In situ hybridization analysis demonstrated that PRDX2 mRNA was detected in oocytes and theca cells as well as granulosa cells of some antral and preovulatory follicles. High levels of PRDX2 mRNA were detected in corpora lutea. Total levels of PRDX2 protein were not changed by gonadotropins. However, levels of hyperoxidized PRDX2 increased within 2-3 h after the hCG injection. Taken together, gonadotropin stimulation of Srx expression and PRDX2 modification in the ovary suggest the existence of an antioxidant system to maintain H(2)O(2) production and elimination during the periovulatory period.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 272,
                "text": "antioxidant"
            }
        },
        {
            "context": "Regulation of NOXO1 activity through reversible interactions with p22 and NOXA1. Reactive oxygen species (ROS) have been known for a long time to play important roles in host defense against microbial infections. In addition, it has become apparent that they also perform regulatory roles in signal transduction and cell proliferation. The source of these chemicals are members of the NOX family of NADPH oxidases that are found in a variety of tissues. NOX1, an NADPH oxidase homologue that is most abundantly expressed in colon epithelial cells, requires the regulatory subunits NOXO1 (NOX organizing protein 1) and NOXA1 (NOX activating protein 1), as well as the flavocytochrome component p22(phox) for maximal activity. Unlike NOX2, the phagocytic NADPH oxidase whose activity is tightly repressed in the resting state, NOX1 produces superoxide constitutively at low levels. These levels can be further increased in a stimulus-dependent manner, yet the molecular details regulating this activity are not fully understood. Here we present the first quantitative characterization of the interactions made between the cytosolic regulators NOXO1 and NOXA1 and membrane-bound p22(phox). Using isothermal titration calorimetry we show that the isolated tandem SH3 domains of NOXO1 bind to p22(phox) with high affinity, most likely adopting a superSH3 domain conformation. In contrast, complex formation is severely inhibited in the presence of the C-terminal tail of NOXO1, suggesting that this region competes for binding to p22(phox) and thereby contributes to the regulation of superoxide production. Furthermore, we provide data indicating that the molecular details of the interaction between NOXO1 and NOXA1 is significantly different from that between the homologous proteins of the phagocytic oxidase, suggesting that there are important functional differences between the two systems. Taken together, this study provides clear evidence that the assembly of the NOX1 oxidase complex can be regulated through reversible protein-protein interactions.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 454,
                "text": "NOX1"
            }
        },
        {
            "context": "Upper limb function is normal in patients with restless legs syndrome (Willis-Ekbom Disease). OBJECTIVE: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. METHODS: RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy controls (n=17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. RESULTS: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. CONCLUSIONS: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. SIGNIFICANCE: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 105,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. BACKGROUND: Mutations in the FBN1 gene are the cause of the Marfan syndrome, an autosomal dominant disorder with skeletal, ocular, and cardiovascular complications. Aneurysms or dissections of the ascending thoracic aorta are the major cardiovascular complications of the disorder. We tested the hypothesis that FBN1 mutations cause thoracic aortic aneurysms or dissections in patients who do not have the Marfan syndrome. METHODS AND RESULTS: The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who did not have the Marfan syndrome. Individual FBN1 exons were amplified with intron-based exon-specific primers; the DNA fragments were screened for mutations using single-stranded conformational polymorphism analysis; and aberrantly migrating bands were sequenced directly. We identified a missense mutation in one patient, D1155N in exon 27. Dermal fibroblasts from the affected individual were used to study the effect of the missense mutation D1155N on fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix. A second putative FBN1 mutation was identified in the second patient, P1837S in exon 44. Although this alteration was not observed in 234 chromosomes from unrelated individuals, the alteration may represent a rare polymorphism. CONCLUSIONS: Results of these studies support the hypothesis that FBN1 mutations cause thoracic aortic aneurysms in patients who do not have the Marfan syndrome. This information is important for understanding the pathogenesis of aortic aneurysms and identification of individuals at risk for developing thoracic aortic aneurysms or dissections.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 102,
                "text": "FBN1"
            }
        },
        {
            "context": "Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. PURPOSE OF REVIEW: Although glucocorticosteroids are considered the first-line treatment in sarcoidosis, refractory cases require alternatives, such as methotrexate (MTX). The aim of this study was to develop, on behalf of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG), multinational evidence-based recommendations for the use of MTX in sarcoidosis for routine clinical practice. RECENT FINDINGS: A systematic literature search was conducted and combined with the opinions of sarcoidosis experts worldwide to formulate the recommendations. An online survey concerning 10 clinical questions was sent through the WASOG newsletter to sarcoidosis experts. Agreement about the recommendations amongst the world's leading sarcoidologists was evaluated. A total of 237 articles were identified, 43 of which were included. Randomized controlled trial evidence supporting the use of MTX in sarcoidosis was limited. Forty-five per cent (113 of 250) of the sarcoidosis experts contacted completed the survey (Europe 55%, North America 26% and Asia 12%). Ten recommendations were formulated concerning the indications for use, starting dose, folic acid, work-up, contraindications, monitoring, administration options in case of adverse gastrointestinal effects, hepatotoxicity, long-term safety and use during pregnancy and breast feeding. SUMMARY: Ten multinational evidence-based recommendations for the use of MTX in sarcoidosis were developed, which are supported by the world's foremost sarcoidosis experts.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 281,
                "text": "corticosteroids"
            }
        },
        {
            "context": "Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). PURPOSE: To investigate refractive, topometric, pachymetric, and visual rehabilitation changes induced by anterior surface normalization for keratoconus by partial topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking. METHODS: Two hundred thirty-one keratoconic cases subjected to the Athens Protocol procedure were studied for visual acuity, keratometry, pachymetry, and anterior surface irregularity indices up to 3 years postoperatively by Scheimpflug imaging (Oculus Optikgeräte GmbH, Wetzlar, Germany). RESULTS: Mean visual acuity changes at 3 years postoperatively were +0.38 ± 0.31 (range: -0.34 to +1.10) for uncorrected distance visual acuity and +0.20 ± 0.21 (range: -0.32 to +0.90) for corrected distance visual acuity. Mean K1 (flat meridian) keratometric values were 46.56 ± 3.83 diopters (D) (range: 39.75 to 58.30 D) preoperatively, 44.44 ± 3.97 D (range: 36.10 to 55.50 D) 1 month postoperatively, and 43.22 ± 3.80 D (range: 36.00 to 53.70 D) up to 3 years postoperatively. The average Index of Surface Variance was 98.48 ± 43.47 (range: 17 to 208) pre-operatively and 76.80 ± 38.41 (range: 7 to 190) up to 3 years postoperatively. The average Index of Height Decentration was 0.091 ± 0.053 μm (range: 0.006 to 0.275 μm) preoperatively and 0.057 ± 0.040 μm (range: 0.001 to 0.208 μm) up to 3 years postoperatively. Mean thinnest corneal thickness was 451.91 ± 40.02 μm (range: 297 to 547 μm) preoperatively, 353.95 ± 53.90 μm (range: 196 to 480 μm) 1 month postoperatively, and 370.52 ± 58.21 μm (range: 218 to 500 μm) up to 3 years postoperatively. CONCLUSIONS: The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. Progressive potential for long-term flattening validates using caution in the surface normalization to avoid overcorrection.",
            "question": "Which eye condition is managed by the athens protocol?",
            "answers": {
                "answer_start": 1905,
                "text": "keratoconus"
            }
        },
        {
            "context": "Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in lung adenocarcinomas that respond to the EGFR inhibitors gefitinib and erlotinib. Two types of mutations account for approximately 90% of mutated cases: short in-frame deletions in exon 19 and a specific point mutation in exon 21 at codon 858 (L858R). Screening for these mutations has been based mainly on direct sequencing. We report here the development and validation of polymerase chain reaction-based assays for these two predominant types of EGFR mutations. The assay for exon 19 mutations is based on length analysis of fluorescently labeled polymerase chain reaction products, and the assay for the exon 21 L858R mutation is based on a new Sau96I restriction site created by this mutation. Using serial dilutions of DNAs from lung cancer cell lines harboring either exon 19 or 21 mutations, we detected these mutations in the presence of up to approximately 90% normal DNA. In a test set of 39 lung cancer samples, direct sequencing detected mutations in 25 cases whereas our assays were positive in 29 cases, including 4 cases in which mutations were not apparent by sequencing. These assays offer higher sensitivity and ease of scoring and eliminate the need for sequencing, providing a robust and accessible approach to the rapid identification of most lung cancer patients likely to respond to EGFR inhibitors.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 179,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 97,
                "text": "2"
            }
        },
        {
            "context": "[Factors associated with achievement and durability of cytogenetic response in patients with chronic myeloid leukemia treated with imatinib]. BACKGROUND/AIM: Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia and become the standard of care for this disease. The aim of this study was evaluation and analysis of cytogenetic response in different intervals and risk groups as well as finding association between pre-treatment characteristics and later probability of achievement of major cytogenetic response. METHODS: We analyzed a total of 22 adult patients with newly diagnosed Philadelphia positive early chronic phase chronic myeloid leukemia treated at our institution from June 2006 to December 2009. RESULTS: The median follow-up time for patients during treatment with imatinib was 25.7 months (range, 12-42 months). A complete hematologic response was achieved in all of the analyzed patients within 6 months from the start of the treatment. The major cytogenetic response rate was 81.8%, and the complete cytogenetic response rate was 72.7%. The patients with low or moderate relative risk had the rate of complementary achieving major and complete cytogenetic response of 75-90%. A multivariate analysis identified the following independent prognostic factors for achieving major cytogenetic response: the absence of splenomegaly, white blood cell count less than 10 x 10(9)/L, the platelet count less than 450 x 10(9)/L, the presence of less than 5% of bone marrow blasts and basophils, the absence of blasts in peripheral blood, the presence of less than 7% of basophils in peripheral blood. CONCLUSION: Patients who early achieve complete and major cytogenetic response as well as those with low and moderate relative risk have a higher rate of achieving and maintaining complete cytogenetic response. There are also characteristics of patients before treatment that may indicate the treatment outcome.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 260,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Transcription domain-associated repair in human cells. Nucleotide excision repair (NER), which is arguably the most versatile DNA repair system, is strongly attenuated in human cells of the monocytic lineage when they differentiate into macrophages. Within active genes, however, both DNA strands continue to be proficiently repaired. The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes. We now report that the previously termed differentiation-associated repair (DAR) depends upon transcription, but not simply upon RNA polymerase II (RNAPII) encountering a lesion: proficient repair of both DNA strands can occur in a part of a gene that the polymerase never reaches, and even if the translocation of RNAPII is blocked with transcription inhibitors. This suggests that DAR may be a subset of global NER, restricted to the subnuclear compartments or chromatin domains within which transcription occurs. Downregulation of selected NER genes with small interfering RNA has confirmed that DAR relies upon the same genes as global genome repair, rather than upon TCR-specific genes. Our findings support the general view that the genomic domains within which transcription is active are more accessible than the bulk of the genome to the recognition and repair of lesions through the global pathway and that TCR is superimposed upon that pathway of NER.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 494,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Glioblastoma multiforme (GBM) is the most common and deadly of the human brain cancers. The EGF receptor is often amplified in GBM and provides a potential therapeutic target. However, targeting the normal receptor is complicated by its nearly ubiquitous and high level of expression in certain tissues. A naturally occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively active variant originally identified in a high percentage of brain cancer cases, and more importantly is rarely found in normal tissue. A peptide vaccine, rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon 1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy in preclinical models. Recent Phase II clinical trials in patients with newly diagnosed GBM have shown EGFRvIII-specific immune responses and significantly increased time to progression and overall survival in those receiving vaccine therapy, as compared with published results for standard of care. Rindopepimut therefore represents a very promising therapy for patients with GBM.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 752,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "p73, the \"assistant\" guardian of the genome? Although p53 is clearly involved in the salvage pathway to DNA damage, its frequent mutations do not explain the efficacy of radiotherapy and chemotherapy. Indeed, around 50% of all human cancers show mutations in p53, and a further fraction show a functional inactivation of the protein. Nevertheless, patients seem to respond to therapy that would otherwise require a functional p53. At least in part, these responses could be explained by the pathway mediated by p73. This mechanism is parallel to, but independent of the p53 pathway. Several pieces of evidence show a significant interaction between these two proteins. Therefore, while p53 can be rightly defined as the guardian of the genome, we could think of p73 as the \"assistant\" guardian of the genome!",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 686,
                "text": "p53"
            }
        },
        {
            "context": "Treatment of Phthiriasis Palpebrarum and Crab Louse: Petrolatum Jelly and 1% Permethrin Shampoo. Phthiriasis palpebrarum is an uncommon cause of blepharoconjunctivitis in which Pthirus pubis infest the eyelashes. We report a case of unilateral phthiriasis palpebrarum with crab louse. A 45-year-old man presented with conjunctival hyperaemia and moderate itching associated with irritation, and crusty excretions of the eyelashes in the left eye. Careful slit-lamp examination revealed many lice and nits in left eye and mild conjunctival hyperaemia. No abnormality was found in the right eye. On dermatologic examination, only one louse was found at the pubic area. The patient was treated effectively with petrolatum jelly (Vaseline) and 1% permethrin shampoo (Kwellada 1% shampoo). At the end of the first week no louse or nit was present on eyelashes and pubic area.",
            "question": "What is the cause of Phthiriasis Palpebrarum?",
            "answers": {
                "answer_start": 177,
                "text": "Pthirus pubis"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1403,
                "text": "xa"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 429,
                "text": "7"
            }
        },
        {
            "context": "Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that resulted in 655,000 deaths and 216 million clinical cases in 2010 alone. Recent phase 3 trials with malaria vaccine candidate RTS,S/AS01 (RTS,S) in children has demonstrated modest efficacy against clinical and severe malaria. RTS,S targets the pre-erythrocytic phase of the disease and induces high antibody titers against the P. falciparum circumsporozoite protein (CSP) and a moderate CD4(+) T cell response. The individual contribution of these adaptive immune responses to protection from infection remains unknown. Here, we found that prophylactic administration of anti-CSP mAbs derived from an RTS,S-vaccinated recipient fully protected mice with humanized livers from i.v.- and mosquito bite - delivered P. falciparum sporozoite challenge. Titers of anti-CSP that conveyed full protection were within the range observed in human RTS,S vaccine recipients. Increasing anti-CSP titers resulted in a dose-dependent reduction of the liver parasite burden. These data indicate that RTS,S-induced antibodies are protective and provide sterilizing immunity against P. falciparum infection when reaching or exceeding a critical plasma concentration.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 428,
                "text": "malaria"
            }
        },
        {
            "context": "Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 908,
                "text": "NGF"
            }
        },
        {
            "context": "The potential for crizotinib in non-small cell lung cancer: a perspective review. Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 430,
                "text": "cancer"
            }
        },
        {
            "context": "[Promising molecules for treatment of hyperglycemia in patients with type 2 diabetes]. New antidiabetic drugs are being developed today that expand the range of pharmacological intervention, in particular for patients with type 2 diabetes (imeglimin, semaglutide, dulaglutide, FGF 21 analogue). At the same time innovations take place that \"better\" the well-proven molecules, they offer new application forms we have no experience of diabetology (osmotic pump for exenatide, faster acting insulin aspart). New properties are brought by just the change of concentration (insulin glargine in a concentration of 300 U/ml), unexpected positive results are also brought by new fixed-ratio combinations of antidiabetics (fixed-ratio combination of insulin degludec and liraglutide, fixed-ratio combination of insulin glargine and lixisenatide). Also results of clinical studies appear that concern molecules already in use which facilitate the formulation of new recommendations regarding treatment type 2 diabetes.Key words: type 2 diabetes mellitus - dulaglutide - FGF 21 - imeglimin - insulin aspart - insulin degludek - insulin glargine - ITCA 650 - liraglutide - national information diabetes system - semaglutide.",
            "question": "Which disease is treated with semaglutide?",
            "answers": {
                "answer_start": 223,
                "text": "type 2 diabetes"
            }
        },
        {
            "context": "EFFECT OF THE APOE ε4 ALLELE AND COMBAT EXPOSURE ON PTSD AMONG IRAQ/AFGHANISTAN-ERA VETERANS. BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans. METHOD: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report. RESULTS: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5). CONCLUSIONS: Although preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 994,
                "text": "PTSD"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 784,
                "text": "thyroid"
            }
        },
        {
            "context": "Detection of Turner syndrome using high-throughput quantitative genotyping. CONTEXT: Turner syndrome (TS) is the most common genetic problem affecting women and occurs when an X chromosome is completely deleted, portions of an X chromosome are deleted, or chromosomal mosaicism occurs. Girls with TS may also have occult Y chromosome sequences. Whereas some girls with TS are identified in infancy or early childhood, many girls with TS are not detected until after 10 yr of age, resulting in delayed evaluation and treatment. OBJECTIVE: To prevent the delayed recognition and treatment of TS, a quantitative method of genotyping that can be performed as part of newborn screening is needed. DESIGN: To screen for sex chromosome abnormalities, we assembled a panel of informative single nucleotide polymorphism (SNP) markers that span the X chromosome from the dbSNP database. Pyrosequencing assays suitable for quantitative assessment of signal strength from single nucleotides were designed and used to genotype 46,XX; 46,XY; 45,X; and TS mosaics, examining zygosity and signal strength for individual alleles. Pyrosequencing assays were also designed for the detection of Y chromosome material. RESULTS: With just four informative SNP markers for the X chromosome, all TS girls with 45,X, partial X chromosome deletions, or mosaicism were identified with 100% sensitivity. In mosaic individuals, Y chromosomal material was detected with 100% sensitivity. CONCLUSION: These results suggest that inexpensive high-throughput screening is possible for TS and other sex chromosome disorders using quantitative genotyping approaches.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 227,
                "text": "X"
            }
        },
        {
            "context": "How to use … the Monospot and other heterophile antibody tests. Epstein-Barr virus (EBV) is a highly prevalent virus, transmitted via saliva, which often causes asymptomatic infection in children but frequently results in infectious mononucleosis in adolescents. Heterophile antibody tests, including the Monospot test, are red cell or latex agglutination assays, which detect antired cell antibodies produced as part of a polyclonal antibody response occurring during EBV infection. Heterophile antibody tests are rapid, cheap and specific tests that can be performed from the onset of symptoms of infectious mononucleosis. In adolescents, heterophile antibody tests have high specificity and sensitivity in the diagnosis of primary acute EBV infection. However, the tests have low sensitivity and low negative predictive value in young children and are not useful under the age of 4. Heterophile tests may be positive in other viral infections, autoimmune disease and haematological malignancies, but do not appear to be positive in primary bacterial infection. Virus-specific serology is required in children under the age of 4 or if an older child is heterophile negative. Virus-specific serology allows diagnosis and the pattern of positivity and negativity enables the clinician to stage the EBV infection. Virus-specific serology appears to have better sensitivity in young children, but there is cross-reaction with other herpesvirus infections, a longer turnaround time and it is more expensive to perform. Further research is needed to establish which children benefit from and hence require testing for heterophile antibodies, the cost-effectiveness of EBV investigations and whether heterophile titres have predictive value for the severity of infection and the likelihood of complications.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 64,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "An outbreak of Clostridium difficile PCR ribotype 027 in Spain: risk factors for recurrence and a novel treatment strategy. An outbreak of Clostridium difficile infection (CDI) caused by ribotype 027 (B1/NAP1) began in our hospital in November 2014, and produced 141 episodes in the following months. The aim of this study is to describe this outbreak, assess risk factors for recurrence of CDI-027 and to analyze the implementation of a novel treatment strategy. This is a prospective study of all patients with CDI-027, from November 2014 to November 2015. The epidemiological data were collected daily for each patient. We compared clinical characteristics and treatment between patients with and without recurrence of CDI-027. Interestingly, liver cirrhosis was present in 22% of the patients, and most of them received prophylaxis for hepatic encephalopathy with rifaximin. Patients were also taking antimicrobial drugs (93.6%) and proton pump inhibitors (80.1%). Overall, 27 (23.5%) patients had a first recurrence of CDI-027. Liver cirrhosis increased the risk of recurrence (44.4% vs 14.8%). Patients treated with a prolonged oral vancomycin regimen vs the conventional regimen (oral metronidazole or 10 days of vancomycin) had fewer recurrences (8.6 versus 44.7% [p  <  0.01]; OR, 0.91; 95% CI, 0.028-0.294) and less attributable mortality (0% versus 7.1%; p = 0.058). We report an outbreak of CDI-027, mainly in patients with liver cirrhosis. Recurrence of CDI-027 was more common in those patients. A novel approach involving high-dose prolonged vancomycin taper as a first-line treatment, together with a bundle of outbreak measures, seemed to reduce the number of cases of CDI-027, recurrences, and attributable mortality. Nevertheless, this approach warrants further investigation.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 41,
                "text": "ribotype 027"
            }
        },
        {
            "context": "Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as \"rufous/red albinism,\" is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed \"OCA4.\" The encoded protein, MATP (for \"membrane-associated transporter protein\") is predicted to span the membrane 12 times and likely functions as a transporter.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 605,
                "text": "TYR"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 366,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "New anticoagulants: focus on venous thromboembolism. Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 921,
                "text": "xa"
            }
        },
        {
            "context": "EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 674,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype. Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 27,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Connexin43, the major gap junction protein of astrocytes, is down-regulated in inflamed white matter in an animal model of multiple sclerosis. Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter, leading to demyelination and axonal damage. Changes in astrocytic morphology and function are also prominent features of MS and EAE. Resting astrocytes form a network that is interconnected through gap junctions, composed mainly of connexin43 (Cx43) protein. Although astrocytic gap junctional connectivity is known to be altered in many CNS pathologies, little is known about Cx43 expression in inflammatory demyelinating disease. Therefore, we evaluated the expression of Cx43 in spinal cords of EAE mice compared with healthy controls. Lumbar ventral white matter areas were heavily infiltrated with CD11beta-immunoreactive monocytes, and within these infiltrated regions loss of Cx43 immunoreactivity was evident. These regions also showed axonal dystrophy, demonstrated by the abnormally dephosphorylated heavy-chain neurofilament proteins. Astrocytes in these Cx43-depleted lesions were strongly glial fibrillary acidic protein reactive. Significant loss (38%) of Cx43 protein in EAE mouse at the lumbar portion of spinal cords was confirmed by Western blot analysis. Decreased Cx43 transcript level was also observed on cDNA microarray analysis. In addition to changes in Cx43 expression, numerous other genes were altered, including those encoding adhesion and extracellular matrix proteins. Our data support the notion that, in addition to damage of myelinating glia, altered astrocyte connectivity is a prominent feature of inflammatory demyelination.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 176,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene. Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 754,
                "text": "7"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 601,
                "text": "Hsp90"
            }
        },
        {
            "context": "Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1β-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 279,
                "text": "IL-1β"
            }
        },
        {
            "context": "Inhibition by SEA0400, a selective inhibitor of Na+/Ca2+ exchanger, of Na+ -dependent Ca2+ uptake and catecholamine release in bovine adrenal chromaffin cells. The effects of SEA0400, a selective inhibitor of the Na(+)/Ca(2+) exchanger (NCX), on Na(+)-dependent Ca(2+) uptake and catecholamine (CA) release were examined in bovine adrenal chromaffin cells that were loaded with Na(+) by treatment with ouabain and veratridine. SEA0400 inhibited Na(+)-dependent (45)Ca(2+) uptake and CA release, with the IC(50) values of 40 and 100 nM, respectively. The IC(50) values of another NCX inhibitor KB-R7943 were 1.8 and 3.7 microM, respectively. These results indicate that SEA0400 is about 40 times more potent than KB-R7943 in inhibiting NCX working in the reverse mode. In intact cells, SEA0400 and KB-R7943 inhibited CA release induced by acetylcholine and DMPP. The IC(50) values of SEA0400 were 5.1 and 4.5 microM and the values of KB-R7943 were 2.6 and 2.1 microM against the release induced by acetylcholine and DMPP, respectively, indicating that the potency of SEA0400 is about a half of that of KB-R7943 in inhibiting the nicotinic receptor-mediated CA release. The binding of [(3)H]nicotine with nicotinic receptors was inhibited by SEA0400 (IC(50) = 90 microM) and KB-R7943 (IC(50) = 12 microM). From these results, it is concluded that unlike KB-R7943, SEA0400 has a potent and selective action on NCX in bovine adrenal chromaffin cells.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 237,
                "text": "NCX"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 587,
                "text": "stroke"
            }
        },
        {
            "context": "Single-pill combination therapy for type 2 diabetes mellitus: linagliptin plus empagliflozin. BACKGROUND: Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. SCOPE: Publications with titles containing the keywords 'linagliptin' or 'empagliflozin' were identified from a non-systematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012-2014. ClinicalTrials.gov was searched for entries containing these two keywords. Additional references known to the author were included. FINDINGS: The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. CONCLUSIONS: The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 36,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "An overview of current and emerging SERMs. Selective estrogen receptor modulators (SERMs) are compounds that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity, and are used for various indications, including treatment of breast cancer, osteoporosis, and menopausal symptoms. Endometrial safety has been a key differentiator between SERMs in clinical practice. For example, tamoxifen exhibits ER agonist activity in the uterus, resulting in an increased risk of endometrial hyperplasia and malignancy, whereas raloxifene and bazedoxifene have neutral effects on the uterus. Based on their efficacy and long-term safety, SERMs are increasingly being prescribed for women who cannot tolerate other treatment options and for younger women at an increased risk of fracture who may remain on therapy for long periods of time. Continuing advances in the understanding of SERM mechanisms of action and structural interactions with the ER may lead to the development of new agents and combinations of agents to provide optimal treatments to meet the varying needs of postmenopausal women. One such example is the tissue selective estrogen complex, which partners a SERM with 1 or more estrogens, with the aim of blending the desired estrogen-receptor agonist activities of estrogens on vasomotor symptoms, vulvar-vaginal atrophy, and loss of bone mass with the tissue selectivity of a SERM.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 43,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "The rise of methicillin-resistant staphylococcus aureus in U.S. correctional populations. Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging threat to public health, especially in correctional settings. Outbreaks have been seen in jails and prisons in Mississippi, California, Texas, and Georgia in recent years. Also, many correctional settings have seen an increase in MRSA infection greater than in the general population. This article examines the lessons that have been learned about MRSA in correctional settings and ponders what is yet to be learned about this disease in these populations.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 135,
                "text": "MRSA"
            }
        },
        {
            "context": "Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurofibromatosis type 1 (NF1) is a common genetic disease caused by haploinsufficiency of the NF1 tumor-suppressor gene. Different pathogenetic mechanisms have been identified, with the majority (95%) causing intragenic lesions. Single or multiexon NF1 copy number changes occur in about 2% of patients, but little is known about the molecular mechanisms behind these intragenic deletions. We report here on the molecular characterization of a novel NF1 multiexonic deletion. The application of a multidisciplinary approach including multiplex ligation-dependent probe amplification, allelic segregation analysis, and fluorescent in situ hybridization allowed us to map the breakpoints in IVS27b and IVS48. Furthermore, the breakpoint junction was characterized by sequencing. Using bioinformatic analysis, we identified some recombinogenic motifs in close proximity to the centromeric and telomeric breakpoints and predicted the presence of a mutated messenger ribonucleic acid, which was deleted between exons 28 and 48 and encodes a neurofibromin that lacks some domains essential for its function. Through reverse transcriptase-polymerase chain reaction, the expression of the mutated allele was verified, showing the junction between exons 27b and 49 and, as expected, was not subjected to nonsense-mediated decay. Multiexonic deletions represent 2% of NF1 mutations, and until now, the breakpoint has been identified in only a few cases. The fine characterization of multiexonic deletions broadens the mutational repertoire of the NF1 gene, allowing for the identification of different pathogenetic mechanisms causing NF1.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 140,
                "text": "NF1"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 398,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Diagnosis of pneumoperitoneum on supine abdominal radiographs. A blinded, retrospective study was performed to determine the value of supine abdominal radiographs in diagnosing pneumoperitoneum. Supine films from 44 cases of pneumoperitoneum were randomly interspersed among supine films from 87 control subjects without free air, and the films were reviewed for the presence or absence of various signs of pneumoperitoneum, including Rigler's sign (gas on both sides of the bowel wall), the falciform ligament sign (gas outlining the falciform ligament), the football sign (gas outlining the peritoneal cavity), the inverted-V sign (gas outlining the medial umbilical folds), and the right-upper-quadrant gas sign (localized gas in the right upper quadrant). One or more of these signs were present in 26 cases (59%) of pneumoperitoneum, including the right-upper-quadrant gas sign in 18 cases (41%), Rigler's sign in 14 cases (32%), and the falciform ligament and football signs in one case each (2%). Unfortunately, there were frequent errors in the interpretation of the right-upper-quadrant gas sign and Rigler's sign, with a total of 11 false-positive cases (13%). Further analysis of the true-positive right-upper-quadrant gas signs showed that these gas collections were always triangular or linear with an inferolateral to superomedial orientation and, if triangular, a concave superolateral border. In the true-positive Rigler's signs, the bowel wall thickness ranged from 1 to 8 mm, whereas the false positives all had a bowel wall thickness of 1 mm or less. Proper interpretation of the various signs of pneumoperitoneum on supine films should lead to more accurate diagnosis of this condition.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 407,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia. Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 189,
                "text": "neural crest cells"
            }
        },
        {
            "context": "The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. BACKGROUND: The mammalian target of rapamycin (mTOR) has been suggested as a target for radiosensitization. Given that radiotherapy is a primary treatment modality for glioblastoma (GBM) and that mTOR is often dysregulated in GBM, the goal of this study was to determine the effects of AZD2014, a dual mTORC1/2 inhibitor, on the radiosensitivity of GBM stem-like cells (GSCs). METHODS: mTORC1 and mTORC2 activities were defined by immunoblot analysis. The effects of this mTOR inhibitor on the in vitro radiosensitivity of GSCs were determined using a clonogenic assay. DNA double strand breaks were evaluated according to γH2AX foci. Orthotopic xenografts initiated from GSCs were used to define the in vivo response to AZD2014 and radiation. RESULTS: Exposure of GSCs to AZD2014 resulted in the inhibition of mTORC1 and 2 activities. Based on clonogenic survival analysis, addition of AZD2014 to culture media 1 hour before irradiation enhanced the radiosensitivity of CD133+ and CD15+ GSC cell lines. Whereas AZD2014 treatment had no effect on the initial level of γH2AX foci, the dispersal of radiation-induced γH2AX foci was significantly delayed. Finally, the combination of AZD2014 and radiation delivered to mice bearing GSC-initiated orthotopic xenografts significantly prolonged survival as compared with the individual treatments. CONCLUSIONS: These data indicate that AZD2014 enhances the radiosensitivity of GSCs both in vitro and under orthotopic in vivo conditions and suggest that this effect involves an inhibition of DNA repair. Moreover, these results suggest that this dual mTORC1/2 inhibitor may be a radiosensitizer applicable to GBM therapy.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 115,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "Evaluation of Xist expression in preattachment equine embryos. Until now, sex determination in equine embryos has been performed by detection of Y-chromosome-specific sequences only. In the present study, expression of a Barr-body-specific marker, the X-inactivated-specific transcript (Xist) gene, whose gene product consists of RNA which coats and thereby inactivates one of the X chromosomes, was investigated in equine embryos produced in vivo. Preattachment embryos at different times after ovulation (Day 8: n = 9; Day 10: n = 12; Day 12: n = 15) were analyzed for Xist RNA expression using quantitative and qualitative reverse transcription-polymerase chain reaction (RT-PCR). Female and male primary equine dermal cell cultures were used as positive and negative controls, respectively. Embryos tested negative for Xist were evaluated for expression of the male-specific eSRY gene by qualitative PCR at the DNA level. From 36 embryos assessed by qualitative RT-PCR, 18 showed positive Xist expression (50%). From 29 embryos tested by quantitative RT-PCR, 16 showed positive Xist expression (55%). All of the Xist-negative equine embryos tested by quantitative PCR were positive for eSRY. We also demonstrated by strand-specific RT-PCR that in the horse, as in humans, the counter transcript Tsix seems to be truncated not reaching Exon 1. In contrast to many other species, neither Xist nor Tsix was expressed in equine male testicular tissue. The results demonstrate that expression of Xist is restricted to female equine embryos. Xist can thus be considered an X-inactivation-specific marker which can be used in concert with Y-specific markers for sex determination.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 287,
                "text": "Xist"
            }
        },
        {
            "context": "Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BACKGROUND: X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. RESULTS: We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. CONCLUSIONS: Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 267,
                "text": "X"
            }
        },
        {
            "context": "Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor. Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 90,
                "text": "PD-L1"
            }
        },
        {
            "context": "Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene and the spectrum of mutations among Greek-Cypriots with FMF-related symptoms was examined. Sequence analysis for exons 2, 3, 5, and 10 of the MEFV gene was performed in a cohort of 593 patients. A total of 70 patients carried mutations in the homozygote or compound heterozygote state, 128 were identified with one MEFV mutation and 395 had no mutations. Of the 268 identified alleles, p.Val726Ala (27.61%) was the most frequent followed by p.Met694Val (19.40%). The missense mutations p.Arg761His (3.73%) and p.Ala744Ser (2.24%) were identified as the rarest. An interesting finding is the high frequency (18.28%) of the complex p.Phe479Leu-p.Glu167Asp that was identified in 49 of the mutated alleles. The MEFV genotypes did not follow a binomial distribution and proved not to satisfy the HWE (P < 0.001). The high percentage (66.61%) of patients with unidentified mutations could be due to mutations in the rest of the coding or noncoding MEFV gene or due to mutations in other genes that are also causing Hereditary Recurrent Fevers. Results from this work indicate the high incidence of FMF in Cyprus and describe the spectrum of the mutations which occur in the country.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 164,
                "text": "MEFV gene"
            }
        },
        {
            "context": "A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke. INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence. METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance. RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2). CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 251,
                "text": "Acute ischemic stroke"
            }
        },
        {
            "context": "Selective estrogen receptor modulators (SERMs): a review of clinical data. SERMs represent a diverse group of molecules with varying levels of estrogenic agonist and antagonist activity in target tissues. SERMs have a long regulatory approval history and have been studied for a variety of therapeutic indications. The clinical effects of SERMs have been evaluated in a large number of phase 3 clinical trials. Many of the available SERMs have proved to be effective as chemo-preventive agents and treatments for breast cancer and a number are useful for the prevention and treatment of osteoporosis. The endometrial effect of SERMs has been a key differentiator in clinical practice and a major hurdle for regulatory approval. The effect of SERMs in the vagina also represents a major distinction among different SERMs. This review summarized key clinical finding of SERMs in different target tissues.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 0,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Different intracellular compartmentalization of TA and DeltaNp73 in non-small cell lung cancer. The p53 homologue p73 is overexpressed in many tumors, including lung cancer. We have evaluated the differential expression and subcellular localization of the functionally distinct apoptotic (TA) and anti-apoptotic (DeltaN) isoforms of p73 in non-small cell lung cancer (NSCLC), their possible association with p53 expression and determined the methylation status of the two p73 gene promoters (P1 and P2) in this tumor type. Immunohistochemical analysis showed that both isoforms are expressed in the majority of cases. However, the oncogenic DeltaN variant, derived from the transcripts DeltaN'p73 (from P1) and/or DeltaNp73 (from P2), is localized mainly in the nucleus, while the anti-oncogenic TAp73 isoform (derived from a P1 transcript) is sequestered in the cytoplasm in almost all cases analyzed. Significant correlation was found between p53 and DeltaNp73 expression (p=0.041). Methylation analysis conducted on 41 tumor samples showed that the P1 promoter is almost invariably unmethylated (39/41 cases) whereas P2 was found completely methylated in 17 cases and partially or totally unmethylated in 24 samples. No correlation was found between the methylation status of P1 and P2 and p73 expression. Our results demonstrate that both isoforms contribute to p73 overexpression in NSCLC and suggest that their different intracellular localization may reflect an alteration of the functional p53-p73 network that might contribute to lung cancer development.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 473,
                "text": "7"
            }
        },
        {
            "context": "[SERM]. SERM is the abbreviation of the selective estrogen receptor modulator which is the synthetic ligands of estrogen receptor (ER) acting estrogenically or anti-estrogenically among various tissues through modifying the ER function. Clomifene, tamoxifen, toremifene and raloxifene are generally classified as SERM in the clinical use. The main cause of postmenopausal osteoporosis is estrogen deficiency and it was revealed that the continuous combined use of conjugated estrogen and medroxyprogesterone acetate reduced the relative risk of femoral neck fracture to 0.66, however increased the relative risk of cardiovascular event and breast cancer to 1.29 or 1.26, respectively. From the standpoint of safe and clinical compliance for the breast and uterine tissue, raloxifene is recommendable for middle aged postmenopausal osteoporosis.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 40,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Synergistic effect of kaempferol glycosides purified from Laurus nobilis and fluoroquinolones on methicillin-resistant Staphylococcus aureus. In a previous study, we reported that two kaempferol glycosides isolated from Laurus nobilis L., kaempferol-3-O-alpha-L-(2'',4''-di-E-p-coumaroyl)-rhamnoside (C2) and kaempferol-3-O-alpha-L-(2''-E-p-coumaroyl-4''-Z-p-coumaroyl)-rhamnoside (C3), showed strong antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Thereafter we found that these compounds greatly reduced the minimum inhibitory concentrations (MICs) of some fluoroquinolones in MRSA. In other words, C2 and C3 greatly potentiated anti-MRSA activity of fluoroquinolones. The effect of C2 and C3 with fluoroquinolones was found to be synergistic. The potentiation activity was observed with hydrophilic fluoroquinolones, such as norfloxacin and ciprofloxacin, but not with hydrophobic quinolones. We also found that norfloxacin reduced MICs of C2 and C3. The effect was synergistic. Possible mechanism of the synergistic effect was discussed.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 479,
                "text": "MRSA"
            }
        },
        {
            "context": "Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 426,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Systematic review: hand activity and ultrasound of the median nerve. Background: Ultrasound is an established method of viewing the median nerve in the carpal tunnel syndrome (CTS). There is some evidence to suggest that immediate changes may occur in the median nerve before and after hand activity. The evidence for the validity and reliability of ultrasound for testing acute changes in the median nerve has not been systematically reviewed to date. Aims: To evaluate the evidence for visible change in ultrasound appearance of the median nerve after hand activity. Methods: A literature search was designed, and three reviewers independently selected published research for inclusion. Two reviewers independently appraised papers using the Evidence Based Library and Information Practice (EBLIP) appraisal checklist, while the third reviewer resolved discrepancies between appraisals. Results: Ten studies were appraised and the results showed an increase in median nerve cross-sectional area following activity, with a return to normal size within 1 h following activity. Both healthy individuals and those diagnosed with CTS participated, all were small convenience samples. Ultrasonographic measurements of the median nerve were reliable in the four studies reporting this, and the studies demonstrated high quality. Conclusions: Good-quality evidence as identified by the EBLIP appraisal checklist suggests that following hand activity, the median nerve changes in size in the carpal tunnel. The results may not be generalizable to all people and activities due to the use of small convenience sampling and narrow range of activities studied, in all of the studies appraised.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 132,
                "text": "median"
            }
        },
        {
            "context": "Evaluation of the safety and immunogenicity of the RTS,S/AS01E malaria candidate vaccine when integrated in the expanded program of immunization. BACKGROUND: The RTS,S/AS01(E) malaria candidate vaccine is being developed for immunization of African infants through the Expanded Program of Immunization (EPI). METHODS: This phase 2, randomized, open, controlled trial conducted in Ghana, Tanzania, and Gabon evaluated the safety and immunogenicity of RTS,S/AS01(E) when coadministered with EPI vaccines. Five hundred eleven infants were randomized to receive RTS,S/AS01(E) at 0, 1, and 2 months (in 3 doses with diphtheria, tetanus, and whole-cell pertussis conjugate [DTPw]; hepatitis B [HepB]; Haemophilus influenzae type b [Hib]; and oral polio vaccine [OPV]), RTS,S/AS01(E) at 0, 1, and 7 months (2 doses with DTPwHepB/Hib+OPV and 1 dose with measles and yellow fever), or EPI vaccines only. RESULTS: The occurrences of serious adverse events were balanced across groups; none were vaccine-related. One child from the control group died. Mild to moderate fever and diaper dermatitis occurred more frequently in the RTS,S/AS01(E) coadministration groups. RTS,S/AS01(E) generated high anti-circumsporozoite protein and anti-hepatitis B surface antigen antibody levels. Regarding EPI vaccine responses upon coadministration when considering both immunization schedules, despite a tendency toward lower geometric mean titers to some EPI antigens, predefined noninferiority criteria were met for all EPI antigens except for polio 3 when EPI vaccines were given with RTS,S/AS01(E) at 0, 1, and 2 months. However, when antibody levels at screening were taken into account, the rates of response to polio 3 antigens were comparable between groups. CONCLUSION: RTS,S/AS01(E) integrated in the EPI showed a favorable safety and immunogenicity evaluation. Trial registration. ClinicalTrials.gov identifier: NCT00436007 . GlaxoSmithKline study ID number: 106369 (Malaria-050).",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 176,
                "text": "malaria"
            }
        },
        {
            "context": "CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation. Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1S616 phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1S616 preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1's fission-promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1S616 in post-mitotic neurons.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 501,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat-Wilson syndrome. Mowat-Wilson syndrome is a recently delineated autosomal dominant developmental anomaly, whereby heterozygous mutations in the ZFHX1B gene cause mental retardation, delayed motor development, epilepsy and a wide spectrum of clinically heterogeneous features, suggestive of neurocristopathies at the cephalic, cardiac and vagal levels. However, our understanding of the etiology of this condition at the cellular level remains vague. This study presents the Zfhx1b protein expression domain in mouse embryos and correlates this with a novel mouse model involving a conditional mutation in the Zfhx1b gene in neural crest precursor cells. These mutant mice display craniofacial and gastrointestinal malformations that show resemblance to those found in human patients with Mowat-Wilson syndrome. In addition to these clinically recognized alterations, we document developmental defects in the heart, melanoblasts and sympathetic and parasympathetic anlagen. The latter observations in our mouse model for Mowat-Wilson suggest a hitherto unknown role for Zfhx1b in the development of these particular neural crest derivatives, which is a set of observations that should be acknowledged in the clinical management of this genetic disorder.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 258,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. BACKGROUND: PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome. Based on previous reports, patients with PLA2G6 mutations could show axonal dystrophy, dystonia, dementia, and cerebellar signs. Recently, PLA2G6 was also reported as the causative gene for early-onset PARK14-linked dystonia-parkinsonism. METHODS: To clarify the role of PLA2G6 mutation in parkinsonism, we conducted mutation analysis in 29 selected patients with very early-onset ( < 30, mean 21.2 ± 8.4 years, ± SD) parkinsonism. These patients had other clinical features (e.g., mental retardation/dementia [14/29], psychosis [15/29], dystonia [11/29], and hyperreflexia [11/29]). RESULTS: Two novel compound heterozygous PLA2G6 mutations were detected (patient A: p.F72L/p.R635Q; patients B1 and B2: p.Q452X/p.R635Q). All 3 patients had early-onset l-dopa-responsive parkinsonism with dementia and frontotemporal lobar atrophy. Disease progression was relatively rapid. SPECT in patient B1 showed frontotemporal lobar hypoperfusion. MRI in patient A showed iron accumulation in the substantia nigra and striatum. CONCLUSIONS: Although the clinical presentation of PLA2G6-associated neurodegeneration was reported to be homogeneous, our findings suggest patients with PLA2G6 mutation could show heterogeneous phenotype such as dystonia-parkinsonism, dementia, frontotemporal atrophy/hypoperfusion, with or without brain iron accumulation. Based on the clinical heterogeneity, the functional roles of PLA2G6 and the roles of PLA2G6 variants including single heterozygous mutations should be further elucidated in patients with atypical parkinsonism, dementia, or Parkinson disease. PLA2G6 mutations should be considered in patients with early-onset l-dopa-responsive parkinsonism and dementia with frontotemporal lobar atrophy.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 97,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Crohn's disease: influence of age at diagnosis on site and clinical type of disease. BACKGROUND & AIMS: Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals. The aim of this study was to examine the influences of age at diagnosis of Crohn's disease on disease site, type, and course. METHODS: Records of 552 consecutive patients with Crohn's disease were reviewed retrospectively. RESULTS: Younger age at diagnosis (younger than 20 years), compared with an older age (40 years or older), was associated with a greater prevalence of a family history of Crohn's disease (29.9% vs. 13.6%), greater small bowel involvement (88.7% vs. 57.5%), more stricturing disease (45.8% vs. 28.8%), and a higher frequency of surgery (70.6% vs. 55.3%). Older age at diagnosis was associated with a greater prevalence of colonic disease (84.8% vs. 71.2%) and the inflammatory subtype (54.5% vs. 34.4%). A conditional logistic regression analysis confirmed an independent effect of age at diagnosis on ileal disease and surgery for intractable disease. CONCLUSIONS: In Crohn's disease, early age at diagnosis is associated with more complicated disease and a greater likelihood of having affected relatives. Stratification of Crohn's disease by age at diagnosis provides support for the concept of genetic heterogeneity.",
            "question": "What is the most likely age of diagnosis of Crohn's disease (CD)?",
            "answers": {
                "answer_start": 104,
                "text": "Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals."
            }
        },
        {
            "context": "Adenocarcinoma of the jejunum in association with celiac sprue. An increased incidence of small bowel lymphoma in patients with long-standing celiac sprue is well documented in the literature. Less common is the association of adenocarcinoma of the small intestine. We report a patient with celiac sprue who initially responded to a gluten-free diet. Eighteen months later, diarrhea, abdominal cramps, and bloating was found to have its origin in partial small bowel obstruction. At laparotomy, two distinct adenocarcinomas of the jejunum were resected. Celiac patients who initially respond to gluten withdrawal and subsequently suffer exacerbation while adhering to strict dietary therapy should be carefully evaluated for evidence of a small bowel malignancy.",
            "question": "What disease is small bowel lymphoma commonly associated with",
            "answers": {
                "answer_start": 142,
                "text": "celiac spru"
            }
        },
        {
            "context": "Gas vesicle assembly in Microcyclus aquaticus. When observed in the electron microscope intact gas vesicles appeared as transparent areas in whole cells of Microcylus aquaticus, whereas vesicles collapsed by centrifugation were not discernible. Within 5 min of suspending cells containing collapsed vesicles in growth medium, small transparent vesicles were detected. By 15 min the average number of vesicles per cell was 15. This number remained relatively constant while the size of the vesicles increased until they attained their maximum diamtere of 100 nm. At this time the vesicles, interpreted as biconical structures, began to elongate presumably due to the synthesis of the cylindrical midsection. Closely correlated with the time at which vesicles began to elongate was the initiation of smaller vesicles which resulted in a doubling of the number of vesicles per cell by 90 min. This evidence coupled with the isolation of a mutant which assembles only the conical portions of the vesicle suggests that assembly occurs in two distinct stages subject to genetic mutation. Protein and ribonucleic acid synthesis, and presumably adenosine triphosphate formation, were required for gas vesicle assembly. In addition, inhibition of protein or ribonucleic acid synthesis resulted in a loss of extant gas vesicles. Over the time course of our study, deoxyribonucleic acid synthesis was not required for gas vesicle assembly or stability.",
            "question": "What is the approximate size of gas vesicles?",
            "answers": {
                "answer_start": 554,
                "text": "100 nm"
            }
        },
        {
            "context": "A structural mechanism for calcium transporter headpiece closure. To characterize the conformational dynamics of sarcoplasmic reticulum (SR) calcium pump (SERCA) we performed molecular dynamics simulations beginning with several different high-resolution structures. We quantified differences in structural disorder and dynamics for an open conformation of SERCA versus closed structures and observed that dynamic motions of SERCA cytoplasmic domains decreased with decreasing domain-domain separation distance. The results are useful for interpretation of recent intramolecular Förster resonance energy transfer (FRET) distance measurements obtained for SERCA fused to fluorescent protein tags. Those previous physical measurements revealed several discrete structural substates and suggested open conformations of SERCA are more dynamic than compact conformations. The present simulations support this hypothesis and provide additional details of SERCA molecular mechanisms. Specifically, all-atoms simulations revealed large-scale translational and rotational motions of the SERCA N-domain relative to the A- and P-domains during the transition from an open to a closed headpiece conformation over the course of a 400 ns trajectory. The open-to-closed structural transition was accompanied by a disorder-to-order transition mediated by an initial interaction of an N-domain loop (Nβ5-β6, residues 426-436) with residues 133-139 of the A-domain. Mutation of three negatively charged N-domain loop residues abolished the disorder-to-order transition and prevented the initial domain-domain interaction and subsequent closure of the cytoplasmic headpiece. Coarse-grained molecular dynamics simulations were in harmony with all-atoms simulations and physical measurements and revealed a close communication between fluorescent protein tags and the domain to which they were fused. The data indicate that previous intramolecular FRET distance measurements report SERCA structure changes with high fidelity and suggest a structural mechanism that facilitates the closure of the SERCA cytoplasmic headpiece.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 155,
                "text": "SERCA"
            }
        },
        {
            "context": "Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate. Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreER and GFP from ten different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium, including sources for specific subtypes of amygdala neurons. We then focused on deciphering transcriptional mechanisms that control enhancer activity. Using machine-learning computations, in vivo chromosomal occupancy of 13 transcription factors that regulate subpallial patterning and differentiation and analysis of enhancer activity in Dlx1/2 and Lhx6 mutants, we elucidated novel molecular mechanisms that regulate region-specific enhancer activity in the developing brain. Thus, these subpallial enhancer transgenic lines are data and tool resources to study transcriptional regulation of GABAergic cell fate.",
            "question": "Which resource has been developed in order to study the transcriptional regulation of GABAergic cell fate?",
            "answers": {
                "answer_start": 1027,
                "text": "subpallial enhancer transgenic lines"
            }
        },
        {
            "context": "NOXO1 phosphorylation on serine 154 is critical for optimal NADPH oxidase 1 assembly and activation. Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 162,
                "text": "NOX1"
            }
        },
        {
            "context": "Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China. PURPOSE: To assess whether vancomycin minimum inhibitory concentration (MIC) creeps among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in a regional hospital in China. Furthermore, to analyze the causes of vancomycin MIC creeps and the relationship between vancomycin MICs and the outcome among patients with MRSA infection. MATERIALS AND METHODS: All clinical isolates of MRSA from 2006-2010 were retrieved and tested by the broth microdilution procedure to determine their vancomycin MIC. Meanwhile, related patient records were analyzed. RESULTS: While all isolates were susceptive to vancomycin, the percentage of isolates with a vancomycin MIC = 1 mg/L increased significantly from 2006 (37.0%) to 2010 (75.7%). Meanwhile, vancomycin usage density (DDDs/1000 bed-days) had increased significantly from 2006-2010. Mean linear correlation analysis showed a statistically significant positive correlation (r = 0.905, P < 0.05) between the consumption of vancomycin and the percentage of MRSA isolates with a vancomycin MIC = 1 mg/L. Clinical records revealed high vancomycin MIC was associated with a higher microbiologic failure rate in MRSA bloodstream infections. CONCLUSIONS: The data demonstrated vancomycin MIC creep among clinical isolates in our hospital, and the MIC creep may be caused by the increasing usage of vancomycin. Furthermore, the analysis strongly suggested this shift of vancomycin MIC within the susceptible range may be associated with an increasing probability of treatment failure.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 69,
                "text": "MRSA"
            }
        },
        {
            "context": "Arabidopsis homologs of components of the SWR1 complex regulate flowering and plant development. The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes. We compared the phenotype of mutants in the homologs of SWR1C components in Arabidopsis thaliana. Mutations in Arabidopsis SWC6 (AtSWC6), SUPPRESSOR OF FRIGIDA 3 (SUF3) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1), homologs of SWC6, ARP6 and SWR1, respectively, caused similar developmental defects, including leaf serration, weak apical dominance, flowers with extra petals and early flowering by reduction in expression of FLOWERING LOCUS C (FLC), a strong floral repressor. Chromatin immunoprecipitation assays showed that AtSWC6 and SUF3 bind to the proximal region of the FLC promoter, and protoplast transfection assays showed that AtSWC6 colocalizes with SUF3. Protein interaction analyses suggested the formation of a complex between PIE1, SUF3, AtSWC6 and AtSWC2. In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2. Finally, knockdown of the H2AZ genes by RNA interference or artificial microRNA caused a phenotype similar to that of atswc6 or suf3. Our results strongly support the presence of an SWR1C-like complex in Arabidopsis that ensures proper development, including floral repression through full activation of FLC.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 115,
                "text": "SWR1"
            }
        },
        {
            "context": "Chz1, a nuclear chaperone for histone H2AZ. The histone variant H2AZ marks nucleosomes flanking the promoters of most genes of budding yeast. The incorporation of H2AZ into chromatin is dependent on the SWR1 complex, which catalyses the replacement of conventional histone H2A with H2AZ. In cells, the pool of unincorporated histone H2AZ has previously been found in association with Nap1, a chaperone for conventional histone H2A-H2B. Here, we report the discovery of Chz1, a histone chaperone that has preference for H2AZ and can also deliver a source of the histone variant for SWR1-dependent histone replacement. Bacterially expressed Chz1 forms a heterotrimer with H2AZ-H2B, stabilizing the association of the histone dimer. We have identified a conserved motif important for histone variant recognition within the H2AZ-interacting domain of Chz1. The presence of this motif in other metazoan proteins suggests that H2AZ-specific chaperones may be widely conserved.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 203,
                "text": "SWR1"
            }
        },
        {
            "context": "[Familial isolated pituitary adenoma syndrome]. Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 468,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "NSD1 mutations in Sotos syndrome. Sotos syndrome is a genetic disorder characterized by a typical facial appearance, macrocephaly, accelerated growth, developmental delay, and a variable range of associated abnormalities. The NSD1 gene was recently found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have been identified. A significant ethnic difference is found in the prevalence of different types of mutation, with a high percentage of microdeletions identified in Japanese Sotos syndrome patients and with intragenic mutations in most non-Japanese patients. NSD1 aberrations are rather specific for Sotos syndrome, but have also been detected in patients lacking one or more major criteria of the disorder, namely overgrowth, macrocephaly, and advanced bone age. Thus, new diagnostic criteria should be considered. Studies have reported different frequencies of mutations versus non-mutations in Sotos syndrome, thus indicating allelic or locus hetereogeneity. Although some authors have suggested genotype/phenotype correlations, further studies are needed.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 226,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Sarcoplasmic reticulum: the dynamic calcium governor of muscle. The sarcoplasmic reticulum (SR) provides feedback control required to balance the processes of calcium storage, release, and reuptake in skeletal muscle. This balance is achieved through the concerted action of three major classes of SR calcium-regulatory proteins: (1) luminal calcium-binding proteins (calsequestrin, histidine-rich calcium-binding protein, junctate, and sarcalumenin) for calcium storage; (2) SR calcium release channels (type 1 ryanodine receptor or RyR1 and IP3 receptors) for calcium release; and (3) sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA) pumps for calcium reuptake. Proper calcium storage, release, and reuptake are essential for normal skeletal muscle function. We review SR structure and function during normal skeletal muscle activity, the proteins that orchestrate calcium storage, release, and reuptake, and how phenotypically distinct muscle diseases (e.g., malignant hyperthermia, central core disease, and Brody disease) can result from subtle alterations in the activity of several key components of the SR calcium-regulatory machinery.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 368,
                "text": "calsequestrin"
            }
        },
        {
            "context": "The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism. Heme must be synthesized and degraded within an individual nucleated cell. Heme degradation is catalyzed by the two isozymes of heme oxygenase, heme oxygenase-1 (HO-1) and HO-2, eventually yielding biliverdin/bilirubin, CO, and iron. These products possess important physiological roles but are potentially toxic to cells. Characteristically, human HO-1 contains no Cys residues, whereas HO-2 contains the potential heme-binding motifs of the Cys-Pro dipeptide. Expression of HO-1 is inducible or repressible, depending on cell types or cellular microenvironments, but expression levels of HO-2 are fairly constant. Thus, the main regulation of heme catabolism is a problem of the balance between induction and repression of HO-1. Notably, HO-1 expression is induced by heme in all mammalian cells examined, but is repressed by hypoxia in certain types of cultured human cells. The recent discovery of Bach1 as a heme-regulated and hypoxia-inducible repressor for transcription of the HO-1 gene has provided a missing link in the feedback control of heme catabolism. On the other hand, the human HO-1 gene promoter contains the (GT)n repeat polymorphism and a single nucleotide polymorphism (-427A --> T), both of which may contribute to fine-tuning of the transcription. Importantly, long (GT)n alleles are associated with susceptibility to smoking-induced emphysema or coronary artery disease, but may provide with resistance to cerebral malaria. The latter finding suggests a novel therapeutic strategy with inhibitors of HO-1 for the treatment of cerebral malaria. We discuss the potential regulatory role of Bach1 and HO-2 in heme catabolism and update the understanding of the regulation of HO-1 expression.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 1063,
                "text": "repressor"
            }
        },
        {
            "context": "Randomized, controlled trial of telcagepant over four migraine attacks. METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as > 3 successes, and lack of consistent efficacy was defined as > 2 failures, in treatment response. A total of 1677 patients treated > 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence > 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704).",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 106,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 273,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Effect of ingested human antibodies induced by RTS, S/AS01 malaria vaccination in children on Plasmodium falciparum oocyst formation and sporogony in mosquitoes. BACKGROUND: The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS,S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. METHODS: Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated. RESULTS: Polyclonal anti-CS IgG preparations from RTS,S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation. CONCLUSIONS: This study does not support the concept that anti-CS antibodies induced by the RTS,S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 59,
                "text": "malaria"
            }
        },
        {
            "context": "Protective effect of peptide GV1001 against renal ischemia-reperfusion injury in mice. BACKGROUND: Ischemia reperfusion injury (IRI) is a common complication after kidney transplantation. Peptide GV1001 is a peptide vaccine representing a 16-amino acid human telomerase reverse transcriptase sequence, which has been reported to possess potential antineoplastic and anti-inflammatory activity. This study aimed to investigate the potential effects of peptide GV1001 on renal IRI. METHODS: Peptide GV1001 was subcutaneously administered to C57BL6/J mice 30 minutes before and 12 hours after bilateral IRI. Sham operation and phosphate-buffered saline (PBS) injection were used as controls. Blood and renal tissues were harvested at 1 day after IRI. RESULTS: Peptide GV1001 treatment significantly attenuated renal functional deterioration after IRI (peptide GV1001 group vs PBS group; blood urea nitrogen, P < .05; creatinine, P < .05). Peptide GV1001 treatment also attenuated renal tissue injury (tubular injury score; the peptide GV1001 group vs PBS group; P < .001). Renal apoptosis was also lower in the peptide GV1001 group. Immunohistochemical studies showed that IRI increased perirenal infiltration of both neutrophils and macrophages, and that peptide GV1001 significantly attenuated this process. Expression of interleukin-6 and monocyte chemotactic protein-1 was significantly reduced by peptide GV1001 treatment. CONCLUSIONS: Peptide GV1001 ameliorates acute renal IRI by reducing inflammation and apoptosis; therefore, it is promising as a potential therapeutic agent for renal IRI. The mechanisms of protection should be explored in further studies.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 253,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "Cell density-dependent regulation of p73 in breast cancer cells. Molecular regulation of p73, a p53 family member, remains unclear. Here we report that p73 expression is significantly regulated by cell densities. In particular, we found that p73alpha and p73beta are differentially regulated. While p73beta protein levels were inversely correlated with cell densities, p73alpha protein levels behaved oppositely. We further showed that density-dependent changes of p73alpha follow the same patterns as E2F-1 and TAp73 mRNA levels, suggesting transcriptional regulation. Our data also suggest that high levels of p73beta at lower densities may be due to increased protein stability. However, AIP-4/Itch appeared not to be involved in downregulation of p73beta at high densities. Moreover, we also found that subcellular location of p73 isoforms changes with the culture density increases. While high level of p73beta at low density was mainly presented in the nucleus, low levels of this protein at high densities were mainly in the cytosol. Taken together, these findings reveal a novel mechanism that differentially regulates p73 isoforms and underscores the role of cell-cell interaction in p73 regulation, which may advance our understanding of p73 expression and function in human cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 832,
                "text": "7"
            }
        },
        {
            "context": "Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 161,
                "text": "ALS"
            }
        },
        {
            "context": "The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond. Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or undergoes extensive hepatic metabolism. The quest for a predictive biomarker to replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis such as microRNA-122 and keratin 18 may prove useful in identifying patients at risk for severe injury when they initially present with a suspected acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 491,
                "text": "Liver"
            }
        },
        {
            "context": "The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy. Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p=0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot-Marie-Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot-Marie-Tooth Disease type 2.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 205,
                "text": "GAN gene"
            }
        },
        {
            "context": "[Pulmonary sarcoidosis - clinical features, diagnosis and treatment]. Sarcoidosis is a rare multiorgan granulomatous disease of unknown etiology, mostly affecting young adults, with predilection for hilar lymph nodes and the lung. Despite clinical and histologic similarities between sarcoidosis and tuberculosis, the role of M. tuberculosis in the etiopathogenesis of sarcoidosis is still not clear. Over recent years numerous studies identifying peripheral blood T-cell response to various mycobacterial antigens were published. In parallel, there is no direct evidence for the role of alive M. tuberculosis in the development of sarcoidosis, as evidenced by negative culture in these patients. Exclusion of active tuberculosis as the granulomatous disease of known cause, still remain the important step in diagnostic work-up in sarcoidosis. Development of bronchoscopic techniques significantly reduced the number of surgical procedures. Combination of a few biopsy techniques: transbronchial needle aspiration, endobronchial biopsy and transbronchial lung biopsy, can achieve the optimum diagnostic yield. Because of the large percentage of spontaneous remission in sarcoidosis, the decision of treatment should be taken with caution. Corticosteroids still remain first-line therapy in sarcoidosis. Methotrexate is the most commonly used second-line drug. TNFα-antagonists are the therapeutic option in refractory sarcoidosis. In this article we summarise the present knowledge about the most common localization of sarcoidosis - pulmonary sarcoidosis, with special emphasis on the current etiologic hypothesis, possibility of diagnosis and treatment.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 1240,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heart. Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit phospholipid-sensitive Ca2+-dependent phosphorylation of endogenous proteins from the cytosol of the guinea-pig heart. The drug, unexpectedly, also inhibited phosphorylation of separate endogenous proteins in the cardiac cytosol and membranes catalysed by the calmodulin-sensitive species of Ca2+-dependent protein kinase. In both phosphorylation systems, the inhibition by adriamycin was reversed by either phospholipid (phosphatidylserine or cardiolipin) or calmodulin respectively. Adriamycin also inhibited phosphorylation of histone (exogenous protein) catalysed by purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, but not that by cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It appears that Ca2+-dependent protein phosphorylation systems, regulated either by phospholipid or calmodulin, may represent hitherto unrecognized sites of action of adriamycin. It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 1214,
                "text": "cardiotoxicity"
            }
        },
        {
            "context": "Principles of hand ontogenesis in man. Human hand anlagen of different developmental stages are studied light and scanning electron microscopically. The findings are compared with experimental and ultrastructural results obtained from avian limb anlagen. Shaping, cell differentiation and the spatial arrangement of different cells are found to be the basic processes of hand development. The shaping of the arm and hand seems to anticipate future grasping movements. Factors controlling this developmental process are on the one hand the apical ectodermal ridge (AER) that maintains in the underlying mesoderm a high level of mitotic activity, and on the other hand a species-specific pattern of cell death in different zones of arm and hand. Interdigital cell death, microfilament bundles included in the basal compartment of AER cells, and local anchorings of the AER ectoderm by collagen fibrils are involved in finger separation. The flexion creases are genetically fixed and their development cannot be explained by mechanical factors. It is found that the early hand anlage is already composed of relatively autonomous founder cells committed to different lineages. This is true for the muscle precursor cells which originate from the brachial somites. These migrating somite cells are determined to belong to the myogenic lineage. However, their distribution, mitotic activity and later arrangement in single muscles are controlled by factors localized within the hand itself. Tendons develop autonomously from somatopleural cells. Other already committed cells are the angioblasts forming the endothelial lining of the blood vessels, the neural crest cells differentiating into melanocytes and Schwann cells, and the blood-derived cells like chrondro- or osteoclasts. The differentiation of somatopleural cells into cartilage, connective tissue or smooth muscle depends on their position within the hand anlage. Possible mechanisms leading to the specific pattern are discussed.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 1647,
                "text": "neural crest cells"
            }
        },
        {
            "context": "The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 496,
                "text": "phospholamban"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 547,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 201,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Inhibition of DNA methylation in somatic cells. DNA methylation plays a significant role in the expression of the genetic code and affects early growth and development through its influence on gene expression. DNA methyltransferase 1 (Dnmt1) is the enzyme responsible for maintaining the methylation marks through cell division. However, the de novo methyltransferases, Dnmt3a and Dnmt3b, can also contribute to the maintenance of the methylation pattern. Manipulation of these enzymes, especially Dnmt1, provides a means to alter DNA methylation levels. Manipulation of the DNA methylation pattern of somatic cells will allow a better understanding of the different molecular process associated with chromatin structure and gene expression. Different approaches to artificially manipulate the expression of Dnmt1 in somatic cells include the addition of 5-azacytidine, culture of cells for an extended period of time, and the use of small interfering RNA technologies.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 235,
                "text": "Dnmt1"
            }
        },
        {
            "context": "New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib. Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%-8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 243,
                "text": "cancer"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 69,
                "text": "orexin"
            }
        },
        {
            "context": "Frog cardiac calsequestrin. Identification, characterization, and subcellular distribution in two structurally distinct regions of peripheral sarcoplasmic reticulum in frog ventricular myocardium. Calsequestrin is a calcium-binding protein known to sequester calcium accumulated in the sarcoplasmic reticulum (SR) of muscle cells during relaxation. In the present study, we used affinity-purified antibodies to chicken cardiac calsequestrin to identify a 60,000-Da calsequestrin in frog myocardium. Like previously identified cardiac calsequestrins, it is enriched in cardiac microsomes, it is enriched by biochemical procedures previously used to purify cardiac and skeletal calsequestrins, and it exhibits a pH-dependent shift in its apparent Mr on a two-dimensional gel system. Finally, the NH2-terminal amino acid sequence of this 60,000-Da immunoreactive protein purified by fast protein liquid chromatography was identical to that of rabbit skeletal and canine cardiac calsequestrin. Thus, we conclude that this protein corresponds to the calsequestrin isoform in frog ventricular muscle. Frog calsequestrin was localized in discrete foci present at the periphery but absent from the central regions of frog ventricular myocytes as determined by immunofluorescence labeling. Immunoelectron microscopic labeling demonstrated that calsequestrin was confined to the lumen of two structurally distinct regions of the SR, where it was localized in the subsarcolemmal region of the myofibers. One of these appeared to correspond to the terminal SR previously reported to be closely apposed to the sarcolemma of frog myofibers. The other region, although close to the sarcolemma, was not physically joined to it and appeared to correspond to corbular SR. It generally is believed that frog cardiac SR does not provide activator Ca2+ required for excitation-contraction coupling. However, the identification of a calsequestrin isoform very similar to mammalian cardiac calsequestrin that is confined to specialized regions of frog cardiac SR lends support to the idea that frog cardiac SR has the ability to store Ca2+ and thus function in some capacity in frog cardiac muscle contraction.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 197,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "A structural approach to understanding the iron-binding properties of phylogenetically different frataxins. Friedreich's ataxia (FRDA), an autosomal recessive cardio- and neurodegenerative disease, is caused by low expression of frataxin, a small mitochondrial protein, encoded in the nucleus. At the biochemical level, the lack of frataxin leads to dysregulation of mitochondrial iron homeostasis and oxidative damage, which eventually causes neuronal death. It is, however, still unclear whether frataxin is directly involved in iron binding, since the yeast orthologue, but not the human protein, has been shown to form large aggregates in the presence of large iron excess. We have compared the properties of three proteins from the frataxin family--the bacterial CyaY from Escherichia coli, the yeast Yfh1 and human frataxin--as representative of organisms of increasing complexity. We show that the three proteins have the same fold but different thermal stabilities and iron-binding properties. While human frataxin has no tendency to bind iron, CyaY forms iron-promoted aggregates with a behaviour similar to that of yeast frataxin. However, aggregation can be competed by chelator agents or by ionic strength. At physiological salt conditions, almost no aggregation is observed. The design of mutants produced to identify the protein surface involved in iron-promoted aggregation allows us to demonstrate that the process is mediated by a negatively charged surface ridge. Mutation of three of these residues is sufficient to convert CyaY in a protein with properties similar to those of human frataxin. On the other hand, mutation of the exposed surface of the beta sheet, which contains most of the conserved residues, does not affect aggregation, suggesting that iron binding is a non-conserved part of a more complex cellular function of frataxins.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 229,
                "text": "frataxin"
            }
        },
        {
            "context": "Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations. Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1384,
                "text": "xa"
            }
        },
        {
            "context": "SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. Dynamin-related protein (Drp) 1 is a key regulator of mitochondrial fission and is composed of GTP-binding, Middle, insert B, and C-terminal GTPase effector (GED) domains. Drp1 associates with mitochondrial fission sites and promotes membrane constriction through its intrinsic GTPase activity. The mechanisms that regulate Drp1 activity remain poorly understood but are likely to involve reversible post-translational modifications, such as conjugation of small ubiquitin-like modifier (SUMO) proteins. Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. While Drp1 does not harbor consensus SUMOylation sequences, our analysis identified2 clusters of lysine residues within the B domain that serve as noncanonical conjugation sites. Although initial analysis indicates that mitochondrial recruitment of ectopically expressed Drp1 in response to staurosporine is unaffected by loss of SUMOylation, we find that Drp1 SUMOylation is enhanced in the context of the K38A mutation. This dominant-negative mutant, which is deficient in GTP binding and hydrolysis, does not associate with mitochondria and prevents normal mitochondrial fission. This finding suggests that SUMOylation of Drp1 is linked to its activity cycle and is influenced by Drp1 localization.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 19,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Investigational anticoagulants for hematological conditions: a new generation of therapies. INTRODUCTION: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options. AREAS COVERED: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV. EXPERT OPINION: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 615,
                "text": "xa"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 108,
                "text": "Coilin"
            }
        },
        {
            "context": "The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade. X chromosome inactivation begins when a novel chromosomal RNA (cRNA) from the imprinted mouse Xist or human XIST locus coats or \"paints\" one X chromosome in cis and initiates a cascade of chromosome remodeling events. Molecular cytological studies have proven invaluable for understanding the distinctive cellular behavior of this singular RNA involved in chromosome structure and regulation. While the detailed mechanism of XIST/Xist (X-inactivation Specific Transcript) RNA function remains largely unknown, recent advances provide new insights into the complex cellular factors which impact the RNA's localization to the chromosome, as well as the early events of chromosome remodeling that follow painting by Xist RNA. Because chromatin changes can be directly visualized on a silenced chromosome, X chromosome inactivation provides an advantageous model to investigate genome-wide heterochromatin formation and maintenance, with wide-ranging implications for normal cells and disease.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 208,
                "text": "Xist"
            }
        },
        {
            "context": "Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting. Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.",
            "question": "Angelman syndrome is associated with deletion of a part of Chromosome 15 but if the deletion occurs in the paternally inherited chromosome 15, what is the disease?",
            "answers": {
                "answer_start": 617,
                "text": "Prader-Willi syndrome"
            }
        },
        {
            "context": "Co-inoculation of an antibiotic-producing bacterium and a lytic enzyme-producing bacterium for the biocontrol of tomato wilt caused by Fusarium oxysporum f. sp. lycopersici. The antifungal compound 2,4-diacetylphloroglucinol-producing bacterium, Pseudomonas fluorescens strain LRB3W1, inhibits the growth of Fusarium oxysporum f. sp. lycopersici, and controls Fusarium wilt of tomato caused by F. oxysporum f. sp. lycopersici. On the other hand, Serratia marcescens strain B2, which produces cell wall-degrading enzyme chitinases, did not inhibit fungal growth and the suppressive effect of strain B2 against tomato Fusarium wilt was less than that of strain LRB3W1. Combined inoculation of strain LRB3W1 with strain B2 was more effective than treatment with strain LRB3W1 alone. When 2,4-diacetylphloroglucinol and the chitinolytic enzymes were applied in combination, a synergistic inhibitory effect against the pathogen was observed. It was possible that bacteria which produce cell wall-degrading enzymes enhanced the biocontrol effect of the antibiotic-producing bacterium against tomato Fusarium wilt.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 377,
                "text": "tomato"
            }
        },
        {
            "context": "r3Cseq: an R/Bioconductor package for the discovery of long-range genomic interactions from chromosome conformation capture and next-generation sequencing data. The coupling of chromosome conformation capture (3C) with next-generation sequencing technologies enables the high-throughput detection of long-range genomic interactions, via the generation of ligation products between DNA sequences, which are closely juxtaposed in vivo. These interactions involve promoter regions, enhancers and other regulatory and structural elements of chromosomes and can reveal key details of the regulation of gene expression. 3C-seq is a variant of the method for the detection of interactions between one chosen genomic element (viewpoint) and the rest of the genome. We present r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a number of different experimental designs. The package reads a common aligned read input format, provides data normalization, allows the visualization of candidate interaction regions and detects statistically significant chromatin interactions, thus greatly facilitating hypothesis generation and the interpretation of experimental results. We further demonstrate its use on a series of real-world applications.",
            "question": "Which package is available for analysing genomic interactions in R/Bioconductor?",
            "answers": {
                "answer_start": 0,
                "text": "r3Cseq"
            }
        },
        {
            "context": "Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 98,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. The subventricular zone of the rodent brain retains the capacity of generating new neurons in adulthood. The newly formed neuroblasts migrate rostrally toward the olfactory bulb, where they differentiate as granular and periglomerular interneurons. The reported presence of differentiated neurons expressing the neuronal isoform of nitric oxide synthase (NOS) in the periphery of the neurogenic region and the organization of their varicose axons as a network in which the precursors are immersed raised the hypothesis that endogenous nitric oxide (NO) may participate in the control of neurogenesis in the subventricular zone. Systemic administration of the NOS inhibitors N(omega)-nitro-L-arginine methyl ester or 7-nitroindazole to adult mice produced a dose- and time-dependent increase in the number of mitotic cells in the subventricular zone, rostral migratory stream, and olfactory bulb, but not in the dentate gyrus of the hippocampus, without affecting apoptosis. In the subventricular zone, this effect was exerted selectively on a precursor subpopulation expressing nestin but not neuronal or glial cell-specific proteins. In addition, in the olfactory bulb, analysis of maturation markers in the newly generated neurons indicated that chronic NOS inhibition caused a delay in neuronal differentiation. Postmitotic cell survival and migration were not affected when NO production was impaired. Our results suggest that NO, produced by nitrergic neurons in the adult mouse subventricular zone and olfactory bulb, exerts a negative control on the size of the undifferentiated precursor pool and promotes neuronal differentiation.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 1195,
                "text": "nestin"
            }
        },
        {
            "context": "Heterogeneity of Wilson's disease in Israel. In a survey in Israel of 50 patients with Wilson's disease, it was found that this disease occurred in all ethnic groups. In the Arab patients there was a significantly early age of onset and the disease followed a more severe course than that in the Jewish patients. The overall sex ratio of patients was nearly 1:1, and genetic analysis of 20 families confirmed an autosomal recessive mode of inheritance. The very similar age of onset and type of disease within sibships and the varying ages of onset noted between the Arab and Jewish patients suggest that the disease is genetically heterogeneous.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 412,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 217,
                "text": "tyrosinase"
            }
        },
        {
            "context": "[Relationship between arbekacin-susceptibility and aminoglycoside-resistant gene of methicillin-resistant Staphylococcus aureus (MRSA)]. The susceptibility to arbekacin (ABK) of methicillin-resistant Staphylococcus aureus (MRSA) was investigated to find out how it related to aac(6')/aph(2\") gene. In 49 isolates of MRSA for which MIC of ABK ranged from 0.125 to 64 micrograms/ml, the MICs of ABK for 38 strains carrying aac(6')/aph(2\") gene were widely distributed from 0.25 to 64, whereas those for 11 strains without that gene were all < or = 0.5 microgram/ml. Residual rate of ABK activity was higher than that of gentamicin after the reaction with each crude enzyme preparation extracted from 3 isolates of MRSA, carrying aac(6')/aph(2\") and aad(4',4\") genes. Furthermore, 97 strains of MRSA isolated at Kanagawa prefecture in Japan in 1999 were all sensitive to ABK, although 28 strains of them carried aac(6')/aph(2\") gene. These results showed that ABK resistance was not necessarily related to carrying aac(6')/aph(2\") gene in clinical isolates of MRSA.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 129,
                "text": "MRSA"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 874,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1257,
                "text": "CO2"
            }
        },
        {
            "context": "The emerging role of p53 in exercise metabolism. The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-α protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53(Ser15) is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5'adenosine monophosphate-activated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guidelines to strategically target p53 signalling. The emerging role of p53 in skeletal muscle metabolism therefore represents a novel and exciting research area for exercise and muscle physiologists.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 229,
                "text": "p53"
            }
        },
        {
            "context": "Right cerebral hemiatrophy: neurocognitive and electroclinical features. The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS]). Cognitive assessments with a particular emphasis on visuospatial functions, electroclinical features, and neuroimaging characteristics were analyzed for five patients with a clinically and neuroradiologically confirmed diagnosis of right-sided DDMS. Intelligence tests revealed mental retardation in all but one. Neuropsychological assessments demonstrated consistent impairments in tasks that have a spatial component (spatial processing and orientation discrimination), whereas attention, executive functions and verbal memory domains were variably impaired. Electroclinically, the main seizure types were simple partial motor, complex partial, and secondarily generalized seizures. Interictal EEG delineated lower amplitudes and slow background activity in the affected hemisphere. Overall, the cognitive performance of patients with DDMS encompasses a broad spectrum of impairments affecting multiple domains. Our findings support the concept that dorsal visual pathways responsible for spatial processing may be lateralized to the right hemisphere.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 190,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 669,
                "text": "thyroid"
            }
        },
        {
            "context": "[The clinical research of restless leg syndrome and Parkinson's disease]. OBJECTIVES: To investigate the clinical feature of Parkinson's disease (PD) with restless leg syndrome (RLS) and the pathogenesis of RLS. METHODS: We conducted a cross-sectional and control study. The case group concluded 31 PD with RLS patients, meanwhile 39 PD patients were selected as the control group. Clinical history, clinical manifestations, complications and laboratory examinations were compared respectively between the two groups. RESULTS: All the RLS symptoms did not appear in RLS patients until the PD symptoms came out. Significant differences were found in complications such as swallow disturbance, constipation and illusion, when we compared the two PD groups (P < 0.05). Compared with the PD or healthy group, the level of serum ferritin and the H-reflex latency of tibial nerve were significantly decreased in PD with RLS group (P < 0.05). CONCLUSIONS: Secondary RLS is a complication of PD. Deficiency of iron and decreased inhibition function of spinal cord may lead to the occurrence of RLS in PD patients. When their motor symptoms are serious and complications are more common, PD patients are more possible to have RLS symptoms.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1002,
                "text": "iron"
            }
        },
        {
            "context": "A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 44,
                "text": "LPIN2"
            }
        },
        {
            "context": "A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. STUDY OBJECTIVE: To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated. SETTING: Sixteen emergency departments in the United States. POPULATION: Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose. INTERVENTIONS: Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered. MEASUREMENTS AND MAIN RESULTS: Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ. CONCLUSION: Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1803,
                "text": "flumazenil"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 22,
                "text": "TYR"
            }
        },
        {
            "context": "Genomic structure and expression of the mouse ESET gene encoding an ERG-associated histone methyltransferase with a SET domain. ESET (ERG-associated protein with a SET domain, also called SETDB1) is a novel histone methyltransferase that catalyzes methylation of histone H3-lysine 9 (H3-K9). Here we describe the genomic structure and expression of the mouse ESET gene that gives rise to ESET protein and its alternative splicing product. ESET is a 36-kb single copy gene and full-length ESET transcript consisting of 22 exons. The splicing variant retains only the first 12 exons and thus lacks sequences encoding the methyl CpG-binding domain and the catalytic SET domain. The U2 type conserved GT/AG consensus sequence is present at all of the splicing junctions within the ESET gene. The transcription initiation site of the ESET gene was determined by 5'-RACE experiment and by primer extension. The 5'-flanking sequence of the ESET gene does not contain the consensus TATA box. Instead, this ESET promoter region has features such as SP1-binding sites that are typical of housekeeping genes. The ESET promoter was functionally active when tested in transfection and luciferase assay. Full-length ESET transcript appears to be ubiquitously expressed. While the SET domain-deficient splicing variant is present in immortalized cell lines, it is undetectable by RT-PCR in the majority of normal mouse tissues.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 164,
                "text": "SET domain"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1014,
                "text": "MARS"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1143,
                "text": "bicarbonate"
            }
        },
        {
            "context": "The pharmacoepidemiology of antipsychotics for adults with schizophrenia in Canada, 2005 to 2009. OBJECTIVE: To describe the frequency and trends in the use of antipsychotics for adults with schizophrenia in Canada from 2005 to 2009. METHODS: Analyses were performed on IMS Brogan's Canadian Disease and Therapeutic Index (CDTI). The CDTI is a national physician panel study consisting of a representative sample of physicians both geographically and by specialty. Weighting adjustments are made to estimate national drug recommendations. Quarterly, panel physicians record all therapeutic recommendations during a 2-day period, including patient age, sex, and indication. Antipsychotic recommendations were estimated using CDTI data in which schizophrenia was listed as the indication. RESULTS: First-generation antipsychotic (FGA) recommendations for adults with schizophrenia increased by 38% between 2005 and 2009, from 329 380 to 454 960 recommendations. There were notable increases in recommendations for chlorpromazine, loxapine, zuclopenthixol, and flupentixol. Second-generation antipsychotic (SGA) recommendations increased to a much lesser extent (9%), which was mostly attributable to an increase in recommendations for clozapine. Drug recommendations for olanzapine decreased by 9%. CONCLUSION: The rate of increase of FGA use is now greater than that of SGAs. This may be due to data from recent comparative trials, which suggest that clinical efficacy, and the rate of neurological side effects is similar between FGAs and SGAs. The decreasing use of olanzapine may be due to metabolic adverse effects. The increased use of clozapine may be due to data on its superiority in patients who are treatment resistant.",
            "question": "What disease in Loxapine prominently used for?",
            "answers": {
                "answer_start": 191,
                "text": "schizophrenia"
            }
        },
        {
            "context": "Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.",
            "question": "To which disease does the loss of CD28 expression by liver-infiltrating T cells contribute?",
            "answers": {
                "answer_start": 85,
                "text": "primary sclerosing cholangitis"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 717,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Alteration in composition of keratin intermediate filaments in a model of breast cancer progression and the potential to reverse hallmarks of metastasis. BACKGROUND: In breast cancer the development of metastasis is a major turning point in the treatment and outcome of the disease. Throughout tumour development, and especially in the development of metastasis, epithelial mesenchymal transition takes place. During this transformation into a mesenchymal phenotype, the tumour cells undergo a series of structural changes. The loss of structural integrity and adoption of mesenchymal filaments enables cells to detach from the epithelial cell layer and metastasise. Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells. During cancer progression the intermediate filaments are reorganised, and dramatic changes are seen in their protein components. Keratins K8, K18, K19 and vimentin are intermediate filament proteins with altered expression profiles during tumour development. METHOD: We have used in vivo and in vitro models to analyse changes in intermediate filament proteins. Antibody-based methods were used to study K8 levels and proteomic analysis to profile the protein content of metastatic breast cancer cell variants. RESULTS: K8 expression declines as human breast tumours progress into an invasive phenotype. Analysis of IF proteins indicated altered expression profiles of K8, K18, K19 and vimentin, with K8, K18, K19 expressed in high levels in the T47D and MCF-7 cell lines, whereas the highly metastatic cell lines expressed lower levels of K8 and K18 and no detectable K19. Vimentin showed reverse expression profile with T47D and MCF-7 cells having no detectable vimentin expression whereas the highly metastatic MDA-MB-231 and MDA-MB-436 showed high levels. Analysis of acetylation status using specific antibodies suggested acetylation occurred within the central coiled domain in the MCF-7 and T47D cells. Inhibition of tumour growth by tissue factor (TF) shRNA resulted in a dramatic re-elevation of expression of K8 in xenographs of the highly metastatic MDA-MB-436 line. CONCLUSION: Intermediate filament expression alters during epithelial mesenchymal transition. Identified post translational modifications may play a role in alterations seen in the organisation, solubility and stability of these filaments. Epithelial mesenchymal transition can be reversed and an epithelial phenotype re-established.",
            "question": "What are the structures formed when keratin molecules come together?",
            "answers": {
                "answer_start": 37,
                "text": "intermediate filaments"
            }
        },
        {
            "context": "Role of ApoE in conformation-prone diseases and atherosclerosis. Three isoforms of human plasma apolipoprotein E (apoE) are ligands to lipoprotein receptors and influence in different manner the synthesis and catabolism of pro-atherogenic triglyceride-rich lipoproteins. Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD). The conformational transitions of beta-amyloid (Abeta) influenced by apoE and serum amyloid P (SAP) component are key events in AD development, the accumulation of intermediate diffusible and soluble oligomers of Abeta being of particular significance. SAP and apoE, in a different manner for the three isoforms, serve as \"pathological\" chaperones during the aggregation of Abeta considered as a conformation-prone process. In turn, apoE consisting of two domains self-associates in solution and intermediate structures differently populated for the three isoforms exist. The different structures of the three isoforms determine their different distribution among various plasma lipoproteins. The structural and metabolic consideration of the common apoE pathway(s) in two pathologies assumes four molecular targets for AD correction: (i) inhibition of the accumulation of diffusible soluble Abeta oligomers; (ii) inhibition of apoE synthesis and secretion by astrocytes, in particular, under lipid-lowering therapy; (iii) inhibition of the binding of apoE and/or SAP to Abeta; (iv) stimulation of the expression of cholesterol transporter ABCA1.",
            "question": "Which ApoE isoform is associated with atherosclerosis and Alzheimer's disease?",
            "answers": {
                "answer_start": 297,
                "text": "apoE4 isoform"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 165,
                "text": "orexin"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Mortality in patients with celiac disease. Celiac disease is an autoimmune disorder triggered by ingestion of gluten-containing foods. Epidemiologic studies dating from the 1950s established its association with gastrointestinal malignancies, particularly small bowel lymphoma. Corrao et al. recently demonstrated that patients with celiac disease are at increased risk of mortality. Further, this risk is directly related to compliance with a gluten-free diet. Continued research is needed regarding the development of malignant complications related to celiac disease.",
            "question": "What disease is small bowel lymphoma commonly associated with",
            "answers": {
                "answer_start": 43,
                "text": "Celiac disease"
            }
        },
        {
            "context": "McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings. The McLeod syndrome is an X-linked disorder caused by mutations of the XK gene encoding the XK protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxy-glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X-linked trait should be examined for acanthocytosis and Kell/Kx blood group serology.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 186,
                "text": "XK"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 478,
                "text": "Xa"
            }
        },
        {
            "context": "A mammalian herpesvirus uses noncanonical expression and processing mechanisms to generate viral MicroRNAs. Canonical primary microRNA (pri-miRNA) precursors are transcribed by RNA polymerase II and then processed by the Drosha endonuclease to generate approximately 60 nt pre-miRNA hairpins. Pre-miRNAs in turn are cleaved by Dicer to generate mature miRNAs. Previously, some short introns, called miRtrons, were reported to fold into pre-miRNA hairpins after splicing and debranching, and miRNAs can also be excised by Dicer cleavage of rare endogenous short hairpin RNAs. Here we report that the miRNAs encoded by murine gamma-herpesvirus 68 (MHV68) are also generated via atypical mechanisms. Specifically, MHV68 miRNAs are transcribed from RNA polymerase III promoters located within adjacent viral tRNA-like sequences. The resultant pri-miRNAs, which bear a 5' tRNA moiety, are not processed by Drosha but instead by cellular tRNase Z, which cleaves 3' to the tRNA to liberate pre-miRNA hairpins that are then processed by Dicer to yield the mature viral miRNAs.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 177,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules. DNA methylation and nucleosome positioning work together to generate chromatin structures that regulate gene expression. Nucleosomes are typically mapped using nuclease digestion requiring significant amounts of material and varying enzyme concentrations. We have developed a method (NOMe-seq) that uses a GpC methyltransferase (M.CviPI) and next generation sequencing to generate a high resolution footprint of nucleosome positioning genome-wide using less than 1 million cells while retaining endogenous DNA methylation information from the same DNA strand. Using a novel bioinformatics pipeline, we show a striking anti-correlation between nucleosome occupancy and DNA methylation at CTCF regions that is not present at promoters. We further show that the extent of nucleosome depletion at promoters is directly correlated to expression level and can accommodate multiple nucleosomes and provide genome-wide evidence that expressed non-CpG island promoters are nucleosome-depleted. Importantly, NOMe-seq obtains DNA methylation and nucleosome positioning information from the same DNA molecule, giving the first genome-wide DNA methylation and nucleosome positioning correlation at the single molecule, and thus, single cell level, that can be used to monitor disease progression and response to therapy.",
            "question": "What is measured through the NOMe-Seq methodology?",
            "answers": {
                "answer_start": 23,
                "text": "nucleosome positioning and DNA methylation"
            }
        },
        {
            "context": "Manual versus automatic bladder wall thickness measurements: a method comparison study. PURPOSE: To compare repeatability and agreement of conventional ultrasound bladder wall thickness (BWT) measurements with automatically obtained BWT measurements by the BVM 6500 device. METHODS: Adult patients with lower urinary tract symptoms, urinary incontinence, or postvoid residual urine were urodynamically assessed. During two subsequent cystometry sessions the infusion pump was temporarily stopped at 150 and 250 ml bladder filling to measure BWT with conventional ultrasound and the BVM 6500 device. For each method and each bladder filling, repeatability and variation was assessed by the method of Bland and Altman. RESULTS: Fifty unselected patients (30 men, 20 women) aged 21 - 86 years (median 62.5 years) were prospectively evaluated. Invalid BWT measurements were encountered in 2.1 - 14% of patients when using the BVM 6500 versus 0% with conventional ultrasound (significant only during the second measurement at 150 ml bladder filling). Mean difference in BWT values between the measurements of one technique was −0.1 to +0.01 mm. Measurement variation between replicate measurements was smaller for conventional ultrasound and the smallest for 250 ml bladder filling. Mean difference between the two techniques was 0.11 - 0.23 mm and did not differ significantly. The BVM 6500 device was not able to correctly measure BWTs above 4 mm. CONCLUSIONS: Both BWT measurements are repeatable and agree with each other. However, conventional ultrasound measurements have a smaller measurement variance, can measure BWT in all patients, and BWTs above 4 mm.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 152,
                "text": "ultrasound"
            }
        },
        {
            "context": "Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals. Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved. We investigated 94 healthy individuals (60 men, mean age 47.0±18.7, range 23-86) to determine if trait aggression and trait impulsivity were related to frontal cortex 5-HT2A receptor binding (5-HT2AR) as measured with [18F]-altanserin PET imaging. Trait aggression and trait impulsivity were assessed with the Buss-Perry Aggression Questionnaire (AQ) and the Barratt Impulsiveness Scale 11 (BIS-11). Statistical analyses were conducted using a multiple linear regression model and internal consistency reliability of the AQ and BIS-11 was evaluated by Cronbach's alpha. Contrary to our hypothesis, results revealed no significant associations between 5-HT2AR and the AQ or BIS-11 total scores. Also, there was no significant interaction between gender and frontal cortex 5-HT2AR in predicting trait aggression and trait impulsivity. This is the first study to examine how 5-HT2AR relates to trait aggression and trait impulsivity in a large sample of healthy individuals. Our findings are not supportive of a selective role for 5-HT2AR in mediating the 5-HT related effects on aggression and impulsivity in psychiatrically healthy individuals.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 534,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Light-induced isomerization of the LHCII-bound xanthophyll neoxanthin: possible implications for photoprotection in plants. Light-harvesting pigment-protein complex of Photosystem II (LHCII) is the largest photosynthetic antenna complex of plants and the most abundant membrane protein in the biosphere. Plant fitness and productivity depend directly on a balance between excitations in the photosynthetic apparatus, generated by captured light quanta, and the rate of photochemical processes. Excess excitation energy leads to oxidative damage of the photosynthetic apparatus and entire organism and therefore the balance between the excitation density and photosynthesis requires precise and efficient regulation, operating also at the level of antenna complexes. We show that illumination of the isolated LHCII leads to isomerization of the protein-bound neoxanthin from conformation 9'-cis to 9',13- and 9',13'-dicis forms. At the same time light-driven excitation quenching is observed, manifested by a decrease in chlorophyll a fluorescence intensity and shortened fluorescence lifetimes. Both processes, the neoxanthin isomerization and the chlorophyll excitation quenching, are reversible in dim light. The results of the 77K florescence measurements of LHCII show that illumination is associated with appearance of the low-energy states, which can serve as energy traps in the pigment-protein complex subjected to excess excitation. Possible sequence of the molecular events is proposed, leading to a protective excess excitation energy quenching: neoxanthin photo-isomerization→formation of LHCII supramolecular structures which potentiate creation of energy traps→excitation quenching.",
            "question": "Which is the most abundant membrane protein on Earth?",
            "answers": {
                "answer_start": 124,
                "text": "Light-harvesting pigment-protein complex of Photosystem II"
            }
        },
        {
            "context": "One single method to produce native and Tat-fused recombinant human α-synuclein in Escherichia coli. BACKGROUND: Human α-synuclein is a small-sized, natively unfolded protein that in fibrillar form is the primary component of Lewy bodies, the pathological hallmark of Parkinson's disease. Experimental evidence suggests that α-synuclein aggregation is the key event that triggers neurotoxicity although additional findings have proposed a protective role of α-synuclein against oxidative stress. One way to address the mechanism of this protective action is to evaluate α-synuclein-mediated protection by delivering this protein inside cells using a chimeric protein fused with the Tat-transduction domain of HIV Tat, named TAT-α-synuclein. RESULTS: A reliable protocol was designed to efficiently express and purify two different forms of human α-synuclein. The synthetic cDNAs encoding for the native α-synuclein and the fusion protein with the transduction domain of Tat protein from HIV were overexpressed in a BL21(DE3) E. coli strain as His-tagged proteins. The recombinant proteins largely localized ( > 85%) to the periplasmic space. By using a quick purification protocol, based on recovery of periplasmic space content and metal-chelating chromatography, the recombinant α-synuclein protein forms could be purified in a single step to > 95% purity. Both α-synuclein recombinant proteins form fibrils and the TAT-α-synuclein is also cytotoxic in the micromolar concentration range. CONCLUSIONS: To further characterize the molecular mechanisms of α-synuclein neurotoxicity both in vitro and in vivo and to evaluate the relevance of extracellular α-synuclein for the pathogenesis and progression of Parkinson's disease, a suitable method to produce different high-quality forms of this pathological protein is required. Our optimized expression and purification procedure offers an easier and faster means of producing different forms (i.e., both the native and the TAT-fusion form) of soluble recombinant α-synuclein than previously described procedures.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 119,
                "text": "α-synuclein"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 781,
                "text": "xa"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 533,
                "text": "tyr"
            }
        },
        {
            "context": "Role of fusaric acid in the development of 'Fusarium wilt' symptoms in tomato: Physiological, biochemical and proteomic perspectives. Fusarium wilt is one of the most prevalent and damaging diseases of tomato. Among various toxins secreted by the Fusarium oxysporum f. sp. lycopersici (causal agent of Fusarium wilt of tomato), fusaric acid (FA) is suspected to be a potent pathogenicity factor in tomato wilt disease development. With this rationale the present study was carried out with physiological, biochemical and proteomic perspectives. Treatment of FA was given to the leaves of tomato directly through infiltration to show the characteristic features of Fusarium wilt of tomato. The phytotoxic effect of FA was assessed in the form of cell death in tomato leaves which was observed by increased uptake of Evans blue stain. The measurement of electrolyte leakage was used as an indicator of the extent of cell death. The influence of FA on the leaf photosynthesis of tomato plant was investigated and it was found that FA strongly reduced the photosynthetic pigment contents of tomato leaves resulting to heavy suppression of leaf photosynthesis processes, which therefore affected leaf physiology finally leading to leaf wilting and necrosis. This cell death inducer (FA) produced an enormous oxidative burst during which large quantities of reactive oxygen species (ROS) like HO was generated in the treated leaf tissues of tomato plants which was evident from enhancement in lipid peroxidation. To assess the involvement of proteolysis in the cell death cascade induced by FA treatment, total protease activity was measured in the leaf tissues and it was found that the total protease activity increased with the treatment and leading to cell death. Furthermore, proteomic study was used as a powerful tool to understand the alterations in cellular protein expression in response to FA exposure. Differential expression in several proteins was observed in the present study. Proteomic analyses, thus, clearly indicate that proteins belonging to different functional classes are significantly affected in the plant leaf tissues after FA exposure leading to deterioration of structure and metabolism of cells. Thus, it is concluded that FA plays an important role in fungal pathogenicity by decreasing cell viability.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 202,
                "text": "tomato"
            }
        },
        {
            "context": "[Daratumumab--breakthrough drug in multiple myeloma therapy]. Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 181,
                "text": "CD38"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "In silico and functional studies of the regulation of the glucocerebrosidase gene. In Gaucher disease (GD), the inherited deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within lysosomes. Although almost 300 mutations in the glucocerebrosidase gene (GBA) have been identified, the ability to predict phenotype from genotype is quite limited. In this study, we sought to examine potential GBA transcriptional regulatory elements for variants that contribute to phenotypic diversity. Specifically, we generated the genomic sequence for the orthologous genomic region ( approximately 39.4kb) encompassing GBA in eight non-human mammals. Computational comparisons of the resulting sequences, using human sequence as the reference, allowed the identification of multi-species conserved sequences (MCSs). Further analyses predicted the presence of two putative clusters of transcriptional regulatory elements upstream and downstream of GBA, containing five and three transcription factor-binding sites (TFBSs), respectively. A firefly luciferase (Fluc) reporter construct containing sequence flanking the GBA gene was used to test the functional consequences of altering these conserved sequences. The predicted TFBSs were individually altered by targeted mutagenesis, resulting in enhanced Fluc expression for one site and decreased expression for seven others sites. Gel-shift assays confirmed the loss of nuclear-protein binding for several of the mutated constructs. These identified conserved non-coding sequences flanking GBA could play a role in the transcriptional regulation of the gene contributing to the complexity underlying the phenotypic diversity seen in GD.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 136,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "[Progress in molecular chorea diagnosis. McLeod syndrome and chorea acanthocytosis]. McLeod syndrome and chorea-acanthocytosis are classified with the so-called neuroacanthocytosis group of syndromes. Both lead to progressive basal ganglia degeneration and were not easily distinguished in the past. With the discovery of their molecular bases, mutations of the X-linked gene XK and autosomal recessive mutations of the gene coding for chorein, respectively, the two phenotypes can now be differentiated and extend the diagnostic spectrum in patients presenting with chorea. The present review compares the two conditions and proposes a practical approach to diagnosis and treatment. Better-defined disease concepts should eventually replace the umbrella term of \"neuroacanthocytosis.\" Animal models are needed to understand the underlying mechanisms. A final common pathway is likely for the pathogenesis of these conditions and is most probably shared with Huntington's disease.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 376,
                "text": "XK"
            }
        },
        {
            "context": "Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.",
            "question": "Which is the cellular localization of the protein Opa1?",
            "answers": {
                "answer_start": 136,
                "text": "mitochondrial intermembrane space"
            }
        },
        {
            "context": "DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability.",
            "question": "Which technique led to the elucidation of the role of HOXD10 in regulating lymphatic endothelial responses to VEGF-C?",
            "answers": {
                "answer_start": 0,
                "text": "DeepCAGE"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 674,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1158,
                "text": "NCX"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 551,
                "text": "chromDraw"
            }
        },
        {
            "context": "Dinutuximab: An Anti-GD2 Monoclonal Antibody for High-Risk Neuroblastoma. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab. DATA SOURCES: MEDLINE was searched (1964 to January 2016) using the terms ch14.18, dinutuximab, immunotherapy, and neuroblastoma. Other information was identified from package insert, Biologics License Application, abstracts, news releases, and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: Identified English-language articles were reviewed. Selected studies included phase I through III. DATA SYNTHESIS: High-risk neuroblastoma is primarily a childhood cancer with 5-year survival rates of 40% to 50%. Treatment for high-risk neuroblastoma includes induction chemotherapy, surgery, myeloablative chemotherapy with autologous hematopoietic stem cell transplant, and radiation therapy. For patients achieving clinical remission, limited treatments exist for preventing relapse. Dinutuximab is a chimeric, human-murine, anti-GD2 monoclonal antibody approved in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. In phase III trials, dinutuximab increased 2-year event-free survival and overall survival when compared to standard treatment. Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension. CONCLUSIONS: Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. Ongoing research will determine if dinutuximab could be used earlier in treatment, in nonresponders to initial therapies, in combination with chemotherapy, or in other cancers.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 1313,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "DeepBlueR: large-scale epigenomic analysis in R. Motivation: While large amounts of epigenomic data are publicly available, their retrieval in a form suitable for downstream analysis is a bottleneck in current research. The DeepBlue Epigenomic Data Server provides a powerful interface and API for filtering, transforming, aggregating and downloading data from several epigenomic consortia. Results: To make public epigenomic data conveniently available for analysis in R, we developed an R/Bioconductor package that connects to the DeepBlue Epigenomic Data Server, enabling users to quickly gather and transform epigenomic data from selected experiments for analysis in the Bioconductor ecosystem. Availability and Implementation: http://deepblue.mpi-inf.mpg.de/R . Requirements: R 3.3, Bioconductor 3.4. Contact: felipe.albrecht@mpi-inf.mpg.de or markus.list@mpi-inf.mpg.de. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/bioconductor package has been developed to aid in epigenomic analysis?",
            "answers": {
                "answer_start": 0,
                "text": "DeepBlueR"
            }
        },
        {
            "context": "45,X Turner's syndrome in monozygotic twin sisters. A 7-year-old girl was admitted to the hospital for anaemia, secondary to intestinal blood los (melaena). She was found to have 45,X Turner's syndrome. Her identical twin sister also had Turner's syndrome with a 45,X chromosome complement. According to various criteria the probability of monozygosity was 0.9905. Although the incidence of twinning is greater than usual in families of patients with Turner's syndrome, affected cases have only been observed in twin sisters on six occasions. It seems therefore that the 45,X chromosome complement itself is not a factor predisposing to twinning, but that in some families, a factor is at play, which cuases either twinning or the 45,X aneuploidy, or both.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 3,
                "text": "X"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 476,
                "text": "xa"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1338,
                "text": "MARS"
            }
        },
        {
            "context": "Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease. The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing. Data from preclinical studies and clinical trials suggest that gevokizumab is a potentially effective and well-tolerated treatment for the indicated diseases. At the time of publication, phase II clinical trials were ongoing in patients with T1D, T2D and RA, with the T2D trials assessing key cardiovascular markers. Following promising data from a recent pilot trial, XOMA was also planning a phase I/II trial of gevokizumab for the potential treatment of uveitis in patients with the vasculitic inflammatory disorder Behçet's disease and the autoinflammatory conditions familial cold autoinflammatory syndrome and Muckle-Wells syndrome.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 568,
                "text": "IL-1β"
            }
        },
        {
            "context": "Eaf1p Is Required for Recruitment of NuA4 in Targeting TFIID to the Promoters of the Ribosomal Protein Genes for Transcriptional Initiation In Vivo. NuA4 (nucleosome acetyltransferase of H4) promotes transcriptional initiation of TFIID (a complex of TBP and TBP-associated factors [TAFs])-dependent ribosomal protein genes involved in ribosome biogenesis. However, it is not clearly understood how NuA4 regulates the transcription of ribosomal protein genes. Here, we show that NuA4 is recruited to the promoters of ribosomal protein genes, such as RPS5, RPL2B, and RPS11B, for TFIID recruitment to initiate transcription, and the recruitment of NuA4 to these promoters is impaired in the absence of its Eaf1p component. Intriguingly, impaired NuA4 recruitment in a Δeaf1 strain depletes recruitment of TFIID (a TAF-dependent form of TBP) but not the TAF-independent form of TBP to the promoters of ribosomal protein genes. However, in the absence of NuA4, SAGA (Spt-Ada-Gcn5-acetyltransferase) is involved in targeting the TAF-independent form of TBP to the promoters of ribosomal protein genes for transcriptional initiation. Thus, NuA4 plays an important role in targeting TFIID to the promoters of ribosomal protein genes for transcriptional initiation in vivo. Such a function is mediated via its targeted histone acetyltransferase activity. In the absence of NuA4, ribosomal protein genes lose TFIID dependency and become SAGA dependent for transcriptional initiation. Collectively, these results provide significant insights into the regulation of ribosomal protein gene expression and, hence, ribosome biogenesis and functions.",
            "question": "What does the SAGA complex acronym stands for?",
            "answers": {
                "answer_start": 963,
                "text": "Spt-Ada-Gcn5-acetyltransferase"
            }
        },
        {
            "context": "The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 114,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by a deficiency of frataxin, a conserved mitochondrial protein of unknown function. Mitochondrial iron accumulation, loss of iron-sulfur cluster-containing enzymes and increased oxidative damage occur in yeast and mouse frataxin-depleted mutants as well as tissues and cell lines from FRDA patients, suggesting that frataxin may be involved in export of iron from the mitochondria, synthesis of iron-sulfur clusters and/or protection from oxidative damage. We have previously shown that yeast frataxin has structural and functional features of an iron storage protein. In this study we have investigated the function of human frataxin in Escherichia coli and Saccharomyces cerevisiae. When expressed in E.coli, the mature form of human frataxin assembles into a stable homopolymer that can bind approximately 10 atoms of iron per molecule of frataxin. The iron-loaded homopolymer can be detected on non-denaturing gels by either protein or iron staining demonstrating a stable association between frataxin and iron. As analyzed by gel filtration and electron microscopy, the homopolymer consists of globular particles of approximately 1 MDa and ordered rod-shaped polymers of these particles that accumulate small electron-dense cores. When the human frataxin precursor is expressed in S.cerevisiae, the mitochondrially generated mature form is separated by gel filtration into monomer and a high molecular weight pool of >600 kDa. A high molecular weight pool of frataxin is also present in mouse heart indicating that frataxin can assemble under native conditions. In radiolabeled yeast cells, human frataxin is recovered by immunoprecipitation with approximately five atoms of (55)Fe bound per molecule. These findings suggest that FRDA results from decreased mitochondrial iron storage due to frataxin deficiency which may impair iron metabolism, promote oxidative damage and lead to progressive iron accumulation.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 46,
                "text": "frataxin"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 717,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Dinutuximab for the treatment of pediatric patients with high-risk neuroblastoma. Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-year survival rate for HR-NB remains below 40%, with the majority of patients suffering relapse from chemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease and clinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid disialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a, human-mouse chimeric ch14.18 and 3F8. Anti-GD2 MoAb induces cellular cytoxicity against NB and is most effective when effector cells like natural killer cells, granulocytes and macrophages are amplified by cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18 (Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMA approved dinutuximab (Unituxin(R)) in 2015 for the treatment of patients with HR-NB who achieved at least a partial response after multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 67,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1517,
                "text": "XK"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 874,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 369,
                "text": "INCA"
            }
        },
        {
            "context": "A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 1075,
                "text": "FBN1"
            }
        },
        {
            "context": "Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome's epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells.",
            "question": "Do A-type lamins bind euchromatin or heterochromatin?",
            "answers": {
                "answer_start": 790,
                "text": "both euchromatin and heterochromatin"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 42,
                "text": "Xa"
            }
        },
        {
            "context": "The francisella intracellular life cycle: toward molecular mechanisms of intracellular survival and proliferation. The tularemia-causing bacterium Francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes. Because this cycle is essential to Francisella pathogenesis and virulence, much research has focused on deciphering the mechanisms of its intracellular survival and replication and characterizing both bacterial and host determinants of the bacterium's intracellular cycle. Studies of various strains and host cell models have led to the consensual paradigm of Francisella as a cytosolic pathogen, but also to some controversy about its intracellular cycle. In this review, we will detail major findings that have advanced our knowledge of Francisella intracellular survival strategies and also attempt to reconcile discrepancies that exist in our molecular understanding of the Francisella-phagocyte interactions.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 147,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Apoptotic cell death and altered calcium homeostasis caused by frataxin depletion in dorsal root ganglia neurons can be prevented by BH4 domain of Bcl-xL protein. Friedreich ataxia (FRDA) is a neurodegenerative disease characterized by a decreased expression of the mitochondrial protein frataxin. Major neurological symptoms of the disease are due to degeneration of dorsal root ganglion (DRG) sensory neurons. In this study we have explored the neurodegenerative events occurring by frataxin depletion on primary cultures of neurons obtained from rat DRGs. Reduction of 80% of frataxin levels in these cells was achieved by transduction with lentivirus containing shRNA silencing sequences. Frataxin depletion caused mitochondrial membrane potential decrease, neurite degeneration and apoptotic cell death. A marked increase of free intracellular Ca(2+) levels and alteration in Ca(2+)-mediated signaling pathways was also observed, thus suggesting that altered calcium homeostasis can play a pivotal role in neurodegeneration caused by frataxin deficiency. These deleterious effects were reverted by the addition of a cell-penetrant TAT peptide coupled to the BH4, the anti-apoptotic domain of Bcl-x(L). Treatment of cultured frataxin-depleted neurons with TAT-BH4 was able to restore the free intracellular Ca(2+) levels and protect the neurons from degeneration. These observations open the possibility of new therapies of FRDA based on modulating the Ca(2+) signaling and prevent apoptotic process to protect DRG neurons from neurodegeneration.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 288,
                "text": "frataxin"
            }
        },
        {
            "context": "The long Q-T syndromes. Loss of consciousness in childhood may be due to cardiovascular causes, and the Long Q-T syndromes can present with seizures. The Romano-Ward syndrome is of autosomal dominant inheritance, and the Jervell and Lange-Nielson syndrome, with associated deafness, of autosomal recessive inheritance. The diagnosis is often delayed, but a careful history can avoid this. The syndromes can appear to be due to an imbalance in the sympathetic nerve to the ventricular myocardium, and precipitating causes such as stress suggest a CNS influence on this. The electrocardiogram can confirm the prolonged Q-T interval, but this is not always present, at least without an exercise test. Treatment with beta-blockers is often successful. If a wrong diagnosis of epilepsy is made a chance may be missed of avoiding sudden death, quite apart from all the medical, and social consequences that can result from such a diagnosis.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 181,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Remission of ulcerated necrobiosis lipoidica diabeticorum after bariatric surgery. A 32-year-old woman with type 2 diabetes mellitus suffering from morbid obesity with BMI 45,14 kg/m(2) was operated on. Not only the type 2DM but also one of its complication known as necrobiosis lipoidica diabeticorum remitted postoperatively. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals but an epidemic that threatens global well-being. It causes or exacerbates many health problems, and in particular, it is associated with the type 2 diabetes. Necrobiosis lipoidica is a granulomatous skin disease of unknown etiology, associated mainly with diabetes mellitus. We presented in this paper a morbid obese case of necrobiosis lipoidica diabeticorum with dramatic good response to bariatric surgery.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 681,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Transcriptome analysis of the zebrafish model of Diamond-Blackfan anemia from RPS19 deficiency via p53-dependent and -independent pathways. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO), RPS19 and p53 morpholino simultaneously (RPS19+p53 MO) and control morpholino (control). We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 165,
                "text": "DBA"
            }
        },
        {
            "context": "Investigational anticoagulants for hematological conditions: a new generation of therapies. INTRODUCTION: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options. AREAS COVERED: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV. EXPERT OPINION: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 521,
                "text": "Xa"
            }
        },
        {
            "context": "MRSA CC398 in the pig production chain. In 2005, a distinct clone of methicillin resistant Staphylococcus aureus (MRSA CC398) was found in pigs and people in contact with pigs. The structure of the pig production chain in high technology pig husbandry enables pathogens to spread during animal trading, with an increasing prevalence in herds further down the chain. The objective of this study was to quantify the effect of the MRSA status of the supplying herd on the MRSA status of the receiving herd in order to gain more insight into the role of animal trading as a transmission route for MRSA CC398. Nasal samples (60-80 pigs per herd) were collected from 38 herds; in 20 herds, environmental samples were collected as well. Ten MRSA-positive herds (based on the results of nasal swabs of 10 individual pigs per herd) from a prior study were included in the data analysis. Herds were classified as MRSA positive if at least one sample tested positive. The 48 herds were part of 14 complete (40 herds) and 4 incomplete (8 herds) pig production chains. Fifty-six percent of the herds were classified as MRSA positive. MRSA-positive herds were observed at the start (breeding herds), middle (farrowing herds) and the end (finishing herds) of the pig production chain. All of the herds in 8 chains tested MRSA positive;, all of the herds in 5 chains tested MRSA negative and in the remaining 5 chains, MRSA-positive and MRSA-negative herds were detected. Seven spa types were found, which were all previously confirmed to belong to CC398. All of the isolates were susceptible to mupirocin, linezolid, rifampicin, fusidic acid and cotrimoxazole. Resistance against tetracycline, erythromycin and clindamycin was found in 100, 74 and 76% of the isolates, respectively. Seventy-nine percent of herds with a MRSA-positive supplier of pigs were MRSA positive, whereas 23% of herds with a MRSA-negative supplier were MRSA positive (OR=10.8; 95% CI: 1.5-110.1; P=0.011). The presence of entirely MRSA-positive and MRSA-negative chains and the strong association between the MRSA status of herds and their suppliers illustrates a large risk associated with purchasing pigs from MRSA-positive herds; a top-down strategy for future control programs is, therefore, a basic requirement. However, 23% of herds with a MRSA-negative supplier were MRSA positive and furthermore, 46% of the herds at the top of the pig production chain without a supplier tested MRSA positive. This underlined the need for the identification of additional risk factors for MRSA.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 114,
                "text": "MRSA"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 10,
                "text": "tyr"
            }
        },
        {
            "context": "Marfan's syndrome: an overview. Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder affects many parts of the body. The diagnosis of Marfan's syndrome is established in accordance with a review of the diagnostic criteria, known as the Ghent nosology, through a comprehensive assessment largely based on a combination of major and minor clinical manifestations in various organ systems and the family history. Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of Marfan's syndrome. The pathogenesis of Marfan's syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations. The treatment may include prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta, and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in Marfan's syndrome. The present article aims to provide an overview of this rare hereditary disorder.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 892,
                "text": "connective tissue"
            }
        },
        {
            "context": "Functional expression of a Drosophila gene in yeast: genetic complementation of DNA topoisomerase II. Since DNA topoisomerase II (EC 5.99.1.3) is an essential enzyme in yeast, heterologous topoisomerase II gene expression in yeast cells can provide a system for analyzing the structure and function of topoisomerase II genes from other species. A series of yeast expression plasmids was constructed in which segments of the cDNA sequences encoding Drosophila DNA topoisomerase II were inserted under the transcriptional control of yeast GAL1 promoter. Expression of the functional form of Drosophila topoisomerase II cDNA can complement conditionally lethal, temperature-sensitive mutations in the yeast topoisomerase II gene (TOP2), as well as mutations in which the TOP2 locus was disrupted. The survival of these yeast cells depends upon the continuous expression of Drosophila topoisomerase II. Repression of Drosophila gene expression by glucose causes these yeast cells to cease dividing after a few generations. In addition to these genetic complementation data, the expression of the Drosophila topoisomerase II gene in yeast cells with a disruption in TOP2 can also be detected by immunochemical methods with an antibody specific for Drosophila topoisomerase II.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 302,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 575,
                "text": "early"
            }
        },
        {
            "context": "Clinical and genetic studies in a Chinese family with giant axonal neuropathy. The objective of the study was to investigate a girl with giant axonal neuropathy and detect the mutation of GAN gene in her family. The encoding exons of GAN gene were amplified from genomic DNA of the proband and her parents by polymerase chain reaction and directly sequenced after purification. The proband manifested typical neurological symptoms and pathological abnormalities. The case had 2 heterozygous missense mutations in GAN gene: 1. c. 224 T>A in exon 2, her mother was a heterozygote of this mutation and had normal phenotype; 2. c.1634G>A in exon 10, and her father was a heterozygote of this mutation and had normal phenotype. Both of the mutations caused amino acid changes in the gigaxonin protein. In this family, missense mutation of c.224 T>A and missense mutation of c.1634G>A in GAN gene caused the phenotype of giant axonal neuropathy in the proband. Her parents are heterozygotes of the disease without symptoms.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 882,
                "text": "GAN gene"
            }
        },
        {
            "context": "Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristics of the BD GeneOhm MRSA assay, the Xpert MRSA assay, and broth-enriched culture in an area with a low prevalence of MRSA infections. Universal surveillance upon patient admission is important in reducing the transmission of methicillin-resistant Staphylococcus aureus (MRSA) and associated disease in hospitals. High costs for the health care system in conjunction with MRSA have promoted the development of rapid screening methods to detect MRSA carriers. This study compared two real-time PCR methods, the BD GeneOhm MRSA assay (BDGO) and the Xpert MRSA assay, with broth-enriched culture to define their performance characteristics and rapidity in an area with low MRSA prevalence. In total, 414 swabs from the nose and 389 swabs from the groin from 425 patients were tested. Of those 425 patients, 378 had swabs from both the nose and groin in parallel. Two hundred thirty-one and 194 patients were randomly assigned to the BDGO group and the Xpert MRSA group, respectively. In general, sensitivity, specificity, and negative predictive value (NPV) were high for the BDGO (100%, 98.5%, and 100%, respectively) and the Xpert MRSA (100%, 98.2%, and 100%, respectively), irrespective of whether or not nasal and inguinal specimens were considered alone or combined. In contrast, the positive predictive value (PPV) was lower: before the resolution of discrepant results, the PPVs for nasal and inguinal specimens alone and combined were 87.5%, 86.7%, and 82.4% for the BDGO and 91.7%, 66.7%, and 92.9% for the Xpert MRSA, respectively. After the resolution of discrepant results, PPVs were 93.8%, 93.3% and 94.1% for the BDGO and 91.7%, 88.9% and 92.9% for the Xpert MRSA, respectively. With the BDGO, 4 of 16 carriers were each identified by nasal or inguinal swabs alone, whereas in the Xpert MRSA group, 4 of 13 carriers were exclusively identified by nasal swabs and 2 of 13 were identified by inguinal swabs alone. Both PCR methods showed no significant difference in the number of discrepant results (odds ratio, 0.70 [P = 0.789]), but specimens from wounds and other body sites (axilla, vagina, and throat) produced discrepancies more often than nasal and groin specimens (odds ratios, 4.724 [P = 0.058] and 12.163 [P < 0.001], respectively). The facts that no false-negative PCR results were detected and increased PPVs were found after the resolution of discrepant results point to PCR as the actual gold standard. Since both sensitivity and NPV were exceptionally high for PCR, backup cultures may, therefore, be unnecessary in an area with low prevalence and with a preemptive isolation strategy but may still be useful for PCR-positive specimens because of the lower PPV for both methods and the possibility of susceptibility testing. The median time for analysis, including extraction, hands-on time, and actual PCR was 2 h 20 min for the Xpert MRSA versus 5 h 40 min for the BDGO. Concerning reporting time, including administration and specimen collection, the Xpert MRSA was faster than the BDGO (7 h 50 min versus 17 h).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 58,
                "text": "MRSA"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 719,
                "text": "IgG4"
            }
        },
        {
            "context": "Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb. Epigenomic mapping of enhancer-associated chromatin modifications facilitates the genome-wide discovery of tissue-specific enhancers in vivo. However, reliance on single chromatin marks leads to high rates of false-positive predictions. More sophisticated, integrative methods have been described, but commonly suffer from limited accessibility to the resulting predictions and reduced biological interpretability. Here we present the Limb-Enhancer Genie (LEG), a collection of highly accurate, genome-wide predictions of enhancers in the developing limb, available through a user-friendly online interface. We predict limb enhancers using a combination of >50 published limb-specific datasets and clusters of evolutionarily conserved transcription factor binding sites, taking advantage of the patterns observed at previously in vivo validated elements. By combining different statistical models, our approach outperforms current state-of-the-art methods and provides interpretable measures of feature importance. Our results indicate that including a previously unappreciated score that quantifies tissue-specific nuclease accessibility significantly improves prediction performance. We demonstrate the utility of our approach through in vivo validation of newly predicted elements. Moreover, we describe general features that can guide the type of datasets to include when predicting tissue-specific enhancers genome-wide, while providing an accessible resource to the general biological community and facilitating the functional interpretation of genetic studies of limb malformations.",
            "question": "Which resource contains accurate enhancer predictions in the developing limb?",
            "answers": {
                "answer_start": 536,
                "text": "Limb-Enhancer Genie (LEG)"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 250,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 243,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Immunodetection of human double homeobox 4. Double homeobox 4 (DUX4) is a candidate disease gene for facioscapulohumeral dystrophy (FSHD), one of the most common muscular dystrophies characterized by progressive skeletal muscle degeneration. Despite great strides in understanding precise genetics of FSHD, the molecular pathophysiology of the disease remains unclear. One of the major limitations has been the availability of appropriate molecular tools to study DUX4 protein. In the present study, we report the development of five new monoclonal antibodies targeted against the N- and C-termini of human DUX4, and characterize their reactivity using Western blot and immunofluorescence staining. Additionally, we show that expression of the canonical full coding DUX4 induces cell death in human primary muscle cells, whereas the expression of a shorter splice form of DUX4 results in no such toxicity. Immunostaining with these new antibodies reveals a differential effect of two DUX4 isoforms on human muscle cells. These antibodies will provide an excellent tool for investigating the role of DUX4 in FSHD pathogenesis.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 132,
                "text": "FSHD"
            }
        },
        {
            "context": "Antiviral activity of benzimidazole derivatives. I. Antiviral activity of 1-substituted-2-[(benzotriazol-1/2-yl)methyl]benzimidazoles. Forty-three 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles, bearing either linear (dialkylamino)alkyl- or bulkier (quinolizidin-1-yl)alkyl moieties at position 1, were evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representative of two of the three genera of the Flaviviridae family, i.e. Flaviviruses (Yellow Fever Virus (YFV)) and Pestiviruses (Bovine Viral Diarrhoea Virus (BVDV)), as Hepaciviruses can hardly be used in routine cell-based assays. Compounds were also tested against representatives of other virus families. Among ssRNA+ viruses were a retrovirus (Human Immunodeficiency Virus type 1 (HIV-1)), two picornaviruses (Coxsackie Virus type B2 (CVB2), and Poliovirus type-1, Sabin strain (Sb-1)); among ssRNA- viruses were a Paramyxoviridae (Respiratory Syncytial Virus (RSV)) and a Rhabdoviridae (Vesicular Stomatitis Virus (VSV)) representative. Among double-stranded RNA (dsRNA) viruses was a Reoviridae representative (Reo-1). Two representatives of DNA virus families were also included: Herpes Simplex type 1, (HSV-1; Herpesviridae) and Vaccinia Virus (VV; Poxviridae). Most compounds exhibited potent activity against RSV, with EC(50) values as low as 20 nM. Moreover, some compounds, in particular when bearing a (quinolizidin-1-yl)alkyl residue, were also moderately active against BVDV, YFV, and CVB2.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 141,
                "text": "three"
            }
        },
        {
            "context": "Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received > 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade > 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade > 3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 1473,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Neurofibromatosis type 1 (NF1) is a common familial tumour syndrome with multiple clinical features such as neurofibromas, café-au-lait spots (CLS), iris Lisch nodules, axillary freckling, optic glioma, specific bone lesions and an increased risk of malignant tumours. It is caused by a wide spectrum of mutations affecting the NF1 gene. Most mutations result in the loss of one allele at the DNA, mRNA or protein level and thus in the loss of any function of the gene product neurofibromin. The idea of the simultaneous loss of several different neurofibromin functions has been postulated to explain the pleiotropic effects of its loss. However, we have identified a novel missense mutation in a family with a classical multi-symptomatic NF1 phenotype, including a malignant schwannoma, that specifically abolishes the Ras-GTPase-activating function of neurofibromin. In this family, Arg1276 had mutated into proline. Based on complex biochemical studies as well as the analysis of the crystal structure of the GTPase-activating protein (GAP) domain of p120GAP in the presence of Ras, we unequivocally identified this amino acid as the arginine finger of the neurofibromin GAP-related domain (GRD)-the most essential catalytic element for RasGAP activity. Here, we present data demonstrating that the mutation R1276P, unlike previously reported missense mutations of the GRD region, does not impair the secondary and tertiary protein structure. It neither reduces the level of cellular neurofibromin nor influences its binding to Ras substantially, but it does completely disable GAP activity. Our findings provide direct evidence that failure of neurofibromin GAP activity is the critical element of NF1 pathogenesis. Thus, therapeutic approaches aimed at the reduction of Ras.GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 109,
                "text": "NF1"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1076,
                "text": "IL-1β"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1339,
                "text": "xa"
            }
        },
        {
            "context": "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy. RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase. SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1335,
                "text": "xa"
            }
        },
        {
            "context": "MR enterography of small-bowel lymphoma: potential for suggestion of histologic subtype and the presence of underlying celiac disease. OBJECTIVE: The objective of our study was to evaluate the morphologic appearances of small-bowel lymphoma using MR enterography to identify key morphologic traits capable of providing an association between imaging manifestations and likely histologic diagnosis. MATERIALS AND METHODS: Over a 54-month period, 10 patients with subsequently confirmed small-bowel lymphoma were imaged using a standardized MR enterography technique. Retrospective chart review was performed to detect associated disease processes, such as celiac disease. The morphologic characteristics of each segment with lymphomatous involvement were evaluated with respect to tumor location, tumor size, mural characteristics, fold features, loop dilatation, luminal stricturing, mesenteric or antimesenteric distribution, mesenteric involvement, and signal intensity. RESULTS: Nineteen distinct segments of lymphomatous involvement were identified in 10 patients, and underlying celiac disease was confirmed in six of the 10 patients. This patient group comprised 10 patients with non-Hodgkin's lymphoma (NHL) of various subtypes. No cases of Hodgkin's lymphoma were encountered. Analysis revealed celiac NHL enteropathy to have a tendency toward localization to a single, long (> 10 cm), smooth continuous bowel segment, often with aneurysmal loop dilatation, in the absence of a distinct mesenteric or antimesenteric distribution. Luminal stricturing was encountered in cases of low-grade lymphoma, whereas mesenteric fat infiltration represented a characteristic of high-grade disease. CONCLUSION: We describe the characteristics of small-bowel lymphoma on MR enterography, identifying a number of key features that may help the interpreting radiologist in suggesting the underlying histologic subtype and whether the presence of underlying celiac disease is likely.",
            "question": "What disease is small bowel lymphoma commonly associated with",
            "answers": {
                "answer_start": 1949,
                "text": "celiac disease"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1014,
                "text": "MARS"
            }
        },
        {
            "context": "The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights. Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) and exert agonist or antagonist effects on ERs in a tissue-specific manner. Tamoxifen, a first generation SERM, is used for treatment of ER positive breast cancer. Raloxifene, a second generation SERM, was used to prevent postmenopausal osteoporosis. The third-generation SERM bazedoxifene (BZA) effectively prevents osteoporosis while preventing estrogenic stimulation of breast and uterus. Notably, BZA combined with conjugated estrogens (CE) is a new menopausal treatment. The menopausal state predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs on metabolic homeostasis are gaining attention. Here, we summarize knowledge of SERMs' impacts on metabolic, homeostasis, obesity and diabetes in rodent models and postmenopausal women.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 117,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Zika virus emergence in mosquitoes in southeastern Senegal, 2011. BACKGROUND: Zika virus (ZIKV; genus Flavivirus, family Flaviviridae) is maintained in a zoonotic cycle between arboreal Aedes spp. mosquitoes and nonhuman primates in African and Asian forests. Spillover into humans has been documented in both regions and the virus is currently responsible for a large outbreak in French Polynesia. ZIKV amplifications are frequent in southeastern Senegal but little is known about their seasonal and spatial dynamics. The aim of this paper is to describe the spatio-temporal patterns of the 2011 ZIKV amplification in southeastern Senegal. METHODOLOGY/FINDINGS: Mosquitoes were collected monthly from April to December 2011 except during July. Each evening from 18:00 to 21:00 hrs landing collections were performed by teams of 3 persons working simultaneously in forest (canopy and ground), savannah, agriculture, village (indoor and outdoor) and barren land cover sites. Mosquitoes were tested for virus infection by virus isolation and RT-PCR. ZIKV was detected in 31 of the 1,700 mosquito pools (11,247 mosquitoes) tested: Ae. furcifer (5), Ae. luteocephalus (5), Ae. africanus (5), Ae. vittatus (3), Ae. taylori, Ae. dalzieli, Ae. hirsutus and Ae. metallicus (2 each) and Ae. aegypti, Ae. unilinaetus, Ma. uniformis, Cx. perfuscus and An. coustani (1 pool each) collected in June (3), September (10), October (11), November (6) and December (1). ZIKV was detected from mosquitoes collected in all land cover classes except indoor locations within villages. The virus was detected in only one of the ten villages investigated. CONCLUSIONS/SIGNIFICANCE: This ZIKV amplification was widespread in the Kédougou area, involved several mosquito species as probable vectors, and encompassed all investigated land cover classes except indoor locations within villages. Aedes furcifer males and Aedes vittatus were found infected within a village, thus these species are probably involved in the transmission of Zika virus to humans in this environment.",
            "question": "To which family does the Zika virus belong?",
            "answers": {
                "answer_start": 121,
                "text": "Flaviviridae"
            }
        },
        {
            "context": "Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Dementia with Lewy bodies (DLB) is characterized by the widespread presence of Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is expressed as two main isoforms (112 and 140), but little is known about their differential expression in the brain. We compared alpha-synuclein 112 and alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB patients, eight Alzheimer disease (AD) patients, and six control subjects. Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were determined by real-time polymerase chain reaction with competimer technology using a LightCycler System. Whereas total alpha-synuclein levels were just marginally elevated in DLB in comparison with the other groups, alpha-synuclein 112 was seen to be markedly increased in DLB compared with AD cases and controls. In contrast, alpha-synuclein 140 levels were significantly diminished in both neurodegenerative disorders in comparison with controls. These results show differential overexpression of alpha-synuclein 112 in DLB, a finding that could be of importance in DLB pathogenesis.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 193,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "ddm1 plants are sensitive to methyl methane sulfonate and NaCl stresses and are deficient in DNA repair. UNLABELLED: Plant response to stress includes changes in gene expression and chromatin structure. Our previous work showed that Arabidopsis thaliana Dicer-like (DCL) mutants were impaired in transgenerational response to stress that included an increase in recombination frequency, cytosine methylation and stress tolerance. It can be hypothesized that changes in chromatin structure are important for an efficient stress response. To test this hypothesis, we analyzed the stress response of ddm1, a mutant impaired in DDM1, a member of the SWI/SNF family of adenosine triphosphate-dependent chromatin remodeling genes. We exposed Arabidopsis thaliana ddm1 mutants to methyl methane sulfonate (MMS) and NaCl and found that these plants were more sensitive. At the same time, ddm1 plants were similar to wild-type plants in sensitivity to temperature and bleomycin stresses. Direct comparison to met1 plants, deficient in maintenance methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl. The level of DNA strand breaks upon exposure to MMS increased in wild-type plants but decreased in ddm1 plants. DNA methylation analysis showed that heterozygous ddm1/DDM1 plants had lower methylation as compared to fourth generation of homozygous ddm1/ddm1 plants. Exposure to MMS resulted in a decrease in methylation in wild-type plants and an increase in ddm1 plants. Finally, in vitro DNA excision repair assay showed lower capacity for ddm1 mutant. Our results provided a new example of a link between genetic genome stability and epigenetic genome stability. KEY MESSAGE: We demonstrate that heterozygous ddm1/DDM1 plants are more sensitive to stress and have more severe changes in methylation than homozygous ddm1/ddm1 plants.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1056,
                "text": "MET1"
            }
        },
        {
            "context": "Contribution of gut bacteria to the metabolism of the spleen tyrosine kinase (Syk) inhibitor R406 in cynomolgus monkey. The spleen tyrosine kinase (Syk) inhibitor R406 is orally administered as the prodrug R788. Following administration of R788 (12.5 mg kg(-1), 20 microCi kg(-1 14)C-R788) to intact and bile duct-cannulated cynomolgus monkeys, drug-related radioactivity was rapidly observed in plasma. No R788 was observed in plasma, while R406 was the major radioactive peak observed at all time points. Only low levels of metabolites were observed in plasma. The half-life for plasma radioactivity was 2.0-2.8 h. The majority (68.9%) of drug-related radioactivity was eliminated into bile. No intact R406 was observed in excreta. Biliary and urinary metabolites consisted of glucuronide and sulfate conjugates of the para-O-demethylated metabolite of R406 (R529), and a direct N-glucuronide of R406. The major metabolite in faeces from intact and bile duct-cannulated monkeys was a unique 3,5-benzene diol metabolite of R406. This metabolite was formed following the sequential O-demethylation and para-dehydroxylation of R529 by anaerobic gut bacteria.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 124,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Perisigmoid Abscess Leading to a Diagnosis of Ehlers-Danlos Syndrome Type IV. The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. Ehlers-Danlos syndrome type IV places patients at risk for life-threatening, spontaneous, vascular or visceral rupture due to reduced or abnormal secretion of type III collagen. We present an adolescent male who was found to have a perisigmoid abscess with a fistula connecting to adjacent sigmoid colon secondary to undiagnosed EDS type IV. Conservative management with antibiotics and bowel rest was pursued to allow for elective resection for his acute complicated diverticulitis at a safer time.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 127,
                "text": "connective tissue"
            }
        },
        {
            "context": "Distinctive patterns of memory function in subgroups of females with Turner syndrome: evidence for imprinted loci on the X-chromosome affecting neurodevelopment. X-monosomy is a form of Turner syndrome (TS) in which an entire X chromosome is missing. It is usually assumed that neuropsychological deficits in females with TS result from insufficient dosage of gene products from alleles on the sex chromosomes. If so, then parental origin of the single X chromosome should be immaterial. However, if there are imprinted genes on the X chromosome affecting brain development, neuropsychological development will depend on the parental origin of the single X chromosome. We contrasted verbal and visuospatial memory in females with a single paternal X chromosome (45,X(p)) and those with a single maternal X (45,X(m)). Neither group showed any impairment on immediate story recall; if anything, performance was above control levels. Groups did not differ on a measure of delayed recall. However, when delayed recall was considered after adjusting for level of immediate recall, 45,X(m) females showed enhanced verbal forgetting relative to controls over a delay. On the Rey figure, both groups were poor at copying the figure, but, after adjusting scores for initial copy score and strategy, only the 45,X(p) females showed disproportionate forgetting relative to controls. We propose there may be one or more imprinted genes on the X chromosome that affect the development of lateralised brain regions important for memory function.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 226,
                "text": "X"
            }
        },
        {
            "context": "NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 235,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Delayed cell cycle progression from SEPW1 depletion is p53- and p21-dependent in MCF-7 breast cancer cells. Selenium (Se) is an essential redox-active trace element with close connections to cancer. Most of Se's biological functions have been attributed to the antioxidant properties of Se-containing proteins. However, the relative contribution of selenoproteins and small Se compounds in cancer protection is still a matter of debate. The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the \"guardian of the genome\". In response to genomic stresses, p53 causes cell cycle arrest to allow time for genomic damage to be repaired before cell division or induces apoptosis to eliminate irreparably damaged cells. Selenoprotein W (SEPW1) is a highly conserved small thioredoxin-like protein required for cell cycle progression. The present work shows that SEPW1 facilitates the G1 to S-phase transition by down-regulating expression of the cyclin-dependent kinase inhibitor p21. SEPW1 controls p21 by modulating levels of the p53 transcription factor, and this is associated with changes in phosphorylation of Ser-33 in p53. More work is needed to identify the mechanism by which SEPW1 regulates phosphorylation of Ser-33 and the kinase or phosphatase enzymes involved.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 458,
                "text": "p53"
            }
        },
        {
            "context": "Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus. Mouse microphthalmia transcription factor (Mitf) mutations affect the development of four cell types: melanocytes, mast cells, osteoclasts, and pigmented epithelial cells of the eye. The mutations are phenotypically diverse and can be arranged in an allelic series. In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. Mitf mice thus represent an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcriptionally complex and is capable of generating at least 13 different Mitf isoforms. Some of these isoforms are missing important functional domains of the protein, suggesting that they might play an inhibitory role in Mitf function and signal transduction. In addition, we determined the molecular basis for six microphthalmia mutations. Two of the mutations are reported for the first time here (Mitf(mi-enu198) and Mitf(mi-x39)), while the others (Mitf(mi-ws), Mitf(mi-bws), Mitf(mi-ew), and Mitf(mi-di)) have been described but the molecular basis for the mutation not determined. When analyzed in terms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects. Interestingly, three of the mutations (Mitf(mi-x39), Mitf(mi-bws), and Mitf(mi-ws)) produce proteins that are missing important functional domains of the protein identified in in vitro studies, further confirming a biological role for these domains in the whole animal.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 361,
                "text": "MITF"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2246,
                "text": "stroke"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 2116,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease. PURPOSE: The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together. METHODS: This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16. RESULTS: Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR. CONCLUSION: The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1142,
                "text": "RET"
            }
        },
        {
            "context": "Anti-TNFα treatment for recalcitrant ulcerative necrobiosis lipoidica diabeticorum: A case report and review of the literature. INTRODUCTION: Necrobiosis lipoidica diabeticorum (NLD) is a rare degenerative connective tissue disorder associated with diabetes mellitus, which usually presents with red papules or plaques with raised edges and occasional ulceration. Ulcerating NLD is notoriously difficult to treat. We present a young patient with ulcerative NLD who was successfully treated with the anti-TNFα agent infliximab. Case presentation is followed by a review of therapeutic TNFα blockade in NLD. CASE PRESENTATION: A 17-year old woman with type 1 diabetes since the age of 8, presented with a long-standing and extensively ulcerated and infected NLD lesion on her left shin. After achieving better glycemic control and treating her for infection of the wound, several NLD treatments failed to help, including corticosteroids and hyperbaric oxygen. She was treated successfully with 4 monthly sessions of 5mg/kg body weight intravenous infliximab, achieving complete resolution of ulceration. DISCUSSION: A multitude of available treatments have been suggested for NLD over the past decades, based on two axes, one through wound healing and the other through immunosuppression. Anti-TNFα agents are relatively new drugs that brought a revolution in chronic inflammatory diseases and have been on the rise as novel potential treatments for NLD. Three out of the five available anti-TNFα agents have been safely tested so far, both topically and systematically, with mostly favorable results. CONCLUSION: Intravenous infliximab was successful in the treatment of recalcitrant ulcerating NLD in our patient. Taken together with an increasing number of similar reports revealing a pathogenetic role of TNFα in NLD, we suggest that anti-TNFα agents are promising drugs in the management of this condition.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 249,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Characterization of neural stem/progenitor cells expressing VEGF and its receptors in the subventricular zone of newborn piglet brain. Neural stem/progenitor cell (NSP) biology and neurogenesis in adult central nervous system (CNS) are important both towards potential future therapeutic applications for CNS repair, and for the fundamental function of the CNS. In the present study, we report the characterization of NSP population from subventricular zone (SVZ) of neonatal piglet brain using in vivo and in vitro systems. We show that the nestin and vimentin-positive neural progenitor cells are present in the SVZ of the lateral ventricles of neonatal piglet brain. In vitro, piglet NSPs proliferated as neurospheres, expressed the typical protein of neural progenitors, nestin and a range of well-established neurodevelopmental markers. Upon dissociation and subculture, piglet NSPs differentiated into neurons and glial cells. Clonal analysis demonstrates that piglet NSPs are multipotent and retain the capacity to generate both glia and neurons. These cells expressed VEGF, VEGFR1, VEGFR2 and Neuropilin-1 and -2 mRNAs. Real time PCR revealed that SVZ NSPs from newborn piglet expressed total VEGF and all VEGF splice variants. These findings show that piglet NSPs may be helpful to more effectively design growth factor based strategies to enhance endogenous precursor cells for cell transplantation studies potentially leading to the application of this strategy in the nervous system disease and injury.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 775,
                "text": "nestin"
            }
        },
        {
            "context": "A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. STUDY OBJECTIVE: To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated. SETTING: Sixteen emergency departments in the United States. POPULATION: Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose. INTERVENTIONS: Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered. MEASUREMENTS AND MAIN RESULTS: Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ. CONCLUSION: Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 2579,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma. Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro. We evaluated the safety, pharmacokinetics, immunogenicity, and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. This open-label, phase 1, dose-escalating study used two doses of siltuximab: 5.5 and 11.0 mg/kg (administered on day 1 of each 21-day cycle). In total, nine patients were treated. The most common grade 3/4 adverse events, lymphopenia (89 %) and thrombocytopenia (44 %), occurred in patients receiving both doses of siltuximab; however, no dose-limiting toxicities (DLTs) were observed. Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg, the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner. Mean half-life, total systemic clearance, and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg. Across both doses, six of the nine patients had complete or partial response (22 and 44 %, respectively). In conclusion, as no DLT was observed, the recommended dose for this combination is 11.0 mg/kg once every 3 weeks. The study is registered at http://www.clinicaltrials.gov as NCT01309412.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 195,
                "text": "interleukin-6"
            }
        },
        {
            "context": "[Regulation of melanogenesis: the role of cAMP and MITF]. The article presents the melanogenesis pathway and the role of cyclic adenosine monophosphate (cAMP) and microphthalmia transcription factor (MITF) in regulation of this process. Products of melanogenesis are eu- and/or pheomelanins synthesized in a multistage process of tyrosine oxidation and polymerization. The conversions require the presence of tyrosinase (TYR, key enzyme), tyrosine hydroxylase isoform I (THI) and tyrosinase related proteins (TRP1 and TRP2). Many types of signal molecules and transcription factors participate in regulation of melanin synthesis, but the most important are cAMP and MITF. cAMP is the second messenger in the intracellular signal cascade, which is synthesized from adenosine triphosphate (ATP) by adenylyl cyclase, activated among others by the melanocortin receptor and the αS subunit of G protein. The signal molecule cAMP regulates MITF, TYR, THI, GTP-cyclohydroxylase I (GTP-CHI) transcription and phenylalanine hydroxylase (PAH) phosphorylation at Ser16 by protein kinase A (PKA). Mutations of genes encoding proteins belonging to the cAMP signal cascade may lead to McCune-Albright and Carney syndromes. MITF is one of the most important nuclear transcription factors regulating melanogenesis. Currently 10 isoforms of human MITF are known, but in melanocytes only MITF-M, MITF-Mdel, MITF-A and MITF-H occur. MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. It also affects expression of other factors regulating melanosome maturation, biogenesis and transport. Moreover, it regulates melanocyte proliferation and protection against apoptosis. Mutations of the MITF gene may lead to hereditary diseases: Waardenburg type II and Tietz syndromes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1725,
                "text": "MITF"
            }
        },
        {
            "context": "Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 380,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 1079,
                "text": "CisMapper"
            }
        },
        {
            "context": "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling. We identified the mitochondrial processing peptidase beta (MPPbeta) as a frataxin protein partner using the yeast two-hybrid assay. In in vitro assays, MPPbeta binds frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41-210) that is processed further to the mature form. In vitro and in vivo experiments suggest that two C-terminal missense mutations found in FRDA patients modulate interaction with MPPbeta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 88,
                "text": "Frataxin"
            }
        },
        {
            "context": "Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression. The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ~50%; p<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (p<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer > 1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 115,
                "text": "SERCA"
            }
        },
        {
            "context": "Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels. Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. They are multi-domain proteins, containing primarily calcium binding epidermal growth factor-like (cbEGF) domains and 8-cysteine/transforming growth factor-beta binding protein-like (TB) domains. Mutations in the fibrillin-1 gene give rise to Marfan syndrome, a connective tissue disorder with clinical complications in the cardiovascular, skeletal, ocular and other organ systems. Here, we review the consequences of engineered Marfan syndrome mutations in fibrillin-1 at the protein, cellular and organismal levels. Representative point mutations associated with Marfan syndrome in affected individuals have been introduced and analyzed in recombinant fibrillin-1 fragments. Those mutations affect fibrillin-1 on a structural and functional level. Mutations which impair folding of cbEGF domains can affect protein trafficking. Protein folding disrupted by some mutations can lead to defective secretion in mutant fibrillin-1 fragments, whereas fragments with other Marfan mutations are secreted normally. Many Marfan mutations render fibrillin-1 more susceptible to proteolysis. There is also evidence that some mutations affect heparin binding. Few mutations have been further analyzed in mouse models. An extensively studied mouse model of Marfan syndrome expresses mouse fibrillin-1 with a missense mutation (p.C1039G). The mice display similar characteristics to human patients with Marfan syndrome. Overall, the analyses of engineered mutations leading to Marfan syndrome provide important insights into the pathogenic molecular mechanisms exerted by mutated fibrillin-1.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 493,
                "text": "connective tissue"
            }
        },
        {
            "context": "Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. Hydrogen sulfide (H₂S), a gasotransmitter, facilitates pain sensation by targeting Ca(v)3.2 T-type calcium channels. The H₂S/Ca(v)3.2 pathway appears to play a role in the maintenance of surgically evoked neuropathic pain. Given evidence that chemotherapy-induced neuropathic pain is blocked by ethosuximide, known to block T-type calcium channels, we examined if more selective T-type calcium channel blockers and also inhibitors of cystathionine-γ-lyase (CSE), a major H₂S-forming enzyme in the peripheral tissue, are capable of reversing the neuropathic pain evoked by paclitaxel, an anti-cancer drug. It was first demonstrated that T-type calcium channel blockers, NNC 55-0396, known to inhibit Ca(v)3.1, and mibefradil inhibited T-type currents in Ca(v)3.2-transfected HEK293 cells. Repeated systemic administration of paclitaxel caused delayed development of mechanical hyperalgesia, which was reversed by single intraplantar administration of NNC 55-0396 or mibefradil, and by silencing of Ca(v)3.2 by antisense oligodeoxynucleotides. Systemic administration of dl-propargylglycine and β-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Ca(v)3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H(2)S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Ca(v)3.2, and then suggests that paclitaxel-evoked neuropathic pain might involve the enhanced activity of T-type calcium channels and/or CSE in rats, but not upregulation of Ca(v)3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Ca(v)3.2 was dramatically upregulated in DRG.",
            "question": "Which calcium channels does ethosuximide target?",
            "answers": {
                "answer_start": 459,
                "text": "T-type calcium channels"
            }
        },
        {
            "context": "The ring plus project: safety and acceptability of vaginal rings that protect women from unintended pregnancy. BACKGROUND: Research is ongoing to develop multipurpose vaginal rings to be used continuously for contraception and to prevent Human Immunodeficiency Virus (HIV) infection. Contraceptive vaginal rings (CVRs) are available in a number of countries and are most of the time used intermittently i.e. three weeks out of a 4-week cycle. Efficacy trials with a dapivirine-containing vaginal ring for HIV prevention are ongoing and plans to develop multi-purpose vaginal rings for prevention of both HIV and pregnancy have been elaborated. In contrast with the CVRs, multi-purpose vaginal rings will have to be used continuously. Women who continuously use a CVR will no longer have menses. Furthermore, some safety aspects of CVR use have never been studied in-depth in the past, such as the impact of the vaginal ring on the vaginal microbiota, biofilm formation and induction of inflammation. We studied acceptability and these novel aspects of safety in Rwandan women. Although significant progress has been made over the past decade, Rwanda still has a high unmet need for contraception (with 47% unplanned births) and a generalized HIV epidemic, and CVRs are not yet available. METHODS: We will conduct an open label, single centre, randomized controlled trial. A total of 120 HIV-negative women will be randomized to intermittent CVR use (to allow menstruation) or continuous CVR use. Women will be followed for a maximum of 14 weeks. In parallel, we will conduct a qualitative study using in-depth interview and focus group discussion methodology. DISCUSSION: In addition to evaluating the safety and acceptability of intermittent and continuous CVR use in Rwandan women, we hope that our findings will inform the development of future multipurpose vaginal rings, will prepare Rwandan study populations for future clinical trials of multipurpose vaginal rings, and will pave the way for introduction of CVRs on African markets. TRIAL REGISTRATION: Clinicaltrials.gov NCT01796613 . Registered 14 February 2013.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 604,
                "text": "HIV"
            }
        },
        {
            "context": "Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 179,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 397,
                "text": "tyr"
            }
        },
        {
            "context": "Induction of hemeoxygenase-1 expression after inhibition of hemeoxygenase activity promotes inflammation and worsens ischemic brain damage in mice. Hemeoxygenase (HO) is an enzymatic system that degrades heme. HO-1 is an inducible isoform whereas HO-2 is constitutive. Stroke strongly induces HO-1 expression but the underlying mechanisms are not fully elucidated. Cytokines that are up-regulated after ischemia, like interleukin (IL)-10, can induce HO-1 gene expression, which is positively regulated by the transcriptional activator nuclear factor erythroid 2-related factor 2 (Nrf2) and negatively regulated by the transcriptional repressor breast cancer type 1 susceptibility protein (BRCA1) associated C-terminal helicase 1 (Bach-1). While Nrf2 is activated after ischemia and drugs promoting Nrf2 activation increase HO-1 and are beneficial, the involvement of Bach-1 is unknown. Here we investigated mechanisms involved in HO-1 induction and evaluated the effects of HO activity inhibition in mouse permanent middle cerebral artery occlusion (pMCAO). HO-1 was induced after ischemia in IL-10-deficient mice suggesting that post-ischemic HO-1 induction was IL-10-independent. Attenuation of Bach-1 gene repression after ischemia was associated to enhanced HO-1 induction. Administration of the HO activity inhibitor zinc proto-porphyrin IX (ZnPP) i.p. 24h before pMCAO exacerbated ischemia-induced tumor necrosis factor-α (TNF-α) and IL-1β, nitro-oxidative stress, and the presence of neutrophils at 8h, and increased infarct volume at day 4. However, ZnPP did not worsen ischemic damage when given 30min before pMCAO. ZnPP induced HO-1 expression in the cerebral vasculature at 24h, when it was still detected by high-performance liquid chromatography (HPLC) in plasma. While ZnPP was not found in brain tissue extracts of controls, it could be detected after ischemia, supporting that a small fraction of the injected drug can reach the tissue following blood-brain barrier breakdown. The deleterious effect of inhibiting HO activity in ischemia became apparent in the presence of ZnPP-induced HO-1, which is known to exert effects independent of its enzymatic activity. In conclusion, HO-1 induction after ischemia was associated to down-regulation of transcriptional repressor Bach-1, and induction of HO-1 when HO enzymatic activity was inhibited was related to worst outcome after brain ischemia.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 2277,
                "text": "repressor"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1491,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Necrobiosis lipoidica and diabetic control revisited. Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 146,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "A review of sudden unexpected death in epilepsy: prediction of patients at risk. This review attempts to provide up-to-date quantitative data from published reports on sudden unexpected death in epilepsy (SUDEP) appearing on Medline and, especially, to provide a means to predict the probability of SUDEP in a given patient. The mean incidence of SUDEP was 1.8/1000, similar to the median of 1.5. The mean standardized mortality ratio was 6.8, and the mean percentage of SUDEP cases among deaths from epilepsy was 16.6. Seventeen risk factors were identified, each given a value according to the number of studies in the literature that specified that condition as a significant risk. The addition of these 17 values then indicated the risk for a given patient. The author calculated these for a group of 91 patients who died of SUDEP and also for 91 live patients. Many of their values for the different risks were significantly different. The sensitivity of these SUDEP values was 71.3%, the specificity 81.8%, and the positive predictive value 84.6%. A discussion includes the question of whether the death in SUDEP is primarily cardiac or pulmonary and the suggestion that it may be either or both in a given patient. The most important risk factor in this study was noncompliance with antiepileptic medication, and the main message of this study to caregivers is that therapeutic drug levels are crucial to avoid SUDEP.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 168,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 413,
                "text": "Xa"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 398,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Host-preferential Fusarium graminearum gene expression during infection of wheat, barley, and maize. Fusarium graminearum is a broad host pathogen threatening cereal crops in temperate regions around the world. To better understand how F. graminearum adapts to different hosts, we have performed a comparison of the transcriptome of a single strain of F. graminearum during early infection (up to 4 d post-inoculation) of barley, maize, and wheat using custom oligomer microarrays. Our results showed high similarity between F. graminearum transcriptomes in infected wheat and barley spike tissues. Quantitative RT-PCR was used to validate the gene expression profiles of 24 genes. Host-specific expression of genes was observed in each of the three hosts. This included expression of distinct sets of genes associated with transport and secondary metabolism in each of the three crops, as well as host-specific patterns for particular gene categories such as sugar transporters, integral membrane protein PTH11-like proteins, and chitinases. This study identified 69 F. graminearum genes as preferentially expressed in developing maize kernels relative to wheat and barley spikes. These host-specific differences showcase the genomic flexibility of F. graminearum to adapt to a range of hosts.",
            "question": "The pathogen Fusarium graminearum affects what type of plant species?",
            "answers": {
                "answer_start": 159,
                "text": "cereal crops"
            }
        },
        {
            "context": "Hereditary conjugated hyperbilirubinaemia: 37 years later. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 636,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Diagnosis of pneumoperitoneum on supine abdominal radiographs. A blinded, retrospective study was performed to determine the value of supine abdominal radiographs in diagnosing pneumoperitoneum. Supine films from 44 cases of pneumoperitoneum were randomly interspersed among supine films from 87 control subjects without free air, and the films were reviewed for the presence or absence of various signs of pneumoperitoneum, including Rigler's sign (gas on both sides of the bowel wall), the falciform ligament sign (gas outlining the falciform ligament), the football sign (gas outlining the peritoneal cavity), the inverted-V sign (gas outlining the medial umbilical folds), and the right-upper-quadrant gas sign (localized gas in the right upper quadrant). One or more of these signs were present in 26 cases (59%) of pneumoperitoneum, including the right-upper-quadrant gas sign in 18 cases (41%), Rigler's sign in 14 cases (32%), and the falciform ligament and football signs in one case each (2%). Unfortunately, there were frequent errors in the interpretation of the right-upper-quadrant gas sign and Rigler's sign, with a total of 11 false-positive cases (13%). Further analysis of the true-positive right-upper-quadrant gas signs showed that these gas collections were always triangular or linear with an inferolateral to superomedial orientation and, if triangular, a concave superolateral border. In the true-positive Rigler's signs, the bowel wall thickness ranged from 1 to 8 mm, whereas the false positives all had a bowel wall thickness of 1 mm or less. Proper interpretation of the various signs of pneumoperitoneum on supine films should lead to more accurate diagnosis of this condition.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 225,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "Sustained pain freedom and no adverse events as an endpoint in clinical trials of acute migraine treatments: application to patient-level data from a trial of the CGRP receptor antagonist, telcagepant, and zolmitriptan. BACKGROUND: Endpoints used to evaluate the efficacy of acute anti-migraine drugs do not measure the tolerability. Sustained pain-free response with no adverse events has been recommended as a composite endpoint which measures the efficacy and tolerability attributes that patients desire. METHODS: The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, and zolmitriptan in the acute treatment of migraine. Endpoints were 2-24-hour sustained pain freedom and no adverse events from 0-24 hours (SPF24NAE), 2-24 hour sustained pain relief and no adverse events from 0-24 hours (SPR24NAE), pain freedom at 2 hours and no adverse events from 0-24 hours (PF2NAE), and pain relief at 2 hours and no adverse events from 0-24 hours (PR2NAE). RESULTS: Compared with placebo, both telcagepant 300 mg and 150 mg achieved nominal superiority (p values <.05) for SPF24NAE, SPR24NAE, PF2NAE and PR2NAE. Zolmitriptan 5 mg showed nominal superiority versus placebo for SPF24NAE, SPR24NAE and PF2NAE, but not PR2NAE. Telcagepant 300 mg showed nominal superiority versus zolmitriptan for SPF24NAE, SPR24NA and PR2NAE. CONCLUSION: Composite efficacy-plus-tolerability endpoints may be useful for facilitating comparisons between treatments.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 718,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Molecular cloning and expression of alfalfa (Medicago sativa L.) vestitone reductase, the penultimate enzyme in medicarpin biosynthesis. Medicarpin, the major phytoalexin in alfalfa, is synthesized by way of the isoflavonoid branch of phenylpropanoid metabolism. One of the final steps of medicarpin biosynthesis, from vestitone to 7,2'-dihydroxy-4'-methoxyisoflavanol, is catalyzed by vestitone reductase. A 1245-bp cDNA clone which encodes vestitone reductase was identified utilizing internal amino acid sequence of purified vestitone reductase. When expressed in Escherichia coli, the cloned enzyme exhibits strict substrate stereospecificity for (3R)-vestitone, as was observed for vestitone reductase purified from alfalfa. The calculated molecular weight of the protein (35,918) is similar to that of purified vestitone reductase from alfalfa (38 kDa by SDS-PAGE). The levels of vestitone reductase transcript (1.35 kb) greatly increase within 2 h of elicitor addition to alfalfa cell suspension cultures, preceding the rapid increases in vestitione reductase enzyme activity and medicarpin biosynthesis. In healthy alfalfa plants, the highest levels of transcripts were detected in roots and root nodules, consistent with the synthesis of medicarpin and its conjugate in these tissues. The cloning of the vestitone reductase gene provides a specific tool for the study and manipulation of pterocarpan biosynthesis in legumes.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 137,
                "text": "Medicarpin"
            }
        },
        {
            "context": "Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development. BACKGROUND: zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies. MATERIALS AND METHODS: We identified a patient with Mowat-Wilson syndrome who also developed cholestasis and histopathologic features consistent with biliary atresia, suggesting that mutations involving zfhz1b may lead to biliary developmental anomalies or injury to the biliary tract. We used the zebrafish model system to determine whether zfhx1b has a role in vertebrate biliary development. RESULTS: Using zebrafish we determined that zfhx1b was expressed in the developing liver during biliary growth and remodeling, and that morpholino antisense oligonucleotide-mediated knockdown of zfhx1b led to defects in biliary development. These findings were associated with decreased expression of vhnf1, a transcription factor known to be important in biliary development in zebrafish and in mammals. CONCLUSIONS: Our studies underscore the importance of genetic contributions in the etiology of infantile hepatobiliary disorders, including biliary atresia.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 120,
                "text": "zfhx1b"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 976,
                "text": "Xa"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 239,
                "text": "TYR"
            }
        },
        {
            "context": "SOX2 anophthalmia syndrome and dental anomalies. SOX2 anophthalmia syndrome is an uncommon autosomal dominant syndrome caused by mutations in the SOX2 gene and clinically characterized by severe eye malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly involving brain, esophagus, and genitalia. In this work, a patient with the SOX2 anophthalmia syndrome and exhibiting a novel dental anomaly is described. SOX2 genotyping in this patient revealed an apparently de novo c.70del20 deletion, a commonly reported SOX2 mutation. A review of the phenotypic variation observed in patients carrying the recurrent SOX2 c.70del20 mutation is presented. Although dental anomalies are uncommonly reported in the SOX2 anophthalmia syndrome, we suggest that a dental examination should be performed in patients with SOX2 mutations.",
            "question": "Which disease is associated with mutated Sox2?",
            "answers": {
                "answer_start": 49,
                "text": "SOX2 anophthalmia syndrome"
            }
        },
        {
            "context": "Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 315,
                "text": "FBN1"
            }
        },
        {
            "context": "The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells. OBJECTIVE: Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process. METHODS: CD4+ T cells, CD14+ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump. RESULTS: Tofacitinib treatment of CD4+ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-γ (IFNγ) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14+ monocytes. However, conditioned medium from CD4+ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14+ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage. CONCLUSION: Tofacitinib directly suppressed the production of IL-17 and IFNγ and the proliferation of CD4+ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14+ cells and decreased cartilage destruction. In CD4+ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 149,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 840,
                "text": "TYR"
            }
        },
        {
            "context": "Proteomic identification of novel proteins associated with Lewy bodies. The manifestation of Lewy bodies (LB) in the brain is a hallmark of Parkinson's disease. Here, we present a comprehensive analysis of protein elements in Lewy bodies by comparative mass spectrometry. Cortical LB inclusions were enriched by sucrose gradient centrifugation from postmortem brains, and a negative control sample was prepared from specimen without LB pathology. Whereas approximately 550 proteins were identified in the LB-enriched sample by mass spectrometry, quantitative comparison with the control sample revealed that approximately 40 proteins were co-enriched with alpha-synuclein, the major component in Lewy bodies. As expected, the list of proteins included previously reported constituents, such as those involved in protein folding, membrane trafficking and oxidative stress. More interestingly, we discovered in the LB-enriched sample several kinases (MAPKK1/MEK1, protein kinase C, and doublecortin-like kinase), a novel deubiquitinating enzyme (otubain 1), and numerous ubiquitin ligases (KPC and SCF). The proteomic studies provide enzyme candidates to investigate the regulation of alpha-synuclein and/or other LB proteins, which may contribute to the formation of Lewy bodies and the toxicity of alpha-synuclein in the related neurodegenerative disorders.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 656,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Woman with x-linked recessive dystonia-parkinsonism: clue to the epidemiology of parkinsonism in Filipino women? IMPORTANCE: Despite recessive inheritance, X-linked dystonia-parkinsonism (Lubag disease) has also been described in women presenting with a late-onset isolated parkinsonian syndrome. Interestingly, unlike in other populations, there is a slight female predominance in the prevalence of parkinsonism in the Philippines. OBSERVATIONS: In a Filipino woman with suspected Parkinson disease, we confirmed the presence of all changes specific for X-linked dystonia-parkinsonism in genomic DNA. Subsequently, we analyzed complementary DNA and evaluated the methylation status of the androgen receptor gene. Owing to extremely skewed (98%:2%) X-chromosome inactivation, the patient expressed almost solely the mutated allele in a disease-specific change, rendering her molecularly comparable with a hemizygously affected man. CONCLUSIONS AND RELEVANCE: Skewed X-chromosome inactivation is the likely cause of parkinsonism in this heterozygous mutation carrier. Because women carriers of the genetic changes specific for X-linked dystonia-parkinsonism are common in the Philippines, the epigenetic factor of nonrandom X-chromosome inactivation may contribute to the skewing of the sex prevalence of parkinsonism toward women in this country, warranting further investigation.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 156,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "The anti-apoptotic protein HAX-1 is a regulator of cardiac function. The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as a regulator of contractility and calcium cycling in the heart. HAX-1 overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium kinetics and mechanics. Conversely, downregulation of HAX-1 enhanced calcium cycling and contractility. The inhibitory effects of HAX-1 were abolished upon phosphorylation of phospholamban, which plays a fundamental role in controlling basal contractility and constitutes a key downstream effector of the beta-adrenergic signaling cascade. Mechanistically, HAX-1 promoted formation of phospholamban monomers, the active/inhibitory units of the calcium pump. Indeed, ablation of PLN rescued HAX-1 inhibition of contractility in vivo. Thus, HAX-1 represents a regulatory mechanism in cardiac calcium cycling and its responses to sympathetic stimulation, implicating its importance in calcium homeostasis and cell survival.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 69,
                "text": "The HS-1 associated protein X-1"
            }
        },
        {
            "context": "[Prevention of MRSA spread in the neurosurgical field]. We investigated the distribution of MRSA (methicillin-resistant Staphylococcus aureus) on and around six patients with MRSA infection in our neurosurgical ward. All patients had a disturbance of consciousness and had sputum colonization of MRSA. Samples were obtained from 11 sites (patients' hands, attendances' hands, floors, sidetables, bedclothes, chairs, walls, curtains, door knobs, faucets and disposable gloves) in the patients' rooms by the wiping method. High counts of MRSA were detected on horizontal planes such as floors, sidetables and chairs, but MRSA was not detected on vertical planes such as curtains and walls. The reason why MRSA was detected on the horizontal planes was due to a fall of MRSA spread from sputum in the air. These findings indicate that the disinfection of horizontal planes is important for preventing the spread of MRSA. We also evaluated what disinfectant was useful for floor disinfection and concluded that 0.5% chlorhexidine digluconate (Hibitane) and 0.5% benzalkonium chloride (Osvan) were more effective than the other usually-used disinfectants such as alkyldiaminoethyl glycine (Tego-51).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 175,
                "text": "MRSA"
            }
        },
        {
            "context": "Mouse models of Machado-Joseph disease and other polyglutamine spinocerebellar ataxias. Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion. Although there is no treatment available at present to cure or delay the onset of MJD, mouse models have been generated to facilitate the development of a therapy. In this review, the published reports on mouse models of MJD and other polyglutamine spinocerebellar ataxias are compared. Based on these studies, the following approaches will be discussed as candidate treatments for MJD: 1) interfering with the formation of the mutant ataxin-3 cleavage fragment and possibly aggregate or inclusions, 2) reducing the disease protein nuclear localization, and 3) decreasing mutant ataxin-3 expression in neurons.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 181,
                "text": "ataxin-3"
            }
        },
        {
            "context": "[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. Hypo- and hyperpigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function and melanocytoses connected with melanocyte development. The article presents some hereditary hypomelanocytoses, which are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations. It has been demonstrated that mutations of the same gene may cause different hypopigmentation syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome. It has also been demonstrated that mutations of different genes may cause an identical syndrome. For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. In turn, mutation of the KIT gene and/or heterozygous deletion of the SNAI2 gene result in piebaldism disease. The knowledge of the exact mechanisms of pigmentary disorders may be useful in the development of new therapeutic approaches to their treatment.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1080,
                "text": "MITF"
            }
        },
        {
            "context": "The essential function of Swc4p - a protein shared by two chromatin-modifying complexes of the yeast Saccharomyces cerevisiae - resides within its N-terminal part. The Swc4p protein, encoded by an essential gene, is shared by two chromatin-remodeling complexes in Saccharomyces cerevisiae cells: NuA4 (nucleosome acetyltransferase of H4) and SWR1. The SWR1 complex catalyzes ATP-dependent exchange of the nucleosomal histone H2A for H2AZ (Htz1p). The activity of NuA4 is responsible mainly for the acetylation of the H4 histone but also for the acetylation of H2A and H2AZ. In this work we investigated the role of the Swc4p protein. Using random mutagenesis we isolated a collection of swc4 mutants and showed that the essential function of Swc4p resides in its N-terminal part, within the first 269 amino acids of the 476-amino acid-long protein. We also demonstrated that Swc4p is able to accommodate numerous mutations without losing its functionality under standard growth conditions. However, when swc4 mutants were exposed to methyl methanesulfonate (MMS), hydroxyurea or benomyl, severe growth deficiencies appeared, pointing to an involvement of Swc4p in many chromatin-based processes. The mutants' phenotypes did not result from an impairment of histone acetylation, as in the mutant which bears the shortest isolated variant of truncated Swc4p, the level of overall H4 acetylation was unchanged.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 342,
                "text": "SWR1"
            }
        },
        {
            "context": "Naltrexone/bupropion for the treatment of obesity and obesity with Type 2 diabetes. Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification. Its safety and efficacy were assessed in four randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies demonstrated statistically significant and clinically meaningful weight loss following up to 52 weeks of treatment with naltrexone/bupropion compared with placebo. The average weight loss from baseline across the four studies was approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for weight loss, as well as significant improvements in cardiometabolic markers. This review focuses on the four studies, their outcomes and the mechanism of action of Contrave.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 224,
                "text": "obesity"
            }
        },
        {
            "context": "A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 142,
                "text": "dabigatran"
            }
        },
        {
            "context": "In silico analysis of DosR regulon proteins of Mycobacterium tuberculosis. One of the challenges faced by Mycobacterium tuberculosis (M. tuberculosis) in dormancy is hypoxia. DosR/DevR of M. tuberculosis is a two component dormancy survival response regulator which induces the expression of 48 genes. In this study, we have used DosR regulon proteins of M. tuberculosis H37Rv as the query set and performed a comprehensive homology search against the non-redundant database. Homologs were found in environmental mycobacteria, environmental bacteria and archaebacteria. Analysis of genomic context of DosR regulon revealed that they are distributed as nine blocks in the genome of M. tuberculosis with many transposases and integrases in their vicinity. Further, we classified DosR regulon proteins into eight functional categories. One of the hypothetical proteins Rv1998c could probably be a methylisocitrate lyase or a phosphonomutase. Another hypothetical protein, Rv0572 was found only in mycobacteria. Insights gained in this study can potentially aid in the development of novel therapeutic interventions.",
            "question": "How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?",
            "answers": {
                "answer_start": 292,
                "text": "48 genes"
            }
        },
        {
            "context": "Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance. The majority of breast cancers are estrogen receptor (ER) positive and depend on estrogen for growth. Therefore, blocking estrogen mediated actions remains the strategy of choice for the treatment and prevention of breast cancer. The selective estrogen receptor modulators (SERMs) are molecules that block estrogen action in breast cancer, but can still potentially maintain the beneficial effects of estrogen in other tissues, such as bone and cardiovascular system. Tamoxifen, the prototypical drug of this class has been used extensively for the past 30 years to treat and prevent breast cancer. The target of drug action, ERs alpha and beta, are the two receptors which are responsible for the first step in estrogen and SERM action. The SERM binds to the ERs and confers a unique conformation to the complex. In a target site which expresses antiestrogenic actions, the conformation of the ER is distinctly different from estrogen bound ER. The complex recruits protein partners called corepressors to prevent the transcription of estrogen responsive genes. In contrast, at a predominantly estrogenic site coactivators for estrogen action are recruited. Unfortunately at an antiestrogenic site such as breast cancer, long term SERM therapy causes the development of acquired resistance. The breast and endometrial tumor cells selectively become SERM stimulated. Overexpression of receptor tyrosine kinases, HER-2, EGFR and IGFR and the signaling cascades following their activation are frequently involved in SERM resistant breast cancers. The aberrantly activated PI3K/AKT and MAPK pathways and their cross talk with the genomic components of the ER action are implicated in SERM resistance. Other down stream factors of HER-2 and EGFR signaling, such as PI3K/AKT, MAPK or mTOR pathways has also been found to be involved in resistance mechanisms. Blocking the actions of HER-2 and EGFR represent a rational strategy for treating SERM resistant phenotypes and may in fact restore the sensitivity to the SERMs. Another approach exploits the discovery that low dose estrogen will induce apoptosis in the SERM resistant breast cancers. Numerous clinical studies are addressing these issues.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 328,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Severe Marfan syndrome due to FBN1 exon deletions. Marfan syndrome is an autosomal dominant condition, with manifestations mainly in the skeletal, ocular, and cardiovascular systems. The disorder is caused by mutations in fibrillin-1 gene (FBN1). The majority of these are family-specific point mutations, with a small number being predicted to cause exon-skipping. To date, there have only been five reports of in-frame exon deletions in FBN1, with the largest of these spanning three exons. Mosaicism is rarely recorded and has only been reported in the unaffected, or mildly affected, parents of probands. Here, we report on the clinical histories of two children with exon deletions in FBN1. Both have severe Marfan syndrome with significant signs in infancy. One patient has a deletion of exon 33, which has not previously been reported. The other has the largest reported deletion, which spans 37 exons, and also represents the first reported case of mosaicism in a patient with Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 30,
                "text": "FBN1"
            }
        },
        {
            "context": "Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study. Human chorionic gonadotropin (hCG) is a pregnancy hormone secreted by the placental synctiotrophoblast cell layer that has been linked to fetal growth and various placental, uterine and fetal functions. In order to investigate the effects of hCG on clinical endpoints, knowledge on reference range (RR) methodology and determinants of gestational hCG levels is crucial. Moreover, a better understanding of gestational hCG physiology can improve current screening programs and future clinical management. Serum total hCG levels were determined in 8195 women participating in the Generation R Study. Gestational age specific RRs using 'ultrasound derived gestational age' (US RRs) were calculated and compared with 'last menstrual period derived gestational age' (LMP RRs) and a model-based RR. We also investigated which pregnancy characteristics were associated with hCG levels. Compared to the US RRs, the LMP RRs were lower, most notably for the median and lower limit levels. No considerable differences were found between RRs calculated in the general population or in uncomplicated pregnancies only. Maternal smoking, BMI, parity, ethnicity, fetal gender, placental weight and hyperemesis gravidarum symptoms were associated with total hCG. We provide gestational RRs for total hCG and show that total hCG values and RR cut-offs during pregnancy vary depending on pregnancy dating methodology. This is likely due to the influence of hCG on embryonic growth, suggesting that ultrasound based pregnancy dating might be less reliable in women with high/low hCG levels. Furthermore, we identify different pregnancy characteristics that influence total hCG levels considerably and should therefore be accounted for in clinical studies.",
            "question": "Which protein is associated with hyperemesis gravidarum during pregrancy?",
            "answers": {
                "answer_start": 1337,
                "text": "hCG"
            }
        },
        {
            "context": "Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. STUDY OBJECTIVE: The literature suggests that the d -dimer is useful in patients suspected of having pulmonary embolism and who have a low pretest probability of disease. A previously defined clinical decision rule, the Wells Criteria, may provide a reliable and reproducible means of determining this pretest probability. We evaluate the interrater agreement and external validity of Wells Criteria in determining pretest probability in patients suspected of having pulmonary embolism. METHODS: This was a prospective observational study. Trained research assistants enrolled patients during 120 random 8-hour shifts. Patients who underwent imaging for pulmonary embolism after a medical history, physical examination, and chest radiograph were enrolled. Treating providers and research assistants determined pretest probability according to Wells Criteria in a blinded fashion. Two d -dimer assays were run. Three-month follow-up for the diagnosis of pulmonary embolism was performed. Interrater agreement tables were created. kappa Values, sensitivities, and specificities were determined. RESULTS: Of the 153 eligible patients, 3 patients were missed, 16 patients declined, and 134 (88%) patients were enrolled. Sixteen (12%) patients were diagnosed with pulmonary embolism. The kappa values for Wells Criteria were 0.54 and 0.72 for the trichotomized and dichotomized scorings, respectively. When Wells Criteria were trichotomized into low pretest probability (n=59, 44%), moderate pretest probability (n=61, 46%), or high pretest probability (n=14, 10%), the pulmonary embolism prevalence was 2%, 15%, and 43%, respectively. When Wells Criteria were dichotomized into pulmonary embolism-unlikely (n=88, 66%) or pulmonary embolism-likely (n=46, 34%), the prevalence was 3% and 28%, respectively. The immunoturbidimetric and rapid enzyme-linked immunosorbent assay d -dimer assays had similar sensitivities (94%) and specificities (45% versus 46%). CONCLUSION: Wells Criteria have a moderate to substantial interrater agreement and reliably risk stratify pretest probability in patients with suspected pulmonary embolism.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 1671,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Hungarian Isradipine Study (HIS): long-term (3-year) effects on blood pressure and plasma lipids. These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 429,
                "text": "hypertension"
            }
        },
        {
            "context": "Oridonin in combination with imatinib exerts synergetic anti-leukemia effect in Ph+ acute lymphoblastic leukemia cells in vitro by inhibiting activation of LYN/mTOR signaling pathway. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by constitutively activated BCR-ABL and SRC family tyrosine kinases.They account for the activations of multiple growth-signaling pathways, including Raf/MEK/ERK, Akt/mTOR and STAT5 pathways. The BCR-ABL tyrosine kinase inhibitor imatinib is the standard treatment for Ph+ leukemia and plays efficacious role in CML. However, imatinib has few inhibitory effects on SRC tyrosine kinase with response rate of Ph+ ALL lower and relapse more frequent and quicker compared with CML. Previous studies showed that oridonin inhibits proliferation and induces apoptosis in many tumor cells. However, the anticancer activity and mechanism of oridonin in Ph+ ALL is unknown. To investigate the anticancer activity of oridonin, we examined its role in constitutively activated Akt/mTOR, Raf/MEK/ERK, STAT5 and SRC pathway, mRNA level of bcr/abl gene, cell viability and apoptosis in Ph+ ALL SUP-B15 cells. Furthermore, we detected synergetic effect of oridonin plus imatinib. Our results showed that oridonin inhibiting activations of LYN (one of SRC family kinases) and ABL and their downstream Akt/mTOR, Raf/MEK/ERK and STAT5 pathways, downregulated Bcl-2 but upregulated Bax protein and then induced apoptosis in Ph+ ALL cells. Oridonin plus imatinib exerted synergetic effects by overcoming imatinib defect of upregulating Akt/mTOR and LYN signaling. Additionally, we examined the effect of oridonin on the signaling pathways in the primary specimens from Ph+ ALL patients. Our data showed that oridonin remarkably suppressed activations of Akt/mTOR, Raf/MEK and STAT5 pathway in these primary specimens and oridonin with imatinib exerted synergetic suppressive effects on mTOR, STAT5 and LYN signaling in one imatinib resistant patient specimen. Additional evaluation of oridonin as a potential therapeutic agent for Ph+ ALL seems warranted.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 465,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Molecular basis of congenital hypopigmentary disorders in humans: a review. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 1770,
                "text": "tyr"
            }
        },
        {
            "context": "Discovery of an antibody for pan-ebolavirus therapy. During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. However, due to the antigenic differences among the five ebolavirus species, the current therapeutic monoclonal antibodies are only effective against viruses of the species Zaire ebolavirus. Although this particular species has indeed caused the majority of human infections in Central and, recently, West Africa, other ebolavirus species (e.g., Sudan ebolavirus and Bundibugyo ebolavirus) have also repeatedly caused outbreaks in Central Africa and thus should not be neglected in the development of countermeasures against ebolaviruses. Here we report the generation of an ebolavirus glycoprotein-specific monoclonal antibody that effectively inhibits cellular entry of representative isolates of all known ebolavirus species in vitro and show its protective efficacy in mouse models of ebolavirus infections. This novel neutralizing monoclonal antibody targets a highly conserved internal fusion loop in the glycoprotein molecule and prevents membrane fusion of the viral envelope with cellular membranes. The discovery of this highly cross-neutralizing antibody provides a promising option for broad-acting ebolavirus antibody therapy and will accelerate the design of improved vaccines that can selectively elicit cross-neutralizing antibodies against multiple species of ebolaviruses.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 83,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "DNA methyltransferase 1-associated protein (DMAP1) is a co-repressor that stimulates DNA methylation globally and locally at sites of double strand break repair. Correction of double strand DNA breaks proceeds in an error-free pathway of homologous recombination (HR), which can result in gene silencing of half of the DNA molecules caused by action by DNA methyltransferase 1 (DNMT1) (Cuozzo, C., Porcellini, A., Angrisano, T., Morano, A., Lee, B., Di Pardo, A., Messina, S., Iuliano, R., Fusco, A., Santillo, M. R., Muller, M. T., Chiariotti, L., Gottesman, M. E., and Avvedimento, E. V. (2007) PLoS Genet. 3, e110). To explore the mechanism that leads to HR-induced silencing, a genetic screen was carried out based on the silencing of a GFP reporter to identify potential partners. DMAP1, a DNMT1 interacting protein, was identified as a mediator of this process. DMAP1 is a potent activator of DNMT1 methylation in vitro, suggesting that DMAP1 is a co-repressor that supports the maintenance and de novo action of DNMT1. To examine critical roles for DMAP1 in vivo, lentiviral shRNA was used to conditionally reduce cellular DMAP1 levels. The shRNA transduced cells grew poorly and eventually ceased their growth. Analysis of the tumor suppressor gene p16 methylation status revealed a clear reduction in methylated CpGs in the shRNA cells, suggesting that reactivation of a tumor suppressor gene pathway caused the slow growth phenotype. Analysis of HR, using a fluorescence-based reporter, revealed that knocking down DMAP1 also caused hypomethylation of the DNA repair products following gene conversion. DMAP1 was selectively enriched in recombinant GFP chromatin based on chromatin immunoprecipitation analysis. The picture that emerges is that DMAP1 activates DNMT1 preferentially at sites of HR repair. Because DMAP1 depleted cells display enhanced HR, we conclude that it has additional roles in genomic stability.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 899,
                "text": "DNMT1"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 151,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 553,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Oral health in prevalent types of Ehlers-Danlos syndromes. BACKGROUND: The Ehlers-Danlos syndromes (EDS) comprise a heterogenous group of heritable disorders of connective tissue, characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Most EDS types are caused by mutations in genes encoding different types of collagen or enzymes, essential for normal processing of collagen. METHODS: Oral health was assessed in 31 subjects with EDS (16 with hypermobility EDS, nine with classical EDS and six with vascular EDS), including signs and symptoms of temporomandibular disorders (TMD), alterations of dental hard tissues, oral mucosa and periodontium, and was compared with matched controls. RESULTS: All EDS subjects were symptomatic for TMD and reported recurrent temporomandibular joint (TMJ) dislocations. Abnormal pulp shape (13%) and pulp calcification (78%) were observed in subjects affected with classical EDS. Caries experience was higher in EDS compared with controls and was related to poor oral hygiene, influenced by increased mucosal fragility and restraint of (wrist) joint mobility. The overall periodontal status in EDS was poor, with 62% of EDS subjects presenting high periodontal treatment needs (community periodontal index for treatment need, CPITN = II). CONCLUSION: Oral health may be severely compromised in EDS as a result of specific alterations of collagen in orofacial structures. When considering dental treatment in EDS, a number of tissue responses (mucosa, periodontium, pulp) and precautions (TMJ dislocation) should be anticipated.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 161,
                "text": "connective tissue"
            }
        },
        {
            "context": "Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. BACKGROUND: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterised by seizures and conglomerates of neural cells around the lateral ventricles of the brain, caused by FLNA mutations. FLNA encodes filamin A, an actin binding protein involved in cytoskeletal organisation. The amino-terminal actin binding domain (ABD) of filamins contains two tandem calponin homology domains, CHD1 and CHD2. OBJECTIVE: To report clinical and genetic analyses in a Spanish family affected by a connective tissue disorder suggestive of EDS type III and PNH. METHODS: A clinical and molecular study was undertaken in the three affected women. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies, and skin biopsies were done. Genetic analysis of the FLNA gene was undertaken by direct sequencing and restriction fragment length polymorphism analysis. RESULTS: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383C-->T) segregating with the combination of both syndromes. This mutation results in a substitution of an alanine residue (A128V) in CHD1. CONCLUSIONS: The findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype. This association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 189,
                "text": "connective tissue"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 459,
                "text": "IL-1β"
            }
        },
        {
            "context": "hCINAP is an atypical mammalian nuclear adenylate kinase with an ATPase motif: structural and functional studies. Human coilin interacting nuclear ATPase protein (hCINAP) directly interacts with coilin, a marker protein of Cajal Bodies (CBs), nuclear organelles involved in the maturation of small nuclear ribonucleoproteins UsnRNPs and snoRNPs. hCINAP has previously been designated as an adenylate kinase (AK6), but is very atypical as it exhibits unusually broad substrate specificity, structural features characteristic of ATPase/GTPase proteins (Walker motifs A and B) and also intrinsic ATPase activity. Despite its intriguing structure, unique properties and cellular localization, the enzymatic mechanism and biological function of hCINAP have remained poorly characterized. Here, we offer the first high-resolution structure of hCINAP in complex with the substrate ADP (and dADP), the structure of hCINAP with a sulfate ion bound at the AMP binding site, and the structure of the ternary complex hCINAP-Mg(2+) ADP-Pi. Induced fit docking calculations are used to predict the structure of the hCINAP-Mg(2+) ATP-AMP ternary complex. Structural analysis suggested a functional role for His79 in the Walker B motif. Kinetic analysis of mutant hCINAP-H79G indicates that His79 affects both AK and ATPase catalytic efficiency and induces homodimer formation. Finally, we show that in vivo expression of hCINAP-H79G in human cells is toxic and drastically deregulates the number and appearance of CBs in the cell nucleus. Our findings suggest that hCINAP may not simply regulate nucleotide homeostasis, but may have broader functionality, including control of CB assembly and disassembly in the nucleus of human cells.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 120,
                "text": "coilin"
            }
        },
        {
            "context": "Regulation of neuronal differentiation by proteins associated with nuclear bodies. Nuclear bodies are large sub-nuclear structures composed of RNA and protein molecules. The Survival of Motor Neuron (SMN) protein localizes to Cajal bodies (CBs) and nuclear gems. Diminished cellular concentration of SMN is associated with the neurodegenerative disease Spinal Muscular Atrophy (SMA). How nuclear body architecture and its structural components influence neuronal differentiation remains elusive. In this study, we analyzed the effects of SMN and two of its interaction partners in cellular models of neuronal differentiation. The nuclear 23 kDa isoform of Fibroblast Growth Factor - 2 (FGF-2(23)) is one of these interacting proteins - and was previously observed to influence nuclear bodies by destabilizing nuclear gems and mobilizing SMN from Cajal bodies (CBs). Here we demonstrate that FGF-2(23) blocks SMN-promoted neurite outgrowth, and also show that SMN disrupts FGF-2(23)-dependent transcription. Our results indicate that FGF-2(23) and SMN form an inactive complex that interferes with neuronal differentiation by mutually antagonizing nuclear functions. Coilin is another nuclear SMN binding partner and a marker protein for Cajal bodies (CBs). In addition, coilin is essential for CB function in maturation of small nuclear ribonucleoprotein particles (snRNPs). The role of coilin outside of Cajal bodies and its putative impacts in tissue differentiation are poorly defined. The present study shows that protein levels of nucleoplasmic coilin outside of CBs decrease during neuronal differentiation. Overexpression of coilin has an inhibitory effect on neurite outgrowth. Furthermore, we find that nucleoplasmic coilin inhibits neurite outgrowth independent of SMN binding revealing a new function for coilin in neuronal differentiation.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1166,
                "text": "Coilin"
            }
        },
        {
            "context": "Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation. INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). β-Catenin is a key component of the Wnt/β-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. METHODS AND RESULTS: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of β-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a β-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the β-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the β-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that β-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. CONCLUSION: Our findings indicate that β-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 840,
                "text": "EGFR"
            }
        },
        {
            "context": "Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. INTRODUCTION: Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer. METHODS: IL-6 and STAT3 activation levels were compared with tumor histology and presence of KRAS mutations in snap-frozen, non-small-cell lung cancer tumors. The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model. We examined the influence of cancer-associated fibroblasts (CAFs) on tumor growth and siltuximab effects. RESULTS: IL-6 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of KRAS mutations. Tyrosine phosphorylation status of STAT3 did not correlate with tumor IL-6 levels. Serine phosphorylation of STAT3 was correlated with KRAS mutation status. Both tumor and stromal cells contributed to total IL-6 within tumors. Siltuximab had minimal effect as a single agent in xenografts with tumor cells alone; however, in models coadministered with CAFs, siltuximab had more potent effects on tumor inhibition. We observed no effects of combined erlotinib and siltuximab. CONCLUSIONS: IL-6 is elevated in subsets of human NSCLCs, especially with squamous cell histology. Tumors supported by stromal production of IL-6 seem to be the most vulnerable to tumor growth inhibition by siltuximab.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 31,
                "text": "interleukin-6"
            }
        },
        {
            "context": "[Update on the treatment of sarcoidosis]. Sarcoidosis is a granulomatous disease characterized by variable manifestations and course. About 50% of patients will require systemic treatment, while the remaining will present spontaneous resolution of the disease. When a systemic therapy is necessary, it is prolonged and relapse rate is high when it is discontinued. Systemic corticosteroids are the first line treatment in sarcoidosis. Because of many side effects, it is essential to consider other drugs in case of intolerance to steroids, as steroid-sparing agents, or in case of inefficiency of corticotherapy alone.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 374,
                "text": "corticosteroids"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 103,
                "text": "MRSA"
            }
        },
        {
            "context": "Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles.",
            "question": "Cytochrome p450 CYP3A is induced by rifampicin  and compounds used to treat what virus?",
            "answers": {
                "answer_start": 423,
                "text": "HIV"
            }
        },
        {
            "context": "Expression of TAP73 and DeltaNP73 in malignant gliomas. The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. We studied differential expression of these forms in normal brain as well as glial tumors, by semiquantitative RT-PCR. The expression of p73 was low or undetectable in normal brain tissues. Most of the tumors and non-tumor brain tissues also lacked significant expression of p73 in patients with low-grade astrocytomas. In contrast, most high-grade glial tumors displayed strong up-regulation of TAp73, whereas only a few displayed DeltaNp73 expression. These aberrations may reflect the inactivation of retinoblastoma pathway in these tumors which result in the activation of E2F transcription factors, since TAp73 is a known target of E2F1 gene. The study of TAp73 expression in brain tumors may serve as a means to evaluate the retinoblastoma pathway-dependent tumor progression.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 114,
                "text": "7"
            }
        },
        {
            "context": "Type I Gaucher disease due to homozygosity for the 259T mutation in a Bedouin patient. A 26-year-old Bedouin with moderate thrombocytopenia and enlarged spleen and liver was diagnosed as having type I Gaucher disease based on the presence of Gaucher cells in the bone marrow biopsy and enzymatic determination of glucocerebrosidase activity. Molecular analysis excluded 10 common mutations in the glucocerebrosidase gene. Homozygosity for the C --> T mutation in nucleotide 259 of the cDNA (1763 genomic) was detected by digestion with restriction enzyme StyI after an amplification of a portion of exon 3 by mismatched primers. This is the first known case of homozygosity for this mutation. The fact that it produces a very mild phenotype, confirms a previous suggestion that 259T can be classified as a \"mild\" mutation. Association of the 259T mutation with the \"Pv 1.1 +\" haplotype is consistent with a common origin of the mutated alleles.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 397,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 614,
                "text": "Thyroid"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 717,
                "text": "tyr"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 1432,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Comparison of the BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay and the BD GeneOhm MRSA achromopeptidase assay with direct- and enriched-culture techniques using clinical specimens for detection of MRSA. We evaluated the new, fully automated molecular BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay for detection of methicillin-resistant S. aureus in a low-prevalence (4.1%) setting. Sensitivity, specificity, and positive and negative predictive values were 93.9%, 99.2%, 83.8%, and 99.7%, respectively. The assay reported fewer unresolved results than the BD GeneOhm MRSA ACP assay.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 101,
                "text": "MRSA"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 305,
                "text": "MethPed"
            }
        },
        {
            "context": "Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 22,
                "text": "HEXA"
            }
        },
        {
            "context": "Using Mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes. Plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. To understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. Since extensive data support the proposal that foreign DNA acquires the host's nucleotide composition during long-term residence, comparison of nucleotide composition of plasmids and chromosomes could shed light on a plasmid's evolutionary history. The average absolute dinucleotide relative abundance difference, termed delta-distance, has been commonly used to measure differences in dinucleotide composition, or 'genomic signature', between bacterial chromosomes and plasmids. Here, we introduce the Mahalanobis distance, which takes into account the variance-covariance structure of the chromosome signatures. We demonstrate that the Mahalanobis distance is better than the delta-distance at measuring genomic signature differences between plasmids and chromosomes of potential hosts. We illustrate the usefulness of this metric for proposing candidate long-term hosts for plasmids, focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from Escherichia coli O157:H7, as well as the broad host range multi-drug resistance plasmid pB10 from an unknown host.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 767,
                "text": "delta-distance"
            }
        },
        {
            "context": "Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 153,
                "text": "FBN1"
            }
        },
        {
            "context": "Rilonacept in the treatment of chronic inflammatory disorders. Rilonacept (IL-1 Trap/Arcalyst) is a long-acting interleukin-1 (IL-1) blocker developed by Regeneron Pharmaceuticals. Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. CAPS is a group of inherited inflammatory disorders consisting of FCAS, MWS, neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; Kineret(R) or anakinra/ Amgen, Inc.), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. A high-affinity protein called rilonacept has been produced by cytokine Trap technology and was developed by Regeneron. The desirable longer half-life of rilonacept offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined whether rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis.",
            "question": "What is the indication of ARCALYST?",
            "answers": {
                "answer_start": 600,
                "text": "cryopyrin-associated periodic syndromes (CAPS) disorders"
            }
        },
        {
            "context": "Dynamin-related protein Drp1 and mitochondria are important for Shigella flexneri infection. Shigella infection in epithelial cells induces cell death which is accompanied by mitochondrial dysfunction. In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined. Significant lactate dehydrogenase (LDH) release was detected in the culture supernatant when HeLa cells were infected with Shigella at a high multiplicity of infection. Drp1 inhibition with Mdivi-1 and siRNA knockdown significantly reduced LDH release. HeLa cell death was also accompanied by mitochondrial fragmentation. Tubular mitochondrial networks were partially restored when Drp1 was depleted with either siRNA or inhibited with Mdivi-1. Surprisingly either Mdivi-1 treatment or Drp1 siRNA-depletion of HeLa cells also reduced Shigella plaque formation. The effect of Mdivi-1 on Shigella infection was assessed using the murine Sereny model, however it had no impact on ocular inflammation. Overall our results suggest that Drp1 and the mitochondria play important roles during Shigella infection.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 232,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Human rabies--Alberta, Canada, 2007. On April 26, 2007, a patient from Alberta, Canada, died after 9 weeks in an intensive care unit (ICU) from encephalitis caused by a rabies virus variant associated with silver-haired bats. This report summarizes the clinical course of disease in that patient, who was treated using the Milwaukee Protocol, an experimental treatment protocol similar to one used for the rabies survivor described in 2005. This report also describes the subsequent epidemiologic investigations by three regional public health departments in Alberta. Rabies continues to be a cause of human death in the developed and developing world. The findings in this report underscore the need for continued public education that promotes rabies prevention and postexposure prophylaxis while emphasizing the importance of bat exposure in rabies transmission.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 406,
                "text": "rabies"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 53,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. The endoplasmic reticulum (ER) can elicit proapoptotic signalling that results in transmission of Ca(2+) to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle. Here, we show that BH3-only BIK activates this pathway at the ER in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. The BIK-induced transformations in mitochondria are dynamic in nature and involve DRP1-dependent remodelling and opening of cristae, where the major stores of cytochrome c reside. This novel function for DRP1 is distinct from its recognized role in regulating mitochondrial fission. Selective permeabilization of the outer membrane with digitonin confirmed that BIK stimulation results in mobilization of intramitochondrial cytochrome c. Of note, BIK can cooperate with a weak BH3-only protein that targets mitochondria, such as NOXA, to activate BAX by a mechanism that is independent of DRP1 enzyme activity. When expressed together, BIK and NOXA cause rapid release of mobilized cytochrome c and activation of caspases.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 763,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 701,
                "text": "MC1R"
            }
        },
        {
            "context": "[Cryptococcal meningitis]. BACKGROUND: Cryptococcus neoformans causes systemic disease in patients with immunodeficiency. The incidence of cryptococcal meningitis has increased in parallel with that of HIV infection. Cancer is also a known predisposing factor. MATERIAL AND METHODS: We present two case reports and a review of the literature concerning the epidemiology, diagnostics and treatment of cryptococcal meningitis. RESULTS: The incidence of cryptococcal meningitis in Scandinavia seems to be lower than in other parts of the world. Clinical signs and symptoms are often uncharacteristic. Detection of antigen in spinal fluid is a sensitive and fast test. INTERPRETATION: Cryptococcal meningitis is a rare disease, often with uncharacteristic symptoms. Patients with haematological malignancies have a higher risk of contracting this disease. It is a differential diagnosis when neurological symptoms occur in these patients.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 202,
                "text": "HIV"
            }
        },
        {
            "context": "A transcription-independent role for TFIIB in gene looping. Recent studies demonstrated the existence of gene loops that juxtapose the promoter and terminator regions of genes with exceptionally long ORFs in yeast. Here we report that looping is not idiosyncratic to long genes but occurs between the distal ends of genes with ORFs as short as 1 kb. Moreover, looping is dependent upon the general transcription factor TFIIB: the E62K (glutamic acid 62 --> lysine) form of TFIIB adversely affects looping at every gene tested, including BLM10, SAC3, GAL10, SEN1, and HEM3. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP. We propose a model suggesting that TFIIB binds RNAP II at the terminator, which in turn associates with the promoter scaffold.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 37,
                "text": "TFIIB"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 68,
                "text": "Dabigatran"
            }
        },
        {
            "context": "Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients. BACKGROUND AND AIM: The aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women. METHODS: We retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center. RESULTS: 45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM-treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio [HR], 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation. CONCLUSIONS: Although SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 180,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination-independent mechanism. The most common transposable genetic element in humans, long interspersed element 1 (L1), constitutes about 20% of the genome. The activity of L1 and related transposons such as Alu elements causes disease and contributes to speciation. Little is known about the cellular mechanisms that control their spread. We show that expression of human APOBEC3B or APOBEC3F decreased the rate of L1 retrotransposition by 5-10-fold. Expression of two related proteins, APOBEC3D or APOBEC3G, had little effect. The mechanism of L1 inhibition did not correlate with an obvious subcellular protein distribution as APOBEC3B appeared predominantly nuclear and APOBEC3F was mostly cytosolic. Two lines of evidence indicated that these APOBEC3 proteins use a deamination-independent mechanism to inhibit L1. First, a catalytically inactive APOBEC3B mutant maintained L1 inhibition activity. Second, cDNA strand-specific C --> T hypermutations were not detected among L1 elements that had replicated in the presence of APOBEC3B or APOBEC3F. In addition, lower levels of retrotransposed L1 DNA accumulated in the presence of APOBEC3B and APOBEC3F. Together, these data combined to suggest a model in which APOBEC3B or APOBEC3F provide a preintegration barrier to L1 retrotransposition. A particularly high level of APOBEC3F protein in human testes and an inverse correlation between L1 activity and APOBEC3 gene number suggest the relevance of this mechanism to mammals.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 727,
                "text": " nuclear"
            }
        },
        {
            "context": "[Analysis of mutations of ribosomal protein genes in 21 cases of Diamond-Blackfan anemia]. This study was aimed to explore the mutations of ribosomal protein (RP) genes in patients with Diamond Blackfan anemia (DBA). Twenty-one cases of DBA admitted in our hospital from Dec 2008 to Aug 2012 were screened by PCR for mutations in the nine known genes associated with DBA: RPS19, RPS24, RPS17, RPL5, RPL11, RPS7, RPL35a, RPS10 and RPS26. The results found that 8 patients (38.1%) with DBA had mutations in the genes coding for ribosomal protein, in which RPS19 mutation was identified in 3 patients, RPS24, RPS7, RPL5, RPL11 and RPL35A mutations were identified respectively in 1 of the patient. No mutations were detected in RPS17, RPS10 or RPS26 genes. Thumb anomalies were found in 2 patients with RPL11 or RPL5 mutation, and hypospadias was found in 1 patient with RPS19 mutation. It is concluded that the mutation frequency of the genes coding for ribosomal protein in the patients with DBA here is lower than that in western countries. The hypospadias can be observed in some patients with RPS19 mutation and some dactyl anomalies are associated with RPL11 and RPL5 mutations.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 367,
                "text": "DBA"
            }
        },
        {
            "context": "Chest pain in a young patient: an unusual complication of Epstein-Barr virus. A 29-year-old man presented with sudden left-sided pleuritic chest pain on a background of sore throat during the preceding week. On examination he had tender cervical lymphadenopathy, he was tachycardic and had a 24 mm Hg blood pressure difference between the left and right arms. Bloods revealed deranged liver function tests and a lymphocytosis. His D-dimer was raised, hence he was treated for presumed pulmonary embolism before imaging was available. Monospot test was positive. He subsequently had both a CT pulmonary angiogram and a CT angiogram of the aorta to exclude pulmonary embolism and aortic dissection. The CT revealed splenomegaly with a large subdiaphragmatic haematoma secondary to splenic rupture. This had likely caused referred pain through diaphragmatic irritation. He was taken to theatre for urgent splenectomy. The unifying diagnosis was infectious mononucleosis complicated by spontaneous splenic rupture secondary to Epstein-Barr virus infection.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 1023,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Marfan syndrome: a case report. Marfan syndrome is an autosomal dominant systemic disorder of the connective tissue. Children affected by the Marfan syndrome carry a mutation in one of their two copies of the gene that encodes the connective tissue protein fibrillin-1. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body. A case report of Marfan syndrome has been reported with oral features. The dental problems of the child were treated under general anesthesia and a one-month review showed intact stainless steel crowns' restorations and no signs of secondary caries.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 231,
                "text": "connective tissue"
            }
        },
        {
            "context": "Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristics of the BD GeneOhm MRSA assay, the Xpert MRSA assay, and broth-enriched culture in an area with a low prevalence of MRSA infections. Universal surveillance upon patient admission is important in reducing the transmission of methicillin-resistant Staphylococcus aureus (MRSA) and associated disease in hospitals. High costs for the health care system in conjunction with MRSA have promoted the development of rapid screening methods to detect MRSA carriers. This study compared two real-time PCR methods, the BD GeneOhm MRSA assay (BDGO) and the Xpert MRSA assay, with broth-enriched culture to define their performance characteristics and rapidity in an area with low MRSA prevalence. In total, 414 swabs from the nose and 389 swabs from the groin from 425 patients were tested. Of those 425 patients, 378 had swabs from both the nose and groin in parallel. Two hundred thirty-one and 194 patients were randomly assigned to the BDGO group and the Xpert MRSA group, respectively. In general, sensitivity, specificity, and negative predictive value (NPV) were high for the BDGO (100%, 98.5%, and 100%, respectively) and the Xpert MRSA (100%, 98.2%, and 100%, respectively), irrespective of whether or not nasal and inguinal specimens were considered alone or combined. In contrast, the positive predictive value (PPV) was lower: before the resolution of discrepant results, the PPVs for nasal and inguinal specimens alone and combined were 87.5%, 86.7%, and 82.4% for the BDGO and 91.7%, 66.7%, and 92.9% for the Xpert MRSA, respectively. After the resolution of discrepant results, PPVs were 93.8%, 93.3% and 94.1% for the BDGO and 91.7%, 88.9% and 92.9% for the Xpert MRSA, respectively. With the BDGO, 4 of 16 carriers were each identified by nasal or inguinal swabs alone, whereas in the Xpert MRSA group, 4 of 13 carriers were exclusively identified by nasal swabs and 2 of 13 were identified by inguinal swabs alone. Both PCR methods showed no significant difference in the number of discrepant results (odds ratio, 0.70 [P = 0.789]), but specimens from wounds and other body sites (axilla, vagina, and throat) produced discrepancies more often than nasal and groin specimens (odds ratios, 4.724 [P = 0.058] and 12.163 [P < 0.001], respectively). The facts that no false-negative PCR results were detected and increased PPVs were found after the resolution of discrepant results point to PCR as the actual gold standard. Since both sensitivity and NPV were exceptionally high for PCR, backup cultures may, therefore, be unnecessary in an area with low prevalence and with a preemptive isolation strategy but may still be useful for PCR-positive specimens because of the lower PPV for both methods and the possibility of susceptibility testing. The median time for analysis, including extraction, hands-on time, and actual PCR was 2 h 20 min for the Xpert MRSA versus 5 h 40 min for the BDGO. Concerning reporting time, including administration and specimen collection, the Xpert MRSA was faster than the BDGO (7 h 50 min versus 17 h).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 170,
                "text": "MRSA"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 379,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Characterization and functional expression of cDNAs encoding methionine-sensitive and -insensitive homocysteine S-methyltransferases from Arabidopsis. Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy). These reactions comprise the SMM cycle. Two Arabidopsis cDNAs specifying enzymes that mediate the SMM --> Met reaction (SMM:Hcy S-methyltransferase, HMT) were identified by homology and authenticated by complementing an Escherichia coli yagD mutant and by detecting HMT activity in complemented cells. Gel blot analyses indicate that these enzymes, AtHMT-1 and -2, are encoded by single copy genes. The deduced polypeptides are similar in size (36 kDa), share a zinc-binding motif, lack obvious targeting sequences, and are 55% identical to each other. The recombinant enzymes exist as monomers. AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM. Both enzymes also use either methyl donor in vivo because both restore the ability to utilize AdoMet or SMM to a yeast HMT mutant. However, AtHMT-1 is strongly inhibited by Met, whereas AtHMT-2 is not, a difference that could be crucial to the control of flux through the HMT reaction and the SMM cycle. Plant HMT is known to transfer the pro-R methyl group of SMM. This enabled us to use recombinant AtHMT-1 to establish that the other enzyme of the SMM cycle, AdoMet:Met S-methyltransferase, introduces the pro-S methyl group. These opposing stereoselectivities suggest a way to measure in vivo flux through the SMM cycle.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 201,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "Neuropathology of pediatric brain tumors. Pediatric central nervous system neoplasms include a spectrum of both glial and nonglial tumors that differ significantly in location and biological behavior from those of adults. Brain tumors in infants and children most often arise from central neuroepithelial tissue, whereas a significant number of adult tumors arise from central nervous system coverings (e.g., meningioma), adjacent tissue (e.g., pituitary adenoma), or metastases. Most adult brain tumors are supratentorial malignant gliomas, whereas the most common malignant pediatric brain tumor is the cerebellar primitive neuroectodermal tumor (medulloblastoma). This article reviews neuropathological characteristics of the more common pediatric brain tumors. Entities, such as the brainstem glioma, and less common neoplasms like the desmoplastic infantile ganglioglioma and the central nervous system atypical teratoid/rhabdoid tumor are reviewed because they occur almost exclusively in children. Known cytogenetic and molecular characteristics of childhood brain tumors are also reviewed.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 649,
                "text": "medulloblastoma"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 128,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Prospective comparison of the clinical impacts of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-susceptible MRSA. Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [>or=0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 microg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 133,
                "text": "MRSA"
            }
        },
        {
            "context": "Determinants of disease phenotype in trypanosomatid parasites. Trypanosomatid parasites infect over 21 million people worldwide, with a range of disease phenotypes. Trypanosoma cruzi causes American trypanosomiasis, wherein 30-40% of infected individuals develop disease manifestations, most commonly cardiomyopathy but also digestive megasyndromes. In the case of Trypanosoma brucei, the etiological agent of African trypanosomiasis, disease progression can be rapid or slow, with early or late central nervous system involvement. Finally, Leishmania species cause leishmaniasis, a disease that ranges from self-healing but scarring cutaneous lesions to fatal visceral leishmaniasis in which parasites disseminate to the liver, spleen, and bone marrow. This review highlights parasite factors involved in disease phenotype in all three trypanosomatid diseases, with a particular focus on recent advances using large-scale 'omics' techniques.",
            "question": "What causes leishmaniasis?",
            "answers": {
                "answer_start": 541,
                "text": "Leishmania species"
            }
        },
        {
            "context": "The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson's disease: a review of in vivo models. Parkinson's disease is the most common neurodegenerative movement disorder. The motor impairments of Parkinson's disease are caused by the loss of dopaminergic neurons in the substantia nigra and associated with the appearance of fibrillar aggregates of α-synuclein (α-syn) called Lewy bodies. Approximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total α-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease. Our laboratory and others have performed experiments using in vivo models of Parkinson's disease to elucidate the role of increased Ser129 phosphorylation in α-syn neurotoxicity. However, there has been a lack of consistency among these models. In this review, we summarize the main findings regarding the relationship between Ser129 phosphorylation and α-syn neurotoxicity, and examine the differences among models. We further discuss the role of Ser129 phosphorylation in α-syn aggregation and the future directions to test the potential of Ser129 phosphorylation as a therapeutic target for slowing the progression of Parkinson's disease.",
            "question": "Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?",
            "answers": {
                "answer_start": 490,
                "text": "serine 129"
            }
        },
        {
            "context": "Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Although no specific phenotype was found to be associated with mutations in either gene, clinical and histological features together with pedigree data may be used in guiding mutation detection. Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication.",
            "question": "What is the mode of inheritance of nemaline myopathy?",
            "answers": {
                "answer_start": 889,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Distinctive patterns of memory function in subgroups of females with Turner syndrome: evidence for imprinted loci on the X-chromosome affecting neurodevelopment. X-monosomy is a form of Turner syndrome (TS) in which an entire X chromosome is missing. It is usually assumed that neuropsychological deficits in females with TS result from insufficient dosage of gene products from alleles on the sex chromosomes. If so, then parental origin of the single X chromosome should be immaterial. However, if there are imprinted genes on the X chromosome affecting brain development, neuropsychological development will depend on the parental origin of the single X chromosome. We contrasted verbal and visuospatial memory in females with a single paternal X chromosome (45,X(p)) and those with a single maternal X (45,X(m)). Neither group showed any impairment on immediate story recall; if anything, performance was above control levels. Groups did not differ on a measure of delayed recall. However, when delayed recall was considered after adjusting for level of immediate recall, 45,X(m) females showed enhanced verbal forgetting relative to controls over a delay. On the Rey figure, both groups were poor at copying the figure, but, after adjusting scores for initial copy score and strategy, only the 45,X(p) females showed disproportionate forgetting relative to controls. We propose there may be one or more imprinted genes on the X chromosome that affect the development of lateralised brain regions important for memory function.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 162,
                "text": "X"
            }
        },
        {
            "context": "The cyclic pattern of blood alcohol levels during continuous ethanol feeding in rats: the effect of feeding S-adenosylmethionine. S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver. The following parameters were studied to determine the effects of SAMe; liver histology, the blood alcohol cycle (BAL), changes in gene expression mined from microarray analysis, changes in histone methylation, changes in liver SAMe levels and its metabolites and ADH. SAMe changed the type of fatty liver, reduced liver ALT levels and prevented the BAL cycle caused by intragastric ethanol feeding. Microarray analysis showed that SAMe feeding prevented most of the changes in gene expression induced by ethanol feeding, presumably by inducing H3K27me3 and gene silencing. H3K27me3 was significantly increased by SAMe with or without ethanol feeding. It is concluded that SAMe feeding stabilized global gene expression so that the changes in gene expression involved in the blood alcohol cycle were prevented.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 132,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival. Cardiac contractility is regulated through the activity of various key Ca(2+)-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis. In the current study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide binding domain are required for its interaction with the C-terminal domain of HAX-1, containing amino acids 203-245. In transiently cotransfected human embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the ER, whereas HAX-1 selectively concentrated at mitochondria. On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2 abrogated the protective effects of HAX-1 on cell survival, after hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca(2+) stores.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 316,
                "text": "PLN"
            }
        },
        {
            "context": "Fusarium Wilt of Banana Is Caused by Several Pathogens Referred to as Fusarium oxysporum f. sp. cubense. ABSTRACT Fusarium wilt of banana (also known as Panama disease) is caused by Fusarium oxysporum f. sp. cubense. Where susceptible cultivars are grown, management is limited to the use of pathogen-free planting stock and clean soils. Resistant genotypes exist for some applications, but resistance is still needed in other situations. Progress has been made with this recalcitrant crop by traditional and nontraditional improvement programs. The disease was first reported in Australia in 1876, but did the greatest damage in export plantations in the western tropics before 1960. A new variant, tropical race 4, threatens the trades that are now based on Cavendish cultivars, and other locally important types such as the plantains. Phylogenetic studies indicate that F. oxysporum f. sp. cubense had several independent evolutionary origins. The significance of these results and the future impact of this disease are discussed.",
            "question": "What is the causative agent of the \"Panama disease\" affecting bananas?",
            "answers": {
                "answer_start": 182,
                "text": "Fusarium oxysporum f. sp. cubense"
            }
        },
        {
            "context": "Visualization of interactions between a pathogenic and a beneficial Fusarium strain during biocontrol of tomato foot and root rot. The soilborne fungus Fusarium oxysporum f. sp. radicis-lycopersici causes tomato foot and root rot (TFRR), which can be controlled by the addition of the nonpathogenic fungus F. oxysporum Fo47 to the soil. To improve our understanding of the interactions between the two Fusarium strains on tomato roots during biocontrol, the fungi were labeled using different autofluorescent proteins as markers and subsequently visualized using confocal laser scanning microscopy. The results were as follows. i) An at least 50-fold excess of Fo47over F. oxysporum f. sp. radicis-lycopersici was required to obtain control of TFRR. ii) When seedlings were planted in sand infested with spores of a single fungus, Fo47 hyphae attached to the root earlier than those of F. oxysporum f. sp. radicis-lycopersici. iii) Subsequent root colonization by F. oxysporum f. sp. radicis-lycopersici was faster and to a larger extent than that by Fo47. iv) Under disease-controlling conditions, colonization of tomato roots by the pathogenic fungus was significantly reduced. v) When the inoculum concentration of Fo47 was increased, root colonization by the pathogen was arrested at the stage of initial attachment to the root. vi) The percentage of spores of Fo47 that germinates in tomato root exudate in vitro is higher than that of the pathogen F. oxysporum f. sp. radicis-lycopersici. Based on these results, the mechanisms by which Fo47 controls TFRR are discussed in terms of i) rate of spore germination and competition for nutrients before the two fungi reach the rhizoplane; ii) competition for initial sites of attachment, intercellular junctions, and nutrients on the tomato root surface; and iii) inducing systemic resistance.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 205,
                "text": "tomato"
            }
        },
        {
            "context": "A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. Inhibition of NEDD8-activating enzyme (NAE) has emerged as a highly promising approach to treat cancer through the adenosine sulfamate analog MLN4924. Here, we show that selective pressure results in HCT116 colorectal carcinoma cells with decreased MLN4924 sensitivity and identify a single-nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3. This reduces the enzyme's affinity for MLN4924 and ATP while increasing NEDD8 activation at physiological ATP concentrations. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death. Our data suggest that the on-target potency of MLN4924 selects for a point mutation in NAE that overcomes the molecule's inhibitory effects, allowing cancer cell survival.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 25,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 0,
                "text": "OikoBase"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 3289,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Maintenance of DNA methylation: Dnmt3b joins the dance. DNA methylation mostly occurs within the context of CpG dinucleotides and is essential for embryonic development and gene repression. It is generally accepted that DNA methyltransferases carry out specific and non-overlapping functions, Dnmt3a and Dnmt3b being responsible for the establishment of methylation around the time of implantation and Dnmt1 ensuring that methylation is faithfully copied to daughter cells via what has come to be known as \"maintenance methylation.\" This longstanding view has been challenged over the years with the observation that Dnmt1 alone is incapable of perfect maintenance methylation. A new model is emerging that takes into account a contribution of the de novo enzymes Dnmt3a and Dnmt3b in the maintenance of the DNA methylation. We recently showed that certain germ line genes are specific targets of Dnmt3b, and that Dnmt3b remains bound to their promoter regions in somatic cells via interaction with the transcriptional repressor E2F6. It is tempting to consider an ongoing role for Dnmt3b in the methylation of germ line genes in somatic cells. We propose here observations in support of the hypothesis that the maintenance of methylation and subsequent silencing of a handful of germ line genes requires Dnmt3b but not Dnmt1. In addition to suggesting a new role for Dnmt3b in the protection of somatic cells against the promiscuous expression of the germ line program, these observations are of particular interest in the field of carcinogenesis, given that the expression of catalytically inactive Dnmt3b isoforms and aberrant expression of germ line genes are commonly observed in cancer cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1320,
                "text": "Dnmt1"
            }
        },
        {
            "context": "The active site of the SET domain is constructed on a knot. The SET domain contains the catalytic center of lysine methyltransferases that target the N-terminal tails of histones and regulate chromatin function. Here we report the structure of the SET7/9 protein in the absence and presence of its cofactor product, S-adenosyl-L-homocysteine (AdoHcy). A knot within the SET domain helps form the methyltransferase active site, where AdoHcy binds and lysine methylation is likely to occur. A structure-guided comparison of sequences within the SET protein family suggests that the knot substructure and active site environment are conserved features of the SET domain.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 64,
                "text": "SET domain"
            }
        },
        {
            "context": "Molecular basis of congenital hypopigmentary disorders in humans: a review. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 1734,
                "text": "tyr"
            }
        },
        {
            "context": "Photodynamic action of red light for treatment of erythrasma: preliminary results. BACKGROUND: Erythrasma is a superficial cutaneous infection caused by Corynebacterium minutissimum and is characterized by fluorescence under Wood's light (UV) because of the presence of porphyrins. These molecules are photosensitizing and we propose to assess efficacy of red light that activates porphyrins (photodynamic reaction) in treatment of this pathology. OBJECTIVES: Assessment of effects of photodynamic action of red light for treatment of erythrasma without exogenous photosensitizing molecules. METHODS: Thirteen patients with erythrasma were treated by one illumination (80 J/cm2) by red light (broad band, peak at 635 nm) without exogenous photosensitizing molecules. Disappearance or reduction of extent of lesions were observed 2 weeks later. If lesions were still present, a second irradiation was conducted with the same method. RESULTS: Preliminary results are presented. As a result of red light irradiation, we noticed a complete recovery for three patients and, in most other cases, reduction of extent of lesions (mean: -29% after one session). The treatment was well tolerated. CONCLUSION: We report first cases of photodynamic treatment of erythrasma. There are other reports of clinical applications of antimicrobial action of photodynamic therapy in dermatology (acne vulgaris, leishmaniasis, warts, etc.). But there are few applications without addition of exogenous photosensitizing agent. The originality and interest of our study is to use spontaneous presence of porphyrins in the lesions. This technique seems to be an interesting alternative, inexpensive and easy, for the treatment of this localized infection. But an optimal method is still to be determined to improve efficacy.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 153,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 0,
                "text": "LARVA"
            }
        },
        {
            "context": "The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma. Medulloblastoma (MB) is the most common malignant pediatric brain tumor which is thought to originate from cerebellar granule cell precursors (CGNPs) that fail to properly exit the cell cycle and differentiate. Although mutations in the Sonic Hedgehog (Shh) signaling pathway occur in 30% of cases, genetic alterations that account for MB formation in most patients have not yet been identified. We recently determined that the cyclin D-dependent kinase inhibitor, p18(Ink4c), is expressed as CGNPs exit the cell cycle, suggesting that this protein might play a central role in arresting the proliferation of these cells and in timing their subsequent migration and differentiation. In mice, disruption of Ink4c collaborates independently with loss of p53 or with inactivation of the gene (Ptc1) encoding the Shh receptor, Patched, to induce MB formation. Whereas loss of both Ink4c alleles is required for MB formation in a p53-null background, Ink4c is haplo-insufficient for tumor suppression in a Ptc(1+/-) background. Moreover, MBs derived from Ptc(1+/-) mice that lack one or two Ink4c alleles retain wild-type p53. Methylation of the INK4C (CDKN2C) promoter and complete loss of p18(INK4C) protein expression were detected in a significant fraction of human MBs again pointing toward a role for INK4C in suppression of MB formation.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 69,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "Dinutuximab: first global approval. United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 209,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Slings in iatrogenic male incontinence: Current status. OBJECTIVES: The increasing number of prostatectomies entails an increasing number of patients suffering from iatrogenic incontinence despite improved surgical techniques. The severity of this problem often requires invasive treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options. Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems. The aim of this review is to critically report the current status of sling systems in the treatment of iatrogenic male incontinence. MATERIALS AND METHODS: MEDLINE and PubMed databases were searched and all articles between 1974 and 2009 were evaluated. RESULTS: With regard to bone-anchored, readjustable, and trans-obturator slings systems, cure rates ranged between 58.0% and 86.0%, 55.5% and 73.0%, and 40.0% and 63.0%, respectively, while major complication rates ranged between 0 and 14.5%, 10.0 and 22.2%, and 0 and 10.0%, respectively. CONCLUSIONS: Suburethral slings are the only alternative techniques which can be favorably compared with the AUS, showing more advantages with respect to AUS implantations which are mainly represented by a quick and less invasive approach, low morbidity, and low costs. In spite of the difficulty in identifying the most effective sling procedure, overall, sling systems can be recommended for patients with persistent mild or moderate incontinence. However, the indication can also be extended to patients with severe incontinence, after appropriate counseling, allowing AUS implantation in the event of sling failure.",
            "question": "What is the gold standard treatment for Iatrogenic male incontinence?",
            "answers": {
                "answer_start": 371,
                "text": "AUS"
            }
        },
        {
            "context": "A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. INTRODUCTION: LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for generation of amyloid beta (Abeta), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Abeta, but has no clear effect on Abeta1-40 or Abeta1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Abeta isoforms, such as Abeta1-16, that in experimental settings increase during gamma-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Abeta isoforms may be biomarkers of gamma-secretase inhibitor treatment in clinical trials. METHODS: In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Abeta isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry. RESULTS: The CSF levels of Abeta1-14, Abeta1-15, and Abeta1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Abeta1-40 and Abeta1-42 were unaffected by treatment. CONCLUSIONS: CSF Abeta1-14, Abeta1-15, and Abeta1-16 increase during gamma-secretase inhibitor treatment in AD, even at doses that do not affect Abeta1-42 or Abeta1-40, probably because of increased substrate availability of the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition. These Abeta isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. TRIAL REGISTRATION: Clinical Trials.gov NCT00244322.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 119,
                "text": "semagacestat"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 456,
                "text": "xa"
            }
        },
        {
            "context": "Proliferation of cultured human gingival fibroblasts caused by isradipine, a dihydropyridine-derivative calcium antagonist. As it was reported earlier that isradipine, a Ca superset 2+ antagonist of dihydropyridine derivative class, caused regression of nifedipine-induced hyperplasia of human gingiva, experiments were performed to examine whether or not isradipine would solely inhibit the proliferation of cultured gingival fibroblasts. Normal human gingival fibroblast Gin-1 cells were used to test the impact of this medication. Fibroblast proliferation in the presence of isradipine (10 microM) was examined by using the reagent water-soluble tetrazolium-1 (WST-1). The level of basic fibroblast growth factor (bFGF) in the cell-free supernatant of each well was determined by using an enzyme-linked immunosorvent assay (ELISA) kit. The production of type I collagen was assayed by ELISA. Isradipine significantly enhanced the cell proliferation from the second day of the culture period. Also, isradipine raised the level of bFGF in the culture medium. The same concentration, also significantly enhanced the production of type I collagen. In conclusion, we were able to prove that isradipine causes the proliferation of cultured gingival fibroblasts as well as other dihydropyridine-derivative Ca superset 2+ antagonists do. In order to prevent the gingival overgrowth, it is advisable to be very careful in the use of isradipine as a therapy for hypertension and other indications.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 1455,
                "text": "hypertension"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 606,
                "text": "xa"
            }
        },
        {
            "context": "New targets, new drugs for metastatic bone pain: a new philosophy. Bone pain is a common symptom in bone metastases. The therapies that are currently available include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, steroids and gabapentin which have been demonstrated to improve neuropathic pain. In addition, preclinical studies indicate that agents such as transient receptor potential vanilloid 1 antagonists and cannabinoid 2 receptor agonist could be considered as adjuncts in ameliorating opioid side effects. New drugs are in the clinical phase of development, among which the most promising molecules seem to be anti-nerve growth factor (NGF) antibodies. Anti-NGF antibody therapy may be particularly effective in blocking bone cancer pain because NGF appears to be integrally involved in the upregulation, sensitization and disinhibition of multiple neurotransmitters, ion channels and receptors in the primary afferent nerve. The best way to treat bone metastases pain is to improve the control of skeletal disease burden. Recently, denosumab, a noncytotoxic IgG2 monoclonal antibody with high affinity for human RANKL, has been demonstrated to significantly prevent clinically relevant increase in pain compared with zoledronic acid across the tumor types. Based on these data, it has been suggested that denosumab has the potential to become a new standard of treatment in bone metastases management.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1132,
                "text": "RANKL"
            }
        },
        {
            "context": "Clonal size-variation of rDNA cluster region on chromosome XII of Saccharomyces cerevisiae. Using pulsed-field gel electrophoresis (PFGE), we have demonstrated clonal variation in the size of chromosome XII in a diploid strain of Saccharomyces cerevisiae X2180-2D. The sizes of the two chromosome XII homologues were very different: 2600 (L-type) and 1450 kb (S-type). The frequency with which we detected clonal size variation in the diploid, compared to that of the parental clones, was about 15-50% of the progeny clones and the range of the size variation of the homologues was 2580-2680 kb (L-type) and 1340-1500 kb (S-type), respectively. The homologue of the L-type appeared to be more frequently variable than that of the S-type. The size variation was shown to be derived from size changes in the rDNA cluster region, which is present in chromosome XII, by digesting the chromosome with XhoI, whose cutting site is not present in a rDNA repeat unit, and hybridizing to rDNA probes. The clonal size variation was also investigated in haploids from spores after meiosis. The L-type and S-type chromosomes segregated 2:2 in an ascus and the sizes of all the S-type chromosomes were shifted up, compared to the original diploid, though the L-type ones were stable. The S-type sizes of 1340, 1450 and 1780 kb in the original diploids changed into the ranges of 1475-1610 kb, 1520-1680 kb and 1820-2010 kb, respectively, in the segregants. Furthermore, we observed that the size of S-type chromosomes in haploid cells was gradually increasing in mitosis during successive subcultures.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 192,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy. Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 160,
                "text": "FSHD"
            }
        },
        {
            "context": "Impaired ribosome biogenesis in Diamond-Blackfan anemia. The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBA-related genes may be involved in the synthesis of the ribosomal subunits.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 159,
                "text": "DBA"
            }
        },
        {
            "context": "New insights into the promoterless transcription of DNA coligo templates by RNA polymerase III. Chemically synthesized DNA can carry small RNA sequence information but converting that information into small RNA is generally thought to require large double-stranded promoters in the context of plasmids, viruses and genes. We previously found evidence that circularized oligodeoxynucleotides (coligos) containing certain sequences and secondary structures can template the synthesis of small RNA by RNA polymerase III in vitro and in human cells. By using immunoprecipitated RNA polymerase III we now report corroborating evidence that this enzyme is the sole polymerase responsible for coligo transcription. The immobilized polymerase enabled experiments showing that coligo transcripts can be formed through transcription termination without subsequent 3' end trimming. To better define the determinants of productive transcription, a structure-activity relationship study was performed using over 20 new coligos. The results show that unpaired nucleotides in the coligo stem facilitate circumtranscription, but also that internal loops and bulges should be kept small to avoid secondary transcription initiation sites. A polymerase termination sequence embedded in the double-stranded region of a hairpin-encoding coligo stem can antagonize transcription. Using lessons learned from new and old coligos, we demonstrate how to convert poorly transcribed coligos into productive templates. Our findings support the possibility that coligos may prove useful as chemically synthesized vectors for the ectopic expression of small RNA in human cells.",
            "question": "What is a coligo?",
            "answers": {
                "answer_start": 356,
                "text": "circularized oligodeoxynucleotides"
            }
        },
        {
            "context": "Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. BACKGROUND: Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. Beta-galactocerebrosidase (GALC) is a specific beta-galactosidase which is defective in GLD. About 90% of GLD patients have an infantile course by fatal cerebral demyelination, but 10% have a later onset (LOGLD) of symptoms and survive for one or several decades. METHODS: Activities of GALC towards galactosylceramide (GC) and galactosylsphingosine (psychosine; PS) were determined in white blood cells and cultured fibroblasts derived from GLD patients and controls using tritium-labelled natural substrates. In the galactosylsphingosine (psychosine) beta-galactosidase (GALC-PS) assay, a thin layer chromatographic technique was used to separate enzymatically released radioactive galactose. RESULTS: Both galactosylceramide beta-galactosidase (GALC-GC) and GALC-PS activities were reduced by at least 85% of the normal in all but 2 of the 10 GLD patients studied. In particular, one 23-year-old severely demyelinated LOGLD patient was strongly deficient (11% of the normal) in GALC-GC but apparently normal for GALC-PS activity. This patient's GALC genotype was the 30-kb-deleted/502T allele combined with a wild-type allele in the 1637C background known to slightly reduce GALC-GC activity. Further, of six LOGLD patients, both of 62- and 63-year-old brothers had the deleted allele combined with an 809G>A mutated 1637C allele. The sibs had strongly reduced GALC-GC and GALC-PS activities but became clinically remarkable only in their 50s with a severe mental downhill course in one of them. CONCLUSIONS: A GALC genotype with one deleted and one polymorphic GALC activity-reducing allele can lead to enzymatic and clinical signs of LOGLD in the absence of marked GALC-PS deficiency. If an active PS hydrolysis in the fibroblasts of a LOGLD patient also reflected such hydrolysis in the brain, the psychosine hypothesis for GLD may need to be revised.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 256,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson's disease. A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 360,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Management of Spontaneous Intracerebral Hemorrhage. PURPOSE OF REVIEW: We review the current evidence for medical and surgical treatments of spontaneous intracerebral hemorrhage (ICH). RECENT FINDINGS: Therapy with hemostatic agents (e.g. factor VIIa and tranexamic acid) if started early after bleeding onset may reduce hematoma expansion, but their clinical effectiveness has not been shown. Rapid anticoagulation reversal with prothrombin concentrates (PCC) plus vitamin K is the first choice in vitamin K antagonist-related ICH. In ICH related to dabigatran, anticoagulation can be rapidly reversed with idarucizumab. PCC are recommended for ICH related to FXa inhibitors, whereas specific reversal agents are not yet approved. While awaiting ongoing trials studying minimally invasive approaches or hemicraniectomy, the role of surgery in ICH remains to be defined. Therapies targeting downstream molecular cascades in order to prevent secondary neuronal damage are promising, but the complexity and multi-phased nature of ICH pathophysiology is challenging. Finally, in addition to blood pressure control, antithrombotic prevention after ICH has to consider the risk of recurrent bleeding as well as the risk of ischemic events. Treatment of acute ICH remains challenging, and many promising interventions for acute ICH await further evidence from trials.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 551,
                "text": "dabigatran"
            }
        },
        {
            "context": "Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1278,
                "text": "thyroid"
            }
        },
        {
            "context": "Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. PURPOSE: The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. The usual clinical dose of gefitinib (250 mg/d) is only one third of its maximum tolerated dose, whereas the dose of erlotinib (150 mg/d) is at its maximum tolerated dose. In NSCLC cell lines, both TKIs have similar micromolar inhibitory concentrations. We explored whether erlotinib at 25 mg/d (trough serum concentration similar to gefitinib 250 mg/d) would be efficacious in EGFR-mutated NSCLC. METHODS: To study the inhibitory concentrations of gefitinib and erlotinib, we exposed EGFR-mutated cell lines (HCC827, H3255, PC-9, and H1975) to increasing concentrations of these TKIs. Further on, we performed a retrospective evaluation of seven patients with advanced EGFR-mutated (exon 19 deletions and L858R) NSCLC that were given erlotinib at 25 mg/d as their first EGFR TKI. RESULTS: Gefitinib and erlotinib generated similar inhibitory curves across our panel of EGFR-mutated NSCLC cell lines with overlapping mean 50% inhibitory concentration 95% confidence intervals for HCC827, PC-9, and H1975. Both drugs also displayed a high degree of correlation in mean 50% inhibitory concentration (Pearson's r = 0.99, p = 0.0417). Of the seven patients, five patients (71.5%) had partial responses to erlotinib 25 mg/d. Median progression-free survival was 17 months (95% confidence interval, 6-35 months). Toxicities were minimal, with only two (28.5%) patients having a rash and none experiencing (0%) diarrhea. CONCLUSIONS: In NSCLC cell lines, gefitinib and erlotinib have similar inhibitory profiles. In patients with NSCLC and EGFR-activating mutations, a dose of erlotinib 25 mg/d (equivalent to gefitinib 250 mg/d) leads to impressive response rates and progression-free survival similar to the growing experience with the approved doses of gefitinib (250 mg/d) and erlotinib (150 mg/d). Identifying prospectively the lowest and clinically active dose ranges of erlotinib and gefitinib will help further to personalize care for patients with tumors harboring EGFR mutations.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 218,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 2116,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Wilson's disease: an update. Wilson's disease (WD) is an inborn error of copper metabolism caused by a mutation to the copper-transporting gene ATP7B. The disease has an autosomal recessive mode of inheritance, and is characterized by excessive copper deposition, predominantly in the liver and brain. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring, and a new diagnostic scoring system has recently been proposed. Mutations in ATP7B can occur anywhere along the entire 21 exons, which makes the identification of gene defects particularly challenging. Identification of carriers and presymptomatic family members of affected individuals is achieved by polymerase-chain-reaction-based marker analysis. The traditional treatment for WD is based on copper chelation with agents such as D-penicillamine, but use of this drug has been questioned because of reported side effects. The use of agents such as trientine and ammonium tetrathiomolybdate has been advocated, although results of long-term trials are awaited. In selected cases, orthotropic hepatic transplantation can reverse the basic metabolic abnormality in WD and improve both hepatic and neurological symptoms. Studies of the underlying defects in ATP7B and its suspected modifiers ATOX1 and COMMD1 are expected to unravel the disease's genotype-phenotype correlation, and should lead to the design of improved drugs for ameliorating the suffering of patients.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 170,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. UNLABELLED: We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 614,
                "text": "SAM"
            }
        },
        {
            "context": "Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation D307H (CASQ2(D307H)) on Ca2+ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated approximately 4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2(WT)) or CASQ2(D307H). Expression of CASQ2(D307H) reduced the Ca2+ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks were reduced significantly in myocytes expressing CASQ2(D307H). Myocytes expressing CASQ2(D307H) also displayed drastic disturbances of rhythmic oscillations in [Ca2+]i and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca2+ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2(D307H) mutation impairs SR Ca2+ storing and release functions and destabilizes the Ca2+-induced Ca2+ release mechanism by reducing the effective Ca2+ buffering inside the SR and/or by altering the responsiveness of the Ca2+ release channel complex to luminal Ca2+. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 122,
                "text": "calsequestrin"
            }
        },
        {
            "context": "Red hair--a desirable mutation? Red hair is one of the most striking variants of human hair coloration and has historically been of profound social importance. Red hair in man is due to certain loss of function mutations of one of the peptide products of the pro-opiomelanocortin (POMC) gene, the melanocortin-1 receptor (MC1R, MIM 155555). Such functional mutations enable the melanocyte to produce red-yellow pheomelanin in preference to the default, black-brown eumelanin. This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 322,
                "text": "MC1R"
            }
        },
        {
            "context": "Implications of the human microbiome in inflammatory bowel diseases. The study of the human microbiome or community of microorganisms and collection of genomes found in the human body is one of the fastest growing research areas because many diseases are reported to be associated with microbiome imbalance or dysbiosis. With the improvement in novel sequencing techniques, researchers are now generating millions of sequences of different sites from the human body and evaluating specific differences in microbial communities. The importance of microbiome constituency is so relevant that several consortia like the Human Microbiome project (HMP) and Metagenomics of the Human Intestinal Tract (MetaHIT) project are focusing mainly on the human microbiome. The aim of this review is to highlight points of research in this field, mainly focusing on particular factors that modulate the microbiome and important insights into its potential impact on our health and well-being.",
            "question": "What does MetaHIT stand for?",
            "answers": {
                "answer_start": 652,
                "text": "Metagenomics of the Human Intestinal Tract"
            }
        },
        {
            "context": "Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.",
            "question": "To which disease does the loss of CD28 expression by liver-infiltrating T cells contribute?",
            "answers": {
                "answer_start": 85,
                "text": "primary sclerosing cholangitis"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 942,
                "text": "XK"
            }
        },
        {
            "context": "Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 48,
                "text": "HIV"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 479,
                "text": "xa"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 846,
                "text": "Genomiser"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 56,
                "text": "orexin"
            }
        },
        {
            "context": "Genetic modeling of Li-Fraumeni syndrome in zebrafish. Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human familial cancer predisposition. Although a key role for the tumor suppressor p53 has been implicated in LFS, the genetic and cellular mechanisms underpinning this disease remain unknown. Therefore, modeling LFS in a vertebrate system that is accessible to both large-scale genetic screens and in vivo cell biological studies will facilitate the in vivo dissection of disease mechanisms, help identify candidate genes, and spur the discovery of therapeutic compounds. Here, we describe a forward genetic screen in zebrafish embryos that was used to identify LFS candidate genes, which yielded a p53 mutant (p53(I166T)) that as an adult develops tumors, predominantly sarcomas, with 100% penetrance. As in humans with LFS, tumors arise in heterozygotes and display loss of heterozygosity (LOH). This report of LOH indicates that Knudson's two-hit hypothesis, a hallmark of human autosomal dominant cancer syndromes, can be modeled in zebrafish. Furthermore, as with some LFS mutations, the zebrafish p53(I166T) allele is a loss-of-function allele with dominant-negative activity in vivo. Additionally, we demonstrate that the p53 regulatory pathway, including Mdm2 regulation, is evolutionarily conserved in zebrafish, providing a bona fide biological context in which to systematically uncover novel modifier genes and therapeutic agents for human LFS.",
            "question": "What is the inheritance pattern of Li–Fraumeni syndrome?",
            "answers": {
                "answer_start": 105,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1352,
                "text": "Xa"
            }
        },
        {
            "context": "Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment. AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 38,
                "text": "proteasome"
            }
        },
        {
            "context": "Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikrein locus will continue to be an important model in the era of genome-wide analyses.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 138,
                "text": "15"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 4,
                "text": "p53-binding protein 1"
            }
        },
        {
            "context": "A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data. PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 244,
                "text": "liver"
            }
        },
        {
            "context": "[Daratumumab--breakthrough drug in multiple myeloma therapy]. Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 181,
                "text": "CD38"
            }
        },
        {
            "context": "Molecular cloning and expression of alfalfa (Medicago sativa L.) vestitone reductase, the penultimate enzyme in medicarpin biosynthesis. Medicarpin, the major phytoalexin in alfalfa, is synthesized by way of the isoflavonoid branch of phenylpropanoid metabolism. One of the final steps of medicarpin biosynthesis, from vestitone to 7,2'-dihydroxy-4'-methoxyisoflavanol, is catalyzed by vestitone reductase. A 1245-bp cDNA clone which encodes vestitone reductase was identified utilizing internal amino acid sequence of purified vestitone reductase. When expressed in Escherichia coli, the cloned enzyme exhibits strict substrate stereospecificity for (3R)-vestitone, as was observed for vestitone reductase purified from alfalfa. The calculated molecular weight of the protein (35,918) is similar to that of purified vestitone reductase from alfalfa (38 kDa by SDS-PAGE). The levels of vestitone reductase transcript (1.35 kb) greatly increase within 2 h of elicitor addition to alfalfa cell suspension cultures, preceding the rapid increases in vestitione reductase enzyme activity and medicarpin biosynthesis. In healthy alfalfa plants, the highest levels of transcripts were detected in roots and root nodules, consistent with the synthesis of medicarpin and its conjugate in these tissues. The cloning of the vestitone reductase gene provides a specific tool for the study and manipulation of pterocarpan biosynthesis in legumes.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 137,
                "text": "Medicarpin"
            }
        },
        {
            "context": "Successful acne management in Apert syndrome twins. Apert syndrome, or acrocephalosyndactyly, is characterized by craniosynostosis and early epiphyseal closure resulting in various deformities of the skull, hands, and feet. Typically a sporadic condition, autosomal dominant inheritance with complete penetrance has been known to occur. Most adolescents with the disorder are prone to the development of severe pustular facial and truncal acne, with extension to the upper arms and forearm. We report twin brothers with Apert syndrome who, after 2 years of standard management by their pediatrician, were referred for management of complicated acne. In our patients there were a constellation of findings consistent with the disorder and, of importance to this report, significant dermatological manifestations. On presentation, each brother was found to have acne vulgaris of a different stage. Our patients were refractory to conventional treatment for acne but one required and had a significant response to isotretinoin. The risk/benefit ratio in treating acne lesions with isotretinoin in a teenager with Apert syndrome is reviewed.",
            "question": "What is the inheritance pattern of Apert syndrome?",
            "answers": {
                "answer_start": 256,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. BACKGROUND: Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. These three mutations are valuable companion diagnostic biomarkers for guiding personalized treatment. Quantitative polymerase chain reaction (qPCR)-based methods have been widely used in the clinic by physicians to guide treatment decisions. The aim of this study was to evaluate the technical and clinical sensitivity and specificity of the droplet digital polymerase chain reaction (ddPCR) method in detecting the three EGFR mutations in patients with lung cancer. METHODS: Genomic DNA from H1975 and PC-9 cells, as well as 92 normal human blood specimens, was used to determine the technical sensitivity and specificity of the ddPCR assays. Genomic DNA of formalin-fixed, paraffin-embedded specimens from 78 Chinese patients with lung adenocarcinoma were assayed using both qPCR and ddPCR. RESULTS: The three ddPCR assays had a limit of detection of 0.02% and a wide dynamic range from 1 to 20,000 copies measurement. The L858R and ex19del assays had a 0% background level in the technical and clinical settings. The T790M assay appeared to have a 0.03% technical background. The ddPCR assays were robust for correct determination of EGFR mutation status in patients, and the dynamic range appeared to be better than qPCR methods. The ddPCR assay for T790M could detect patient samples that the qPCR method failed to detect. About 49% of this patient cohort had EGFR mutations (L858R, 15.4%; ex19del, 29.5%; T790M, 6.4%). Two patients with the ex19del mutation also had a naïve T790M mutation. CONCLUSION: These data suggest that the ddPCR method could be useful in the personalized treatment of patients with lung cancer.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 298,
                "text": "EGFR"
            }
        },
        {
            "context": "From animal models to human disease: a genetic approach for personalized medicine in ALS. Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 431,
                "text": "ALS"
            }
        },
        {
            "context": "Fam118B, a newly identified component of Cajal bodies, is required for Cajal body formation, snRNP biogenesis and cell viability. Cajal bodies are specialized and dynamic compartments in the nucleus that are involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs). Because of the dynamic and varied roles of Cajal bodies, it is of great interest to identify the components of Cajal bodies to better understand their functions. We performed a genome-wide screen to identify proteins that colocalize with coilin, the marker protein of Cajal bodies. In this study, we identified and characterized Fam118B as a newly discovered component of Cajal bodies. Fam118B is widely expressed in a variety of cell lines derived from various origins. Overexpression of Fam118B changes the canonical morphology of Cajal bodies, whereas depletion of Fam118B disrupts the localization of components of Cajal bodies, including coilin, the survival of motor neuron protein (SMN) and the Sm protein D1 (SmD1, also known as SNRPD1). Moreover, depletion of Fam118B reduces splicing capacity and inhibits cell proliferation. In addition, Fam118B associates with coilin and SMN proteins. Fam118B depletion reduces symmetric dimethylarginine modification of SmD1, which in turn diminishes the binding of SMN to this Sm protein. Taken together, these data indicate that Fam118B, by regulating SmD1 symmetric dimethylarginine modification, plays an important role in Cajal body formation, snRNP biogenesis and cell viability.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 519,
                "text": "coilin"
            }
        },
        {
            "context": "piggyBac is a flexible and highly active transposon as compared to sleeping beauty, Tol2, and Mos1 in mammalian cells. A nonviral vector for highly efficient site-specific integration would be desirable for many applications in transgenesis, including gene therapy. In this study we directly compared the genomic integration efficiencies of piggyBac, hyperactive Sleeping Beauty (SB11), Tol2, and Mos1 in four mammalian cell lines. piggyBac demonstrated significantly higher transposition activity in all cell lines whereas Mos1 had no activity. Furthermore, piggyBac transposase coupled to the GAL4 DNA-binding domain retains transposition activity whereas similarly manipulated gene products of Tol2 and SB11 were inactive. The high transposition activity of piggyBac and the flexibility for molecular modification of its transposase suggest the possibility of using it routinely for mammalian transgenesis.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 341,
                "text": "piggyBac"
            }
        },
        {
            "context": "Inappropriate use of naloxone in cancer patients with pain. Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 210,
                "text": "naloxone"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 363,
                "text": "fungi"
            }
        },
        {
            "context": "Effects of the multiple polyadenylation signal AAUAAA on mRNA 3'-end formation and gene expression. Polyadenylation (poly(A)) of eukaryotic mRNA is a critical step for gene expression. In plants, poly(A) signals leading to the formation of polyadenosine tails after mRNAs include the far upstream elements, the AAUAAA-like signals, and the mRNA cleavage sites for poly(A). Multiple AAUAAA signals leading to alternative polyadenosine formation have been found in many genes, but the effects of each AAUAAA signal on gene expression remain to be uncovered. A DNA fragment, whose transcript contains two canonical AAUAAA signals from the 3'-untranslation region of endochitinase gene of tobacco (Nicotiana tabacum L. cv. W38), was mutated and constructed into the downstream of beta-glucuronidase (GUS) coding region. Transient expression of GUS gene from these constructs indicated that the distal AAUAAA signal from the stop codon was more important than the proximal one in stimulating gene expression. Also, the sequence rather than the distance between the stop codon and the AAUAAA signal region was critical for gene expression. Transgenic tobaccos with these constructs were also generated, and the position of the polyadenosine tail formation in this region was mapped. Results revealed that both AAUAAA signals were functional, and that polyadenosine tails of most transcripts were directed by the distal AAUAAA signal. Finally, the RNA stabilities of these variants in transgenic plants were measured. RNAs from the variants with the functional distal AAUAAA signal were more stable than those with the functional proximal one only. The possible secondary structure in this poly(A) signal region was predicted and discussed.",
            "question": "Which is the RNA sequence of the canonical polyadenylation signal?",
            "answers": {
                "answer_start": 47,
                "text": "AAUAAA"
            }
        },
        {
            "context": "Effect of oxandrolone therapy on adult height in Turner syndrome patients treated with growth hormone: a meta-analysis. Turner syndrome is a chromosomal abnormality in which there is complete or partial absence of the X chromosome. Turner syndrome effects 1 in every 2000 live births. Short stature is a cardinal feature of Turner Syndrome and the standard treatment is recombinant human growth hormone. When growth hormone is started at an early age a normal adult height can be achieved. With delayed diagnosis young women with Turner Syndrome may not reach a normal height. Adjuvant therapy with oxandrolone is used but there is no consensus on the optimal timing of treatment, the duration of treatment and the long term adverse effects of treatment. The objective of this review and meta-analysis is to examine the effect of oxandrolone on adult height in growth hormone treated Turner syndrome patients. Eligible trials were identified by a literature search using the terms: Turner syndrome, oxandrolone. The search was limited to English language randomized-controlled trials after 1980. Twenty-six articles were reviewed and four were included in the meta-analysis. A random effects model was used to calculate an effect size and confidence interval. The pooled effect size of 2.0759 (95 % CI 0.0988 to 4.0529) indicates that oxandrolone has a positive effect on adult height in Turner syndrome when combined with growth hormone therapy. In conclusion, the addition of oxandrolone to growth hormone therapy for treatment of short stature in Turner syndrome improves adult height. Further studies are warranted to investigate if there is a subset of Turner syndrome patients that would benefit most from growth hormone plus oxandrolone therapy, and to determine the optimal timing and duration of such therapy.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 218,
                "text": "X"
            }
        },
        {
            "context": "Functional digestive symptoms and quality of life in patients with Ehlers-Danlos syndromes: results of a national cohort study on 134 patients. BACKGROUND AND OBJECTIVES: Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders. Gastrointestinal manifestations in EDS have been described but their frequency, nature and impact are poorly known. We aimed to assess digestive features in a national cohort of EDS patients. METHODS: A questionnaire has been sent to 212 EDS patients through the French patient support group, all of which had been formally diagnosed according to the Villefranche criteria. The questionnaire included questions about digestive functional symptoms, the GIQLI (Gastrointestinal Quality of Life Index), KESS scoring system and the Rome III criteria. RESULTS: Overall, 135 patients (64% response rate) completed the questionnaire and 134 were analyzable (123 women; 91%). Mean age and Body Mass Index were respectively 35±14.7 years and 24.3±6.1 kg/m(2). The most common EDS subtype was hypermobility form (n=108; 80.6%). GIQLI and KESS median values were respectively 63.5 (27-117) and 19 [13.5-22]. Eighty four percent of patients had functional bowel disorders (FBD) according to the Rome III criteria. An irritable bowel syndrome according to the same criteria was observed in 64 patients (48%) and 48 patients (36%) reported functional constipation. A gastro-esophageal reflux disease (GERD) was reported in 90 patients (68.7%), significantly associated with a poorer GIQLI (60.5±16.8 versus 75.9±20.3; p<0.0001). GIQLI was also negatively impacted by the presence of an irritable bowel syndrome or functional constipation (p=0.007). There was a significant correlation between FBD and GERD. CONCLUSIONS: Natural frequency of gastrointestinal manifestations in EDS seems higher than previously assessed. FBD and GERD are very common in our study population, the largest ever published until now. Their impact is herein shown to be important. A systematic clinical assessment of digestive features should be recommended in EDS.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 240,
                "text": "connective tissue"
            }
        },
        {
            "context": "r3Cseq: an R/Bioconductor package for the discovery of long-range genomic interactions from chromosome conformation capture and next-generation sequencing data. The coupling of chromosome conformation capture (3C) with next-generation sequencing technologies enables the high-throughput detection of long-range genomic interactions, via the generation of ligation products between DNA sequences, which are closely juxtaposed in vivo. These interactions involve promoter regions, enhancers and other regulatory and structural elements of chromosomes and can reveal key details of the regulation of gene expression. 3C-seq is a variant of the method for the detection of interactions between one chosen genomic element (viewpoint) and the rest of the genome. We present r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a number of different experimental designs. The package reads a common aligned read input format, provides data normalization, allows the visualization of candidate interaction regions and detects statistically significant chromatin interactions, thus greatly facilitating hypothesis generation and the interpretation of experimental results. We further demonstrate its use on a series of real-world applications.",
            "question": "Which package is available for analysing genomic interactions in R/Bioconductor?",
            "answers": {
                "answer_start": 0,
                "text": "r3Cseq"
            }
        },
        {
            "context": "Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 16,
                "text": "MITF"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 134,
                "text": "tyr"
            }
        },
        {
            "context": "BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 88,
                "text": "PARP"
            }
        },
        {
            "context": "Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 911,
                "text": "xa"
            }
        },
        {
            "context": "[Molecular-genetic aspects of neurofibromatosis]. Two forms of neurofibromatosis, type 1 (NF1) and type 2 (NF2) are connected with genes localized on chromosomes 17 and 22, respectively. The genes that are inactivated in neurofibromatosis code for the proteins neurofibromine and merline, respectively. Since inactivation leads to neoplasia, they are called tumour suppressor genes. Neurofibromine shows resemblances to proteins that serve to inactivate oncogenes. Merline has a relationship with proteins that connect the cytoskeleton and the cell membrane. The precise function of the proteins is still unknown. The NF1 gene is characterized by extraordinarily high sensitivity to mutation; half the NF1 patients have not inherited the disease. In the familial form of neurofibromatosis, a mutated gene is inherited and the normal allele in the tumour is inactivated, making tumour growth possible. In the sporadic form of neurofibromatosis, both normal alleles are inactivated locally in the tissue so that a tumour develops in that place.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 90,
                "text": "NF1"
            }
        },
        {
            "context": "Targeted drugs in chronic myeloid leukemia. Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. The BCR-ABL gene encodes for a 210-kD protein with deregulated tyrosine kinase (TK) activity, which is crucial for malignant transformation in CML. The recognition of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, designed to interfere with BCR-ABL tyrosine kinase activation by competitive binding at the ATP-binding site. The first tyrosine kinase inhibitor (TKI), introduced into clinical practice in 1998, was imatinib mesylate. Imatinib became the first choice drug in chronic phase CML, because of its high efficacy, low toxicity and ability to maintain durable hematological and cytogenetic responses. However, approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance, which is often caused by the appearance of clones expressing mutant forms of BCR-ABL. Second-generation TKIs have provided new therapeutic option for the patients resistant to imatinib. Dasatinib is the first, second-generation TKI, approved in the US and European Union for the treatment of CML patients with imatinib resistance or intolerance. This drug is a dual SRC-ABL kinase inhibitor, active in most clinically relevant BCR-ABL mutations, except highly resistant T315I. Other second-generation TKIs include nilotinib, bosutinib and INNO 406. Apart from TKIs, the promising group of molecules is inhibitors of Aurora family of serine-threonine kinases. One of these molecules, MK0457, has entered clinical trials, and initial reports indicate that this compound could be active in disease associated with T315I mutation. Thus, wide spectrum of new agents, with different mode of action, is currently in clinical development for CML. It is likely that combination therapy will be the best therapeutic strategy in the future.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 301,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, approximately equal to 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate to carbamazepine or whose ECG shows abnormalities typical to those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 286,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Melanocortin receptors, red hair, and skin cancer. Cutaneous pigmentation is a major determinant of the cutaneous response to ultraviolet radiation, and consequently of the risk of developing skin cancer. Over the past 10 years, several genes involved in melanogenesis have been identified, including the melanocortin 1 receptor gene. Recent work on the melanocortin 1 receptor suggests that it is a key player in determining whether eumelanin or pheomelanin is predominantly produced both in vitro and in vivo. In the mouse, variants of this receptor, which differ in their ability to activate adenylyl cyclase, are associated with different coat colors. In humans, melanocortin 1 receptor variants are associated with red hair and fair skin, and work in progress from our laboratory suggests that certain melanocortin 1 receptor variants may preferentially be associated with hair color rather than skin type. In addition, melanocortin 1 receptor variants are a risk factor, possibly independent of skin type, for melanoma susceptibility.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 807,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Mood disorders in restless legs syndrome (Willis-Ekbom disease). OBJECTIVE: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. This narrative review provides an overview of RLS diagnosis and reports epidemiologic evidence for an association between RLS and mood disorders. Possible links between RLS, sleep disturbances, and mood disorders are considered, and theoretical pathophysiologic pathways are discussed. Finally, pharmacologic therapies for RLS are summarized. DATA SOURCES: A PubMed search was performed using the search term restless legs syndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety disorder, attention deficit hyperactivity disorder, depression/depressive disorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, psychiatric disorder, and psychosis. English-language articles published between January 1993 and May 2013 were retrieved. Additional studies were identified from the reference lists of relevant publications. STUDY SELECTION: 173 publications were retrieved. Articles related to the association between idiopathic RLS and depression, anxiety, and mood disorders were reviewed. In total, 32 epidemiologic studies were identified. These studies were reviewed in detail and ranked according to quality. DATA EXTRACTION: Data were extracted on the basis of relevance to the topic. Epidemiologic studies were assessed using 3 parameters: methodology, data quality, and generalizability of the results. Each factor was scored from 1 (high quality) to 4 (low quality), giving a total score of between 3 and 12 for each study. RESULTS AND CONCLUSIONS: RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 76,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Microsporidian infection in a free-living marine nematode. Microsporidia are unicellular fungi that are obligate endoparasites. Although nematodes are one of the most abundant and diverse animal groups, the only confirmed report of microsporidian infection was that of the \"nematode killer\" (Nematocida parisii). N. parisii was isolated from a wild Caenorhabditis sp. and causes an acute and lethal intestinal infection in a lab strain of Caenorhabditis elegans. We set out to characterize a microsporidian infection in a wild nematode to determine whether the infection pattern of N. parisii in the lab is typical of microsporidian infections in nematodes. We describe a novel microsporidian species named Sporanauta perivermis (marine spore of roundworms) and characterize its infection in its natural host, the free-living marine nematode Odontophora rectangula. S. perivermis is not closely related to N. parisii and differs strikingly in all aspects of infection. Examination by transmission electron microscopy (TEM) revealed that the infection was localized in the hypodermal and muscle tissues only and did not involve the intestines. Fluorescent in situ hybridization (FISH) confirmed infection in the muscle and hypodermis, and surprisingly, it also revealed that the parasite infects O. rectangula eggs, suggesting a vertical mode of transmission. Our observations highlight the importance of studying parasites in their natural hosts and indicate that not all nematode-infecting microsporidia are \"nematode killers\"; instead, microsporidiosis can be more versatile and chronic in the wild.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 89,
                "text": "fungi"
            }
        },
        {
            "context": "Crystal structure and functional analysis of the histone methyltransferase SET7/9. Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity. We present here the crystal structure of a large fragment of human SET7/9 that contains a N-terminal beta-sheet domain as well as the conserved SET domain. Mutagenesis identifies two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3. Furthermore, we show how the cofactor AdoMet binds to this domain and present biochemical data supporting the role of invariant residues in catalysis, binding of AdoMet, and interactions with the peptide substrate.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 279,
                "text": "SET domain"
            }
        },
        {
            "context": "RAS2 regulates growth and pathogenesis in Fusarium graminearum. Fusarium graminearum is a ubiquitous pathogen of cereal crops, including wheat, barley, and maize. Diseases caused by F. graminearum are of particular concern because harvested grains frequently are contaminated with harmful mycotoxins such as deoxynivalenol (DON). In this study, we explored the role of Ras GTPases in pathogenesis. The genome of F. graminearum contains two putative Ras GTPase-encoding genes. The two genes (RAS1 and RAS2) showed different patterns of expression under different conditions of nutrient availability and in various mutant backgrounds. RAS2 was dispensable for survival but, when disrupted, caused a variety of morphological defects, including slower growth on solid media, delayed spore germination, and significant reductions in virulence on wheat heads and maize silks. Intracellular cAMP levels were not affected by deletion of RAS2 and exogenous treatment of the ras2 mutant with cAMP did not affect phenotypic abnormalities, thus indicating that RAS2 plays a minor or no role in cAMP signaling. However, phosphorylation of the mitogen-activated protein (MAP) kinase Gpmk1 and expression of a secreted lipase (FGL1) required for infection were reduced significantly in the ras2 mutant. Based on these observations, we hypothesize that RAS2 regulates growth and virulence in F. graminearum by regulating the Gpmk1 MAP kinase pathway.",
            "question": "The pathogen Fusarium graminearum affects what type of plant species?",
            "answers": {
                "answer_start": 113,
                "text": "cereal crops"
            }
        },
        {
            "context": "Analysis of banana transcriptome and global gene expression profiles in banana roots in response to infection by race 1 and tropical race 4 of Fusarium oxysporum f. sp. cubense. BACKGROUND: Cavendish, the most widely grown banana cultivar, is relatively resistant to Race 1 of Fusarium oxysporum f. sp. cubense (Foc1) which caused widespread Panama disease during the first half of the 20th century but is susceptible to Tropical Race 4 of Foc (Foc TR4) which is threatening world banana production. The genome of the diploid species Musa acuminata which is the ancestor of a majority of triploid banana cultivars has recently been sequenced. Availability of banana transcriptomes will be highly useful for improving banana genome annotation and for biological research. The knowledge of global gene expression patterns influenced by infection of different Foc races will help to understand the host responses to the infection. RESULTS: RNA samples from different organs of the Cavendish cultivar were pooled for deep sequencing using the Illumina technology. Analysis of the banana transcriptome led to identification of over 842 genes that were not annotated by the Musa genome project. A large number of simple nucleotide polymorphisms (SNPs) and short insertions and deletion (indels) were identified from the transcriptome data. GFP-expressing Foc1 and Foc TR4 were used to monitor the infection process. Both Foc1 and Foc TR4 were found to be able to invade banana roots and spread to root vascular tissues in the first two days following inoculation. Digital gene expression (DGE) profiling analysis reveal that the infection by Foc1 and Foc TR4 caused very similar changes in the global gene expression profiles in the banana roots during the first two days of infection. The Foc infection led to induction of many well-known defense-related genes. Two genes encoding the ethylene biosynthetic enzyme ACC oxidase and several ethylene-responsive transcription factors (ERF) were among the strongly induced genes by both Foc1 and Foc TR4. CONCLUSIONS: Both Foc1 and Foc TR4 are able to spread into the vascular system of banana roots during the early infection process and their infection led to similar gene expression profiles in banana roots. The transcriptome profiling analysis indicates that the ethylene synthetic and signalling pathways were activated in response to the Foc infection.",
            "question": "What is the causative agent of the \"Panama disease\" affecting bananas?",
            "answers": {
                "answer_start": 277,
                "text": "Fusarium oxysporum f. sp. cubense"
            }
        },
        {
            "context": "Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 83,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 757,
                "text": "CD38"
            }
        },
        {
            "context": "Excessive iron storage in a patient with Wilson's disease. We report on an otherwise healthy female, mother of two children, with severe decompensated liver cirrhosis due to an iron overload and Wilson's disease. The patient was considered heterozygote for hemochromatosis on the basis of the autosomal recessive inheritance for hemochromatosis, the frequency of the hemochromatosis gene, and the laboratory parameters defining her iron overload. The case is interesting because of the coincidence of Wilson's disease and excessive iron storage.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 293,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Using MRSA Screening Tests To Predict Methicillin Resistance in Staphylococcus aureus Bacteremia. Bloodstream infections with Staphylococcus aureus are clinically significant and are often treated with empirical methicillin resistance (MRSA, methicillin-resistant S. aureus) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in S. aureus bacteremia and could help determine the requirement for empirical vancomycin therapy. We reviewed consecutive S. aureus bacteremias over a 5-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-day criterion), as tested within 30 days but accounting for any prior positive results (ever-positive criterion), or as tested in known-positive patients, with patients with unknown MRSA status being labeled negative (known-positive criterion). There were 409 S. aureus bacteremias: 302 (73.8%) methicillin-susceptible S. aureus (MSSA) and 107 (26.2%) MRSA bacteremias. In the 167 patients with MSSA bacteremias, 7.2% had a positive MRSA test within 30 days. Of 107 patients with MRSA bacteremia, 68 were tested within 30 days (54 positive; 79.8%), and another 21 (19.6%) were previously positive. The 30-day criterion provided negative predictive values (NPV) exceeding 90% and 95% if the prevalence of MRSA in S. aureus bacteremia was less than 33.4% and 19.2%, respectively. The same NPVs were predicted at MRSA proportions below 39.7% and 23.8%, respectively, for the ever-positive criterion and 34.4% and 19.9%, respectively, for the known-positive criterion. In MRSA-colonized patients, positive predictive values exceeded 50% at low prevalence. MRSA screening could help avoid empirical vancomycin therapy and its complications in stable patients and settings with low-to-moderate proportions of MRSA bacteremia.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 242,
                "text": "methicillin-resistant S. aureus"
            }
        },
        {
            "context": "Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 5,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1435,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR. Many neurodegenerative diseases are associated with the aggregation of misfolded proteins into amyloid oligomers or fibrils that are deposited as pathological lesions within areas of the brain. An attractive therapeutic strategy for preventing or ameliorating amyloid formation is to identify agents that inhibit the onset or propagation of protein aggregation. Here we demonstrate how solid-state nuclear magnetic resonance (ssNMR) may be used to identify key residues within amyloidogenic protein sequences that may be targeted to inhibit the aggregation of the host protein. For alpha-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease, we have used a combination of ssNMR and biochemical data to identify the key region for self-aggregation of the protein as residues 77-82 (VAQKTV). We used our new structural information to design a peptide derived from residues 77 to 82 of alpha-synuclein with an N-methyl group at the C-terminal residue, which was able to disrupt the aggregation of alpha-synuclein. Thus, we have shown how structural data obtained from ssNMR can guide the design of modified peptides for use as amyloid inhibitors, as a primary step toward developing therapeutic compounds for prevention and/or treatment of amyloid diseases.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 684,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 1005,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 0,
                "text": "Chromosome XII"
            }
        },
        {
            "context": "When hepatoma rupture happens in situs inversus totalis: side matters. The authors reported a 73-year-old alcoholic man with previously-unrecognized situs inversus totalis suffering from left upper quadrant pain. Acute myocardial infarction was diagnosed and coronary angioplasty was performed immediately. However, the massive bleeding from the previously-unfound hepatomas caused hypovolemic shock and fatal outcome. Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. Although being considered a benign entity, it would disturb diagnosis-making of the visceral diseases owing to the altered anatomy. To our knowledge, the coexistence of the coronary artery disease and ruptured hepatomas in situs inversus totalis, as in our patient, is never described. Recognition of any situs anomalies in time is the key to avoid misdiagnosis, inappropriate managements, and unwanted consequences.",
            "question": "What is situs inversus?",
            "answers": {
                "answer_start": 419,
                "text": "Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs."
            }
        },
        {
            "context": "Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 859,
                "text": "Xa"
            }
        },
        {
            "context": "Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 101,
                "text": "7"
            }
        },
        {
            "context": "Intralobular ducts of human major salivary glands contain leptin and its receptor. Leptin, a 16-kDa hormone, plays an important role in the control of food intake and in energy homeostasis both in rodents and in man. Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode. In addition, a leptin receptor has been detected in taste cells of mouse circumvallate papillae and in rat intestinal epithelium. These data prompted us to carry out a detailed study of human salivary glands as potential leptin-producing organs. Biopsies of salivary glands (submandibular and parotid) obtained from male and female patients during surgery for different clinical indications were subjected to immunohistochemical study for the presence of leptin, its functional receptor, insulin and glucagon. The presence and cellular distribution of glucocorticoid receptor in leptin-secreting cells were also investigated. Double immunohistochemical staining (silver-gold intensification and avidin-biotin-peroxidase) was used for the visualization of glucocorticoid receptor and leptin labelling, respectively. The results show that intralobular duct cells of submandibular and parotid glands are immunoreactive for leptin, leptin receptor and glucagon but not for insulin. Leptin was also detected in some microglobules in whole saliva obtained from four healthy volunteers. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands.",
            "question": "From which cell type is leptin secreted?",
            "answers": {
                "answer_start": 259,
                "text": "adipocytes"
            }
        },
        {
            "context": "Subviral pathogens of plants: viroids and viroidlike satellite RNAs. Contrary to earlier beliefs, viruses are not the smallest causative agents of infectious diseases. Single-stranded RNAs as small as 246 nucleotides exist in certain higher plants and cause more than a dozen crop diseases. These RNAs have been termed viroids. Despite their extremely limited information content, viroids replicate autonomously in susceptible cells--that is, they do not require helper functions from simultaneously replicating conventional viruses. Viroids are covalently closed circular molecules with a characteristic rodlike secondary structure in which short helical regions are interrupted by internal and bulge loops. Viroids are not translated; they are replicated by a host enzyme (or enzymes) (probably RNA polymerase II) via oligomeric RNA intermediates by a rolling circle mechanism. Viroidlike satellite RNAs resemble viroids in size and molecular structure, but are found within the capsids of specific helper viruses on which they depend for their own replication. These RNAs are of great interest to molecular biology for at least two reasons: 1) they are the smallest and simplest replicating molecules known, and 2) they may represent living fossils of precellular evolution in a hypothetical RNA world.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 30,
                "text": "viroids"
            }
        },
        {
            "context": "Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 558,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy. Many recent studies have shown that DOX toxicity involves generation of reactive oxygen species (ROS). Although protection or alleviation of DOX toxicity can be achieved by administration of antioxidant vitamins such as ascorbic acid and vitamin E, their cardioprotective effect remains controversial. Thus alternative naturally occurring antioxidants may potentially be candidates for antioxidant therapy. In this study, we investigated the antioxidative and cytoprotective effects of Phyllanthus urinaria (PU) against DOX toxicity using H9c2 cardiac myoblasts. The total antioxidant capacity of PU (1 mg/ml) was 5306.75+/-461.62 FRAP value (microM). DOX IC50 values were used to evaluate the cytoprotective effects of PU ethanolic extract (1 or 10 microg/ml) in comparison with those of ascorbic acid (VIT C, 100 microM) and N-acetylcysteine (NAC, 100 microM). PU treatments (1 or 10 microg/ml) dose dependently caused rightward DOX IC50 shifts of 2.8- and 8.5-fold, respectively while treatments with VIT C and NAC increased DOX IC50 by 3.3- and 4.2-fold, respectively. Additionally, lipid peroxidation and caspase-3 activity were parameters used to evaluate cytoprotective effect. All antioxidants completely inhibited cellular lipid peroxidation and caspase-3 activation induced by DOX (1 microM). Endogenous antioxidant defense such as total glutathione (tGSH), catalase and superoxide dismutase (SOD) activity was also modulated by the antioxidants. PU treatment alone dose dependently increased tGSH, and this effect was retained in the presence of DOX. Similar effect was observed in the assessment of catalase and SOD enzyme activity. The nuclear factor kappaB (NFkappaB) transcription factor assay demonstrated that all antioxidants significantly inhibited DOX-induced NFkappaB activation. Our results suggest that PU protection against DOX cardiotoxicity was mediated through multiple pathways and this plant may serve as an alternative source of antioxidants for prevention of DOX cardiotoxicity.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 109,
                "text": "Cardiac toxicity"
            }
        },
        {
            "context": "Inhibition of CaM kinase II activation and force maintenance by KN-93 in arterial smooth muscle. Ca(+)/calmodulin-dependent protein kinase II (CaM kinase II) has been implicated in the regulation of smooth muscle contractility. The goals of this study were to determine: 1) to what extent CaM kinase II is activated by contractile stimuli in intact arterial smooth muscle, and 2) the effect of a CaM kinase II inhibitor (KN-93) on CaM kinase II activation, phosphorylation of myosin regulatory light chains (MLC(20)), and force. Both histamine (1 microM) and KCl depolarization activated CaM kinase II with a time course preceding maximal force development, and suprabasal CaM kinase II activation was sustained during tonic contractions. CaM kinase II activation was inhibited by KN-93 pretreatment (IC(50) approximately 1 microM). KN-93 inhibited histamine-induced tonic force maintenance, whereas early force development and MLC(20) phosphorylation responses during the entire time course were unaffected. Both force development and maintenance in response to KCl were inhibited by KN-93. Rapid increases in KCl-induced MLC(20) phosphorylation were also inhibited by KN-93, whereas steady-state MLC(20) phosphorylation responses were unaffected. In contrast, phorbol 12,13-dibutyrate (PDBu) did not activate CaM kinase II and PDBu-stimulated force development was unaffected by KN-93. Thus KN-93 appears to target a step(s) essential for force maintenance in response to physiological stimuli, suggesting a role for CaM kinase II in regulating tonic contractile responses in arterial smooth muscle. Pharmacological activation of protein kinase C bypasses the KN-93 sensitive step.",
            "question": "Which kinase is inhibited by the small molecule KN-93?",
            "answers": {
                "answer_start": 739,
                "text": "CaM kinase II"
            }
        },
        {
            "context": "Mutations in MED12 cause X-linked Ohdo syndrome. Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.",
            "question": "What is the genetic basis of Ohdo syndrome?",
            "answers": {
                "answer_start": 1048,
                "text": "mutations in MED12"
            }
        },
        {
            "context": "The CURB65 pneumonia severity score outperforms generic sepsis and early warning scores in predicting mortality in community-acquired pneumonia. BACKGROUND: The performance of CURB65 in predicting mortality in community-acquired pneumonia (CAP) has been tested in two large observational studies. However, it has not been tested against generic sepsis and early warning scores, which are increasingly being advocated for identification of high-risk patients in acute medical wards. METHOD: A retrospective analysis was performed of data prospectively collected for a CAP quality improvement study. The ability to stratify mortality and performance characteristics (sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating curve) were calculated for stratifications of CURB65, CRB65, the systemic inflammatory response syndrome (SIRS) criteria and the standardised early warning score (SEWS). RESULTS: 419 patients were included in the main analysis with a median age of 74 years (men = 47%). CURB65 and CRB65 stratified mortality in a more clinically useful way and had more favourable operating characteristics than SIRS or SEWS; for example, mortality in low-risk patients was 2% when defined by CURB65, but 9% when defined by SEWS and 11-17% when defined by variations of the SIRS criteria. The sensitivity, specificity, positive predictive value and negative predictive value of CURB65 was 71%, 69%, 35% and 91%, respectively, compared with 62%, 73%, 35% and 89% for the best performing version of SIRS and 52%, 67%, 27% and 86% for SEWS. CURB65 had the greatest area under the receiver operating curve (0.78 v 0.73 for CRB65, 0.68 for SIRS and 0.64 for SEWS). CONCLUSIONS: CURB65 should not be supplanted by SIRS or SEWS for initial prognostic assessment in CAP. Further research to identify better generic prognostic tools is required.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 134,
                "text": "pneumonia"
            }
        },
        {
            "context": "Latest concept of Lewy body disease. We proposed the term 'Lewy body disease' (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brainstem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. LBD has neuropathological characteristics whereby numerous Lewy bodies are present in the central and sympathetic nervous systems, and it is a type of alpha-synucleinopathy because the main component of Lewy body is alpha-synuclein. In this paper we explain the most recent concept of LBD from the historical viewpoint.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 614,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Translation of the Philadelphia chromosome into therapy for CML. Throughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy. These range from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease. The successful development of imatinib as a therapeutic agent for CML can be attributed directly to decades of scientific discoveries. These discoveries determined that the BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib, with imatinib significantly improving the long-term survival of patients with CML. Continuing in this tradition of scientific discoveries leading to improved therapies, the understanding of resistance to imatinib has rapidly led to strategies to circumvent resistance. Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 530,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1266,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials ( < 104 weeks' duration; typically 24 weeks' duration) and extension studies (typically  > 76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 52,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes: A Clinical Update of Safety and Efficacy. INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. METHODS: A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized. RESULTS: Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events. CONCLUSION: GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer.",
            "question": "Which disease is treated with semaglutide?",
            "answers": {
                "answer_start": 222,
                "text": "type 2 diabetes"
            }
        },
        {
            "context": "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in > 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 154,
                "text": "CD38"
            }
        },
        {
            "context": "Clinical correlates of 'BRCAness' in triple-negative breast cancer of patients receiving adjuvant chemotherapy. BACKGROUND: We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients. PATIENTS AND METHODS: DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups. Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival. CONCLUSIONS: BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.",
            "question": "What is the most probable defect underlying triple negative breast cancer?",
            "answers": {
                "answer_start": 263,
                "text": "BRCA1 dysfunction"
            }
        },
        {
            "context": "The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. BACKGROUND: Interleukin-6 (IL-6) is associated with prostate cancer morbidity. In several experimental models, IL-6 has been reported to have anti-apoptotic and pro-angiogenic effects. Siltuximab (CNTO 328) is a monoclonal anti-IL-6 antibody which has been successfully applied in several models representing prostate cancer. This study was designed to assess preliminary safety of siltuximab in patients with early prostate cancer. PATIENTS AND METHODS: Twenty patients scheduled to undergo radical prostatectomy received either no drug or siltuximab (6 mg/kg, five patients per group with administration once, two times, and three times prior to surgery). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Expression of elements of IL-6 signaling pathways was analyzed in tumor tissue by immunohistochemistry. Gene analysis in tumor specimens was performed with the DASL array. RESULTS: No adverse events related to siltuximab were observed. Patients treated with siltuximab presented with higher levels of proliferation and apoptosis markers. Following a single dose, serum concentrations of siltuximab declined in a biexponential manner. This study revealed a decrease in phosphorylation of Stat3 and p44/p42 mitogen-activated protein kinases. In addition, gene expression analyses indicate down-regulation of genes immediately downstream of the IL-6 signaling pathway and key enzymes of the androgen signaling pathway. CONCLUSIONS: Preliminary safety of siltuximab is favorable. Future studies in which siltuximab could be combined with androgen-deprivation therapy and experimental therapies in advanced prostate cancer are justified.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 9,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Self-reported ill health in male UK Gulf War veterans: a retrospective cohort study. BACKGROUND: Forces deployed to the first Gulf War report more ill health than veterans who did not serve there. Many studies of post-Gulf morbidity are based on relatively small sample sizes and selection bias is often a concern. In a setting where selection bias relating to the ill health of veterans may be reduced, we: i) examined self-reported adult ill health in a large sample of male UK Gulf War veterans and a demographically similar non-deployed comparison group; and ii) explored self-reported ill health among veterans who believed that they had Gulf War syndrome. METHODS: This study uses data from a retrospective cohort study of reproduction and child health in which a validated postal questionnaire was sent to all UK Gulf War veterans (GWV) and a comparison cohort of Armed Service personnel who were not deployed to the Gulf (NGWV). The cohort for analysis comprises 42,818 males who responded to the questionnaire. RESULTS: We confirmed that GWV report higher rates of general ill health. GWV were significantly more likely to have reported at least one new medical symptom or disease since 1990 than NGWV (61% versus 37%, OR 2.7, 95% CI 2.5-2.8). They were also more likely to report higher numbers of symptoms. The strongest associations were for mood swings (OR 20.9, 95%CI 16.2-27.0), memory loss/lack of concentration (OR 19.6, 95% CI 15.5-24.8), night sweats (OR 9.9, 95% CI 6.5-15.2), general fatigue (OR 9.6, 95% CI 8.3-11.1) and sexual dysfunction (OR 4.6, 95%CI 3.2-6.6). 6% of GWV believed they had Gulf War syndrome (GWS), and this was associated with the highest symptom reporting. CONCLUSIONS: Increased levels of reported ill health among GWV were confirmed. This study was the first to use a questionnaire which did not focus specifically on the veterans' symptoms themselves. Nevertheless, the results are consistent with those of other studies of post-Gulf war illness and thus strengthen overall findings in this area of research. Further examination of the mechanisms underlying the reporting of ill health is required.",
            "question": "What memory problems are reported in the \" Gulf war syndrome\"",
            "answers": {
                "answer_start": 1394,
                "text": "memory loss"
            }
        },
        {
            "context": "Using Mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes. Plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. To understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. Since extensive data support the proposal that foreign DNA acquires the host's nucleotide composition during long-term residence, comparison of nucleotide composition of plasmids and chromosomes could shed light on a plasmid's evolutionary history. The average absolute dinucleotide relative abundance difference, termed delta-distance, has been commonly used to measure differences in dinucleotide composition, or 'genomic signature', between bacterial chromosomes and plasmids. Here, we introduce the Mahalanobis distance, which takes into account the variance-covariance structure of the chromosome signatures. We demonstrate that the Mahalanobis distance is better than the delta-distance at measuring genomic signature differences between plasmids and chromosomes of potential hosts. We illustrate the usefulness of this metric for proposing candidate long-term hosts for plasmids, focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from Escherichia coli O157:H7, as well as the broad host range multi-drug resistance plasmid pB10 from an unknown host.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 767,
                "text": "delta-distance"
            }
        },
        {
            "context": "Sudden cardiac death in patients with hypertrophic cardiomyopathy: from bench to bedside with an emphasis on genetic markers. Hypertrophic cardiomyopathy (HCM) is the most common cause of death in the young, particularly in young competitive athletes. Death often occurs suddenly in asymptomatic, apparently healthy individuals. Several clinical parameters as well as genetic factors have been characterized that can identify those HCM patients who are at high risk for sudden cardiac death (SCD). The clinical parameters that have some predictive values for SCD in HCM patients are the following: a prior history of SCD, a family history of SCD, history of syncope, symptomatic ventricular tachycardia on Holter monitoring, inducible ventricular tachycardia during electrophysiologic studies, and myocardial ischemia in children with HCM. Recent identification of mutations in the beta myosin heavy chain gene and genotype-phenotype correlation in HCM patients have shown that the beta myosin heavy chain mutations are also prognosticators in HCM families. Several mutations such as Arg403Gln and Arg719Gln are associated with a high incidence of SCD, while Leu908Val mutation is associated with a benign course and a low incidence of SCD in HCM families. Additional genetic factors such as a polymorphism in angiotensin-converting enzyme I gene may also contribute to a high incidence of SCD in HCM families. Identification and characterization of HCM patients at high risk for SCD provide the opportunity to render prophylactic therapeutic interventions, such as implantation of defibrillators, in these individuals.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 126,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Spontaneous resolution of invasive cerebral aspergillosis following partial resection in a medically untreated infant. Invasive craniocerebral aspergillosis, often encountered in an immunocompromised setting, is almost uniformly fatal despite radical surgical and medical management, and is frequently a necropsy finding. The authors report a unique, self-resolving clinical course of this aggressive infection in a 10-month-old infant. The infant was brought to the emergency services in altered sensorium with a 1-week history of left-sided hemiparesis, excessive irritability, and vomiting. An MRI study of the brain revealed multiple, heterogeneously enhancing lesions in the right cerebral hemisphere with mass effect. The largest lesion in the frontotemporal cortical and subcortical regions was decompressed on an emergent basis. Histopathological findings were suggestive of invasive aspergillosis, although there was no evidence of the infection in the lungs or paranasal sinuses. Computed tomography-guided aspiration of the remaining lesions and follow-up antifungal therapy were recommended. The parents, however, requested discharge without further treatment. The child was seen at a follow-up visit 3 years later without having received any antifungal treatment. Imaging showed resolution of the infection and features of Dyke-Davidoff-Masson syndrome (cerebral hemiatrophy). This report of invasive cerebral aspergillosis resolving without medical therapy is the first of its kind. Its clinicoradiological aspects are discussed in light of previously reported cases.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 1367,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and p73. The small heat shock protein alphaB-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the alphaB-crystallin gene, we examined the alphaB-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced alphaB-crystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of alphaB-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an alphaB-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the alphaB-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. DeltaNp73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of alphaB-crystallin by p53. Moreover, ectopic expression of DeltaNp73alpha (but not other p73 isoforms) increased alphaB-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone alphaB-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1280,
                "text": "7"
            }
        },
        {
            "context": "Thyroid function and morphology in patients affected by Williams syndrome. OBJECTIVE: To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of patients with Williams syndrome (WS). METHODS: Serum concentrations of free-T3, free-T4, TSH, thyroperoxidase antibodies (TPOA) and thyroglobulin antibodies (TgA), as well as ultrasonographic data, of 20 patients with WS (12 females and eight males), aged 1.7-34.9 years, were evaluated. RESULTS: Three cases (15%) of subclinical hypothyroidism were identified. Overt hypothyroidism was diagnosed in two cases (10%). Thyroid antibodies were negative in all patients. Fourteen patients (70%) showed thyroid hypoplasia involving the entire gland. In these patients, the left thyroid lobe appeared usually, but not significantly, reduced compared with the right thyroid lobe. One patient (5%) showed thyroid hemiagenesis. Only five patients (25%) showed a thyroid with normal volume, and of these five, one patient showed marked thyroid hypoplasia of the left lobe. In all WS patients with diagnosis of subclinical or overt hypothyroidism, thyroid hypoplasia was detected. No cases of subclinical or overt hypothyroidism were found in WS with normal thyroid volume. CONCLUSIONS: This study confirms the presence of alterations of thyroid function in WS and also suggests the frequent occurrence of abnormalities of thyroid morphology in these patients. Patients with WS should be monitored for thyroid function and a thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 552,
                "text": "thyroid"
            }
        },
        {
            "context": "Breathing dysfunction in Rett syndrome: understanding epigenetic regulation of the respiratory network. Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction. Recent studies have begun to characterize the breathing phenotype of Mecp2 mutant mice and to define underlying electrophysiological and neurochemical deficits. The picture that is emerging is one of defects in synaptic transmission throughout the brainstem respiratory network associated with abnormal expression in several neurochemical signaling systems, including brain-derived neurotrophic factor (BDNF), biogenic amines and gamma-amino-butyric acid (GABA). Based on such findings, potential therapeutic strategies aimed at improving breathing by targeting deficits in neurochemical signaling are being explored. This review details our current understanding of respiratory dysfunction and underlying mechanisms in RTT with a particular focus on insights gained from mouse models.",
            "question": "Which methyl-CpG-binding protein when mutant becomes the hallmark for Rett syndrome?",
            "answers": {
                "answer_start": 316,
                "text": "methyl-CpG-binding protein 2 (Mecp2)"
            }
        },
        {
            "context": "The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. PURPOSE: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. EXPERIMENTAL DESIGN: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat. RESULTS: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC(50) 0.45 micromol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed approximately 70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth. CONCLUSION: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 632,
                "text": "telomerase"
            }
        },
        {
            "context": "Kell and XK immunohistochemistry in McLeod myopathy. The McLeod syndrome is an X-linked neuroacanthocytosis manifesting with myopathy and progressive chorea. It is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein of yet unknown function. In erythroid tissues, XK forms a functional complex with the Kell glycoprotein. Here, we present an immunohistochemical study in skeletal muscle of normal controls and a McLeod patient with a XK gene point mutation (C977T) using affinity-purified antibodies against XK and Kell proteins. Histological examination of the affected muscle revealed the typical pattern of McLeod myopathy including type 2 fiber atrophy. In control muscles, Kell immunohistochemistry stained sarcoplasmic membranes. XK immunohistochemistry resulted in a type 2 fiber-specific intracellular staining that was most probably confined to the sarcoplasmic reticulum. In contrast, there was only a weak background signal without a specific staining pattern for XK and Kell in the McLeod muscle. Our results demonstrate that the lack of physiological XK expression correlates to the type 2 fiber atrophy in McLeod myopathy, and suggest that the XK protein represents a crucial factor for the maintenance of normal muscle structure and function.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 479,
                "text": "XK"
            }
        },
        {
            "context": "Mutation characterization and genotype-phenotype correlation in Barth syndrome. Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. We have now evaluated 14 Barth syndrome pedigrees for mutations in G4.5 and have identified unique mutations in all, including four splice-site mutations, three deletions, one insertion, five missense mutations, and one nonsense mutation. Nine of the 14 mutations are predicted to significantly disrupt the protein products of G4.5. The occurrence of missense mutations in exons 3 and 8 suggests that these exons encode essential portions of the G4. 5 proteins, whose functions remain unknown. We found no correlation between the location or type of mutation and any of the clinical or laboratory abnormalities of Barth syndrome, which suggests that additional factors modify the expression of the Barth phenotype. The characterization of mutations of the G4.5 gene will be useful for carrier detection, genetic counseling, and the identification of patients with Barth syndrome who do not manifest all of the cardinal features of this disorder.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 224,
                "text": "Xq28"
            }
        },
        {
            "context": "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy. RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase. SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1308,
                "text": "xa"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 1471,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Antiviral activity of benzimidazole derivatives. I. Antiviral activity of 1-substituted-2-[(benzotriazol-1/2-yl)methyl]benzimidazoles. Forty-three 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles, bearing either linear (dialkylamino)alkyl- or bulkier (quinolizidin-1-yl)alkyl moieties at position 1, were evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representative of two of the three genera of the Flaviviridae family, i.e. Flaviviruses (Yellow Fever Virus (YFV)) and Pestiviruses (Bovine Viral Diarrhoea Virus (BVDV)), as Hepaciviruses can hardly be used in routine cell-based assays. Compounds were also tested against representatives of other virus families. Among ssRNA+ viruses were a retrovirus (Human Immunodeficiency Virus type 1 (HIV-1)), two picornaviruses (Coxsackie Virus type B2 (CVB2), and Poliovirus type-1, Sabin strain (Sb-1)); among ssRNA- viruses were a Paramyxoviridae (Respiratory Syncytial Virus (RSV)) and a Rhabdoviridae (Vesicular Stomatitis Virus (VSV)) representative. Among double-stranded RNA (dsRNA) viruses was a Reoviridae representative (Reo-1). Two representatives of DNA virus families were also included: Herpes Simplex type 1, (HSV-1; Herpesviridae) and Vaccinia Virus (VV; Poxviridae). Most compounds exhibited potent activity against RSV, with EC(50) values as low as 20 nM. Moreover, some compounds, in particular when bearing a (quinolizidin-1-yl)alkyl residue, were also moderately active against BVDV, YFV, and CVB2.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 418,
                "text": "three"
            }
        },
        {
            "context": "Detection of Turner syndrome using high-throughput quantitative genotyping. CONTEXT: Turner syndrome (TS) is the most common genetic problem affecting women and occurs when an X chromosome is completely deleted, portions of an X chromosome are deleted, or chromosomal mosaicism occurs. Girls with TS may also have occult Y chromosome sequences. Whereas some girls with TS are identified in infancy or early childhood, many girls with TS are not detected until after 10 yr of age, resulting in delayed evaluation and treatment. OBJECTIVE: To prevent the delayed recognition and treatment of TS, a quantitative method of genotyping that can be performed as part of newborn screening is needed. DESIGN: To screen for sex chromosome abnormalities, we assembled a panel of informative single nucleotide polymorphism (SNP) markers that span the X chromosome from the dbSNP database. Pyrosequencing assays suitable for quantitative assessment of signal strength from single nucleotides were designed and used to genotype 46,XX; 46,XY; 45,X; and TS mosaics, examining zygosity and signal strength for individual alleles. Pyrosequencing assays were also designed for the detection of Y chromosome material. RESULTS: With just four informative SNP markers for the X chromosome, all TS girls with 45,X, partial X chromosome deletions, or mosaicism were identified with 100% sensitivity. In mosaic individuals, Y chromosomal material was detected with 100% sensitivity. CONCLUSION: These results suggest that inexpensive high-throughput screening is possible for TS and other sex chromosome disorders using quantitative genotyping approaches.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 176,
                "text": "X"
            }
        },
        {
            "context": "Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 831,
                "text": "CD38"
            }
        },
        {
            "context": "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 586,
                "text": "phospholamban"
            }
        },
        {
            "context": "DNA methyltransferase 1 (Dnmt1) mutation affects Snrpn imprinting in the mouse male germ line. DNA methylation and DNA methyltransferases are essential for spermatogenesis. Mutations in the DNA methyltransferase Dnmt1 gene exert a paternal effect on epigenetic states and phenotypes of offspring, suggesting that DNMT1 is important for the epigenetic remodeling of the genome that takes place during spermatogenesis. However, the specific role of DNMT1 in spermatogenesis and the establishment of genomic imprints in the male germ line remains elusive. To further characterize the effect of DNMT1 deficiency on the resetting of methylation imprints during spermatogenesis, we analyzed the methylation profiles of imprinted regions in the spermatozoa of mice that were heterozygous for a Dnmt1 loss-of-function mutation. The mutation did not affect the H19 or IG differentially methylated regions (DMRs) that are usually highly methylated but led to a partial hypermethylation of the Snrpn DMR, a region that should normally be unmethylated in mature spermatozoa. This defect does not appear in mouse models with mutations in Dnmt3a and Mthfr genes and, therefore, it is specific for the Dnmt1 gene and is suggestive of a role of DNMT1 in imprint resetting or maintenance in the male germ line.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1229,
                "text": "DNMT1"
            }
        },
        {
            "context": "[Difficulties associated with Lambert-Eaton syndrome]. INTRODUCTION: The diagnosis and treatment of the neurological paraneoplastic syndromes associated with lung cancer can pose a challenge both to general physicians and neurologists as well as pulmonologists. CASE REPORT: A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma. A lobectomy was performed for a pT2N0M0 lesion. A significant improvement of neurological symptoms was seen. The myasthenic syndrome reappeared 21 months later. A local and general relapse was diagnosed. The patient died 10 months later despite chemotherapy. CONCLUSION: LEMS occurs because of an immunological reaction against voltage-dependent calcium channels. LEMS is generally associated with small cell lung cancer occurring in three percent of cases. However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 1160,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "Mammary epithelial cell polarity is regulated differentially by p73 isoforms via epithelial-to-mesenchymal transition. p73 is expressed as TA and ΔN isoforms, both of which are implicated in tumor suppression and/or promotion. To address how p73 possesses these opposing functions, we developed three-dimensional culture of MCF10A cells, which undergo cell morphogenesis to form polarized spheroids with hollow lumen similar to normal mammary acini in vivo. Here, we showed that upon knockdown of p73, particularly TAp73 but not ΔNp73, MCF10A cells formed irregular and near-normal acini without hollow lumen in three-dimensional culture. We also found that upon knockdown of p73 or TAp73, but not ΔNp73, MCF10A cells underwent epithelial-to-mesenchymal transition (EMT) via down-regulation of E-cadherin coupled with up-regulation of β-catenin and laminin V. In addition, we found that Snail-1, Slug, and Twist, all of which are known to act as EMT inducers by repressing E-cadherin expression, were increased markedly upon knockdown of p73 and TAp73 but little if any by ΔNp73. Furthermore, we showed that knockdown of p73 or TAp73 in MCF10A cells led to a marked increase in cell proliferation and migration. Together, our data suggest that TAp73 is necessary for maintaining normal cell polarity by suppressing EMT.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 120,
                "text": "7"
            }
        },
        {
            "context": "Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization. Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K(+) channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase--a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 297,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 29,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "SUMOylation enhances DNA methyltransferase 1 activity. DNA methylation regulates gene expression through a complex network of protein-protein and protein-DNA interactions in chromatin. The maintenance methylase, DNMT1 (DNA methyltransferase 1), is a prominent enzyme in the process that is linked to DNA replication and drives the heritable nature of epigenetic modifications. The mechanistic details that explain how DNMT1 catalytic action is directed and regulated in chromatin are important in our overall understanding of gene control. In this work, we show that DNMT1 is modified by SUMOylation and we have mapped these SUMOylation sites by defined mutations. SUMOylated DNMT1 is catalytically active on genomic DNA in vivo and we find that SUMOylation significantly enhances the methylase activity of DNMT1 both in vitro and in chromatin. These data suggest that SUMOylation modulates the endogenous activity of a prominent epigenetic maintenance pathway in somatic cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 212,
                "text": "DNMT1"
            }
        },
        {
            "context": "Combination of afatinib with cetuximab in patients with EGFR-mutant non-small-cell lung cancer resistant to EGFR inhibitors. Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown effectiveness for advanced non-small-cell lung cancer (NSCLC) with activating mutations in the EGFR gene. However, resistance to the EGFR TKIs develops mostly secondary to T790M mutation in exon 20. The use of afatinib associated with cetuximab represents a new possibility of therapy following progression on gefitinib or erlotinib. We present two patients who acquired resistance to first-generation TKI and who underwent combination treatment with afatinib plus cetuximab as third-line therapy. Both patients presented partial response, and the time duration of disease control was 8 months and 10 months. The combined use of afatinib plus cetuximab emerges as a new possibility for the treatment of patients with advanced NSCLC harboring mutated EGFR after progression on first-generation EGFR TKIs with consequently acquired resistance to TKIs. Further studies are necessary to consolidate the data.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 357,
                "text": "EGFR"
            }
        },
        {
            "context": "Human bone marrow stroma cells display certain neural characteristics and integrate in the subventricular compartment after injection into the liquor system. Because the neural differentiation capacity of bone marrow stromal cells (BMSCs) is still a matter of controversial debate, we performed a thorough investigation into the differentiation capacity of human BMSCs and examined their therapeutic potency. BMSCs were isolated from the femur and kept in cell cultures with various cultivation protocols being applied. In standard culture conditions using a fetal calf serum-enriched medium, while not exhibiting a neural phenotype, the majority of cells expressed a variety of neuronal marker proteins as well as the astrocyte marker GFAP. Only a minority of stem cells expressed nestin, a marker for neural precursor cells. Cultivation in serum-free medium supplemented with specific growth factors resulted in a markedly higher percentage of nestin-positive cells. To establish the therapeutic potency of bone marrow-derived cells, the synthesis of neurotrophic factors such as NGF, BDNF and GDNF was analyzed under non-stimulating standard culture conditions as well as after a neural selection procedure. The therapeutic potency of BMSCs was further examined with regard to their migratory potential in vitro and after transplantation in vivo. After stereotactic engraftment into the lateral ventricle of adult rats, mesenchymal stem cells were seen to adhere to the ependymocytes and cells of the choroids plexus. Afterwards grafted cells passed through the ependymal barrier, locating in the subventricular space. Their BMSCs took up a close host graft interaction without any degenerative influence on the host cells. Furthermore, there was morphological as well as immunohistochemical evidence for a transdifferentiation within the host tissue. In addition, BMSCs could be efficiently transduced using a third-generation adenoviral vector, indicating their potential feasibility for a gene-therapeutic option.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 782,
                "text": "nestin"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 0,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 868,
                "text": "Xa"
            }
        },
        {
            "context": "X chromosome inactivation and the Xist gene. Recent years have seen rapid progress towards understanding the molecular mechanisms involved in X chromosome inactivation (X inactivation). This progress has largely revolved around the discovery of the X inactive specific transcript (Xist) gene, which is known now to represent the master switch locus regulating X inactivation. In adult cells Xist is transcribed exclusively from the inactive X chromosome. The transcript has no apparent protein-coding potential and is retained in the nucleus in close association with the domain occupied by the inactive X chromosome. It is thus thought to represent a functional RNA molecule which acts as the primary signal responsible for the propagation of X inactivation. Developmental regulation of Xist correlates with the developmental timing of X inactivation. Recent results have demonstrated that Xist is both necessary and sufficient for X inactivation. Goals for the future are to understand the mechanism of Xist regulation which underlies the establishment of appropriate X inactivation patterns and to determine how Xist RNA participates in the process of propagating inactivation in cis.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 281,
                "text": "Xist"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1045,
                "text": "IL-1β"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "Interaction between the skeletal and immune systems in cancer: mechanisms and clinical implications. The skeletal and immune systems have a complex relationship. Both systems are intimately coupled, with osteoclastogenesis and hematopoiesis occurring in the bone marrow. Bone and immune cells also share common hematopoietic precursors. Furthermore, the skeletal and immune systems share various cytokines, receptors, and transcription factors that regulate signal transduction pathways involved in osteoclastogenesis and immune system activation, including the receptor activator of nuclear factor-κΒ ligand/receptor activator of nuclear factor-κΒ/osteoprotegerin (RANKL-RANK-OPG) pathway. Cancer cells can disrupt both the skeletal and immune systems. Interaction between cancer and bone cells results in a vicious cycle of bone destruction and cancer growth. Bone remodeling generates a growth-factor-rich environment that attracts cancer cells and promotes their proliferation. In turn, cancer cells stimulate osteoclast formation and activity, resulting in additional bone resorption that further stimulates cancer cell growth. Currently available bone-targeted therapies may also modulate the immune system. Bisphosphonates such as zoledronic acid exert stimulating effects on the immune system, resulting in possible anticancer activity against malignant cells. Denosumab, an anti-RANKL monoclonal antibody with proven antiosteoclast activity, may suppress immune responses. This may result in the reported association with an increased risk of neoplasms, as well as serious skin and other infections as reported in some studies, mainly in the postmenopausal setting. When assessing bone-targeted therapies, it is important to consider the shared signaling pathways between bone and the immune system, as well as the clinical risk:benefit ratio.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1388,
                "text": "RANKL"
            }
        },
        {
            "context": "Functional expression of a Drosophila gene in yeast: genetic complementation of DNA topoisomerase II. Since DNA topoisomerase II (EC 5.99.1.3) is an essential enzyme in yeast, heterologous topoisomerase II gene expression in yeast cells can provide a system for analyzing the structure and function of topoisomerase II genes from other species. A series of yeast expression plasmids was constructed in which segments of the cDNA sequences encoding Drosophila DNA topoisomerase II were inserted under the transcriptional control of yeast GAL1 promoter. Expression of the functional form of Drosophila topoisomerase II cDNA can complement conditionally lethal, temperature-sensitive mutations in the yeast topoisomerase II gene (TOP2), as well as mutations in which the TOP2 locus was disrupted. The survival of these yeast cells depends upon the continuous expression of Drosophila topoisomerase II. Repression of Drosophila gene expression by glucose causes these yeast cells to cease dividing after a few generations. In addition to these genetic complementation data, the expression of the Drosophila topoisomerase II gene in yeast cells with a disruption in TOP2 can also be detected by immunochemical methods with an antibody specific for Drosophila topoisomerase II.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 112,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis. A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and a major component of the inclusion bodies commonly found with a wide variety of ALS. ALS-linked mutations in UBQLN2 are clustered in a unique proline-X-X repeat region, reportedly leading to impairment of the ubiquitin proteasome system. However, the molecular properties of mutant UBQLN2 remain unclear. To gain insight into the pathogenesis of UBQLN2-linked ALS/FTD, we examined the biochemical and cellular characteristics of mutant UBQLN2 in vitro. UBQLN2 localized in Rab11-positive endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN). These vesicles were ubiquitin- and p62-immunopositive and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN vesicles. UBQLN2 was found to be a potent regulator of the levels of the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. These data suggest a novel disease spectrum and provide new pathological insights into OPTN and UBQLN2, enhancing our understanding of the molecular basis of ALS/FTD.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 210,
                "text": "ALS"
            }
        },
        {
            "context": "Casein kinase II phosphorylates the eukaryote-specific C-terminal domain of topoisomerase II in vivo. The decatenation activity of DNA topoisomerase II is essential for viability as eukaryotic cells traverse mitosis. Phosphorylation has been shown to stimulate topoisomerase II activity in vitro. Here we show that topoisomerase II is a phosphoprotein in yeast and that the level of incorporated phosphate is significantly higher at mitosis than in G1. Comparison of tryptic phosphopeptide maps reveals that the major phosphorylation sites in vivo are targets for casein kinase II. Incorporation of phosphate into topoisomerase II is nearly undetectable at the non-permissive temperature in a conditional casein kinase II mutant. The sites modified by casein kinase II are located in the extreme C-terminal domain of topoisomerase II. This domain is absent in prokaryotic and highly divergent among eukaryotic type II topoisomerases, and may serve to regulate functions of topoisomerase II that are unique to eukaryotic cells.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 135,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 12,
                "text": "interleukin-6"
            }
        },
        {
            "context": "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis. When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 418,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "A selective estrogen receptor modulator for the treatment of hot flushes. A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 76,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Proteomic analysis of the mammalian mitochondrial ribosome. Identification of protein components in the 28 S small subunit. The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. In the previous study, we analyzed 39 S large subunit proteins from bovine mitoribosome (Suzuki, T., Terasaki, M., Takemoto-Hori, C., Hanada, T., Ueda, T., Wada, A., and Watanabe, K. (2001) J. Biol. Chem. 276, 21724-21736). The results suggested structural compensation for the rRNA deficit through proteins of increased molecular mass in the mitoribosome. We report here the identification of 28 S small subunit proteins. Each protein was separated by radical-free high-reducing two-dimensional polyacrylamide gel electrophoresis and analyzed by liquid chromatography/mass spectrometry/mass spectrometry using electrospray ionization/ion trap mass spectrometer to identify cDNA sequence by expressed sequence tag data base searches in silico. Twenty one proteins from the small subunit were identified, including 11 new proteins along with their complete cDNA sequences from human and mouse. In addition to these proteins, three new proteins were also identified in the 55 S mitoribosome. We have clearly identified a mitochondrial homologue of S12, which is a key regulatory protein of translation fidelity and a candidate for the autosomal dominant deafness gene, DFNA4. The apoptosis-related protein DAP3 was found to be a component of the small subunit, indicating a new function for the mitoribosome in programmed cell death. In summary, we have mapped a total of 55 proteins from the 55 S mitoribosome on the two-dimensional polyacrylamide gels.",
            "question": "What is the sedimentation coefficient of the mammalian mitoribosome?",
            "answers": {
                "answer_start": 256,
                "text": "55 S"
            }
        },
        {
            "context": "Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 799,
                "text": "PD-L1"
            }
        },
        {
            "context": "Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. p53 is well known as the \"guardian of the genome\" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for pro-oncogenic cells, p53 also plays an important role as the central regulator of stress response by maintaining cellular homeostasis at the molecular and biochemical level. p53 regulates aerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) steps via transcriptional regulation of its downstream genes TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose-2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS through upregulation of SCO2, a member of the COX-2 assembly involved in the electron-transport chain. It is interesting to notice that p53 antagonistically regulates the inter-dependent glycolytic and OXPHOS cycles. It is important to understand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 is temporally segregated in cancer cells and what is the relation between these paradoxical regulations of glycolytic pathway with the tumor suppressor activity of p53. In this review we will elucidate the importance of p53-mediated regulation of glycolysis and OXPHOS and its relation with the tumor suppressor function of p53. Further since cellular metabolism shares great relation with the process of aging we will also try and establish the role of p53 in regulation of aging via its transcriptional control of cellular metabolism.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 177,
                "text": "p53"
            }
        },
        {
            "context": "Redox regulation of the transcriptional repressor Bach1. Bach1 is a transcriptional repressor of heme oxygenase-1, one of the most inducible phase 2 proteins. Bach1 binds in conjunction with a small Maf protein to tandem repeats of the antioxidant response element (ARE) and quenches the target gene expression. On the other hand, the transactivator Nrf2 binds and up-regulates the ARE-governed gene expression. By using a sulfhydryl oxidizing agent, diamide, here we provide evidence which indicates that the Bach1 function is regulated by the redox state. Diamide showed restricted Nrf2 nuclear translocation and ARE-driven reporter activity but reversed the ARE transcriptional activity suppressed by ectopically expressed Bach1. Substitution of the conserved cysteine residue in the DNA binding domain of Bach1 to serine (C574S mutant) caused a refractory response to the diamide-mediated reactivation of the Bach1-suppressed reporter activity. Moreover, diamide induced cytoplasmic translocation of the GFP-Bach1 fusion protein but failed to translocate the fusion protein consisting of the C574S mutant. These data suggest that redox regulation of Bach1 is an alternative mechanism to induce multiple ARE-governed genes.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 40,
                "text": "repressor"
            }
        },
        {
            "context": "APOBEC3B and AID have similar nuclear import mechanisms. Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 499,
                "text": " nuclear"
            }
        },
        {
            "context": "Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells. The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. Accumulating evidence suggests that certain tissue kallikreins are part of an enzymatic cascade pathway that is activated in ovarian cancer and other malignant diseases. In the present study, OV-MZ-6 ovarian cancer cells were stably co-transfected with plasmids expressing hK4, hK5, hK6, and hK7. These cells displayed similar proliferative capacity as the vector-transfected control cells (which do not express any of the four tissue kallikreins), but showed significantly increased invasive behavior in an in vitro Matrigel invasion assay (p<0.01; Mann-Whitney U-test). For in vivo analysis, the cancer cells were inoculated into the peritoneum of nude mice. Simultaneous expression of hK4, hK5, hK6, and hK7 resulted in a remarkable 92% mean increase in tumor burden compared to the vector-control cell line. Five out of 14 mice in the 'tissue kallikrein overexpressing' group displayed a tumor/situs ratio greater than 0.198, while this weight limit was not exceeded at all in the vector control group consisting of 13 mice (p=0.017; chi2 test). Our results strongly support the view that tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 223,
                "text": "15"
            }
        },
        {
            "context": "Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale in detecting obstructive sleep apnea: A bivariate meta-analysis. Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder; however, it remains underdiagnosed and undertreated. Although screening tools such as the Berlin questionnaire (BQ), STOP-BANG questionnaire (SBQ), STOP questionnaire (STOP), and Epworth sleepiness scale (ESS) are widely used for OSA, the findings regarding their diagnostic accuracy are controversial. Therefore, this meta-analysis investigated and compared the summary sensitivity, specificity, and diagnostic odds ratio (DOR) among the BQ, SBQ, STOP, and ESS according to the severity of OSA. Electronic databases, namely the Embase, PubMed, PsycINFO, ProQuest dissertations and theses A&I databases, and China knowledge resource integrated database, were searched from their inception to July 15, 2016. We included studies examining the sensitivity and specificity of the BQ, SBQ, STOP, and ESS against the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The revised quality assessment of diagnostic accuracy studies was used to evaluate the methodological quality of studies. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, and DOR of the tools. We identified 108 studies including a total of 47 989 participants. The summary estimates were calculated for the BQ, SBQ, STOP, and ESS in detecting mild (AHI/RDI  >  5 events/h), moderate (AHI/RDI  >  15 events/h), and severe OSA (AHI/RDI  >  30 events/h). The performance levels of the BQ, SBQ, STOP, and ESS in detecting OSA of various severity levels are outlined as follows: for mild OSA, the pooled sensitivity levels were 76%, 88%, 87%, and 54%; pooled specificity levels were 59%, 42%, 42%, and 65%; and pooled DORs were 4.30, 5.13, 4.85, and 2.18, respectively. For moderate OSA, the pooled sensitivity levels were 77%, 90%, 89%, and 47%; pooled specificity levels were 44%, 36%, 32%, and 621%; and pooled DORs were 2.68, 5.05, 3.71, and 1.45, respectively. For severe OSA, the pooled sensitivity levels were 84%, 93%, 90%, and 58%; pooled specificity levels were 38%, 35%, 28%, and 60%; and pooled DORs were 3.10, 6.51, 3.37, and 2.10, respectively. Therefore, for mild, moderate, and severe OSA, the pooled sensitivity and DOR of the SBQ were significantly higher than those of other screening tools (P < .05); however, the specificity of the SBQ was lower than that of the ESS (P < .05). Moreover, age, sex, body mass index, study sample size, study populations, presence of comorbidities, PSG or portable monitoring performance, and risk of bias in the domains of the index test and reference standard were significant moderators of sensitivity and specificity (P < .05). Compared with the BQ, STOP, and ESS, the SBQ is a more accurate tool for detecting mild, moderate, and severe OSA. Sleep specialists should use the SBQ to conduct patient interviews for the early diagnosis of OSA in clinical settings, particularly in resource-poor countries and sleep clinics where PSG is unavailable.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 108,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Management of cutaneous erythrasma. Corynebacterium minutissimum is the bacteria that leads to cutaneous eruptions of erythrasma and is the most common cause of interdigital foot infections. It is found mostly in occluded intertriginous areas such as the axillae, inframammary areas, interspaces of the toes, intergluteal and crural folds, and is more common in individuals with diabetes mellitus than other clinical patients. This organism can be isolated from a cutaneous site along with a concurrent dermatophyte or Candida albicans infection. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis and intertrigo, and methods for differentiating include Wood's light examination and bacterial and mycological cultures. Erythromycin 250mg four times daily for 14 days is the treatment of choice and other antibacterials include tetracycline and chloramphenicol; however, the use of chloramphenicol is limited by bone marrow suppression potentially leading to neutropenia, agranulocytosis and aplastic anaemia. Further studies are needed but clarithromycin may be an additional drug for use in the future. Where there is therapeutic failure or intertriginous involvement, topical solutions such as clindamycin, Whitfield's ointment, sodium fusidate ointment and antibacterial soaps may be required for both treatment and prophylaxis. Limited studies on the efficacy of these medications exist, however, systemic erythromycin demonstrates cure rates as high as 100%. Compared with tetracyclines, systemic erythromycin has greater efficacy in patients with involvement of the axillae and groin, and similar efficacy for interdigital infections. Whitfield's ointment has equal efficacy to systemic erythromycin in the axillae and groin, but shows greater efficacy in the interdigital areas and is comparable with 2% sodium fusidate ointment for treatment of all areas. Adverse drug effects and potential drug interactions need to be considered. No cost-effectiveness data are available but there are limited data on cost-related treatment issues. A guideline is proposed for the detection, evaluation, treatment and prophylaxis of this cutaneous eruption.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 36,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "Use of dialectical behavior therapy in a partial hospital program for women with borderline personality disorder. Dialectical behavior therapy, an outpatient psychosocial treatment for chronically suicidal women with borderline personality disorder, has been adapted for use in a partial hospital program for women. Patients attend the program for a minimum of five days of individual and group therapy, and full census is 12 women. About 65 percent of participants meet at least three criteria for borderline personality disorder, and most have suicidal and self-injurious behavior. Their comorbid diagnoses include trauma-related diagnoses and anxiety disorders, severe eating disorders, substance abuse, and depression. The partial hospital program is linked to an aftercare program offering six months of outpatient skills training based on dialectical behavior therapy. Both programs focus on teaching patients four skills: mindfulness (attention to one's experience), interpersonal effectiveness, emotional regulation, and distress tolerance. Two years of operation of the women's partial hospital program provides promising anecdotal evidence that dialectical behavioral therapy, an outpatient approach, can be effectively modified for partial hospital settings and a more diverse population.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 217,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 200,
                "text": "TYR"
            }
        },
        {
            "context": "Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS, S/AS01 malaria vaccine in African children. BACKGROUND: There has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials. METHODS: The present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed. CONCLUSIONS: The methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 116,
                "text": "malaria"
            }
        },
        {
            "context": "FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Disruption of FOXP2, a gene encoding a forkhead-domain transcription factor, causes a severe developmental disorder of verbal communication, involving profound articulation deficits, accompanied by linguistic and grammatical impairments. Investigation of the neural basis of this disorder has been limited previously to neuroimaging of affected children and adults. The discovery of the gene responsible, FOXP2, offers a unique opportunity to explore the relevant neural mechanisms from a molecular perspective. In the present study, we have determined the detailed spatial and temporal expression pattern of FOXP2 mRNA in the developing brain of mouse and human. We find expression in several structures including the cortical plate, basal ganglia, thalamus, inferior olives and cerebellum. These data support a role for FOXP2 in the development of corticostriatal and olivocerebellar circuits involved in motor control. We find intriguing concordance between regions of early expression and later sites of pathology suggested by neuroimaging. Moreover, the homologous pattern of FOXP2/Foxp2 expression in human and mouse argues for a role for this gene in development of motor-related circuits throughout mammalian species. Overall, this study provides support for the hypothesis that impairments in sequencing of movement and procedural learning might be central to the FOXP2-related speech and language disorder.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 529,
                "text": "FOXP2"
            }
        },
        {
            "context": "Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. CONTEXT: Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues. OBJECTIVE: The aim of the study was to identify and screen mutation carriers in the family. PATIENTS: Forty-three family members participated in the study. SETTING: The study was performed in university hospitals. OUTCOME: We conducted genetic and endocrine screening of family members. RESULTS: We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives. CONCLUSIONS: Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 122,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "A phase 1 multiple-dose study of orteronel in Japanese patients with castration-resistant prostate cancer. PURPOSE: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy. RESULTS: Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30%) were hyperlipasemia (47%), hyperamylasemia (40%), and constipation (33%). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50% reduction from baseline in prostate-specific antigen. CONCLUSIONS: Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 368,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Ecm22 and Upc2 regulate yeast mating through control of expression of the mating genes PRM1 and PRM4. Budding yeast mating is an excellent model for receptor-activated cell differentiation. Here we identify the related transcription factors Ecm22 and Upc2 as novel regulators of mating. Cells lacking both ECM22 and UPC2 display strong mating defects whereas deletion of either gene has no effect. Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4. These genes are strongly induced in response to mating pheromone, which is also largely dependent on ECM22 and UPC2. We further show that deletion of PRM4 like PRM1 results in markedly reduced mating efficiency. Expression of PRM1 but not of PRM4 is also regulated by Ste12, a key transcription factor for mating. STE12 deletion lowers basal PRM1 expression, whereas STE12 overexpression strongly increases PRM1 levels. This regulation of PRM1 transcription is mediated through three Ste12-binding sites in the PRM1 promoter. Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways. In summary, we propose a novel mechanism for budding yeast mating. We suggest that Ecm22 and Upc2 regulate mating through the induction of the mating genes PRM1 and PRM4.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 1200,
                "text": "Ecm22"
            }
        },
        {
            "context": "Davidson Trauma Scale (DTS): normative scores in the general population and effect sizes in placebo-controlled SSRI trials. The Davidson Trauma Scale (DTS) was developed as a self-rating for use in diagnosing and measuring symptom severity and treatment outcome in post-traumatic stress disorder (PTSD); 630 subjects were identified by random digit dialing and evaluated for a history of trauma. Prevalence rates of PTSD and subthreshold PTSD with impairment were 2.2 and 4.1%, respectively. In this general population sample, 438 subjects endorsed at least one trauma, and four groups were generated: A) threshold PTSD (n = 13), B) subthreshold PTSD with impairment (n = 26), C) subthreshold PTSD without impairment (n = 78), and D) no PTSD (n = 321). Mean (SD) DTS score in the entire population was 11.0 +/- 18.1. Differences were found in four of the five pairwise between-group contrasts. In a second sample of 447 clinical trial participants from three SSRI vs. placebo studies, we assessed treatment effect size according to different measures. In all three clinical trials, effect size with the DTS was equal to, or better than, those found for the Impact of Event Scale (IES), Clinician Administered PTSD Scale (CAPS), and Structured Interview for PTSD (SIP). These results further affirm the utility of the DTS as a self-rating measure of PTSD symptom severity and in evaluating treatment response.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 265,
                "text": "post-traumatic stress disorder"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 601,
                "text": "Hsp90"
            }
        },
        {
            "context": "Aurora B kinase phosphorylates and instigates degradation of p53. Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of Aurora B in cancer cells with WT p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results define a mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of Aurora B may compromise the tumor suppressor function of p53. We have elucidated the antineoplastic mechanism for Aurora B kinase inhibitors in cancer cells with WT p53.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 367,
                "text": "p53"
            }
        },
        {
            "context": "The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.",
            "question": "Which peptide plays a pivotal role in human cystatin C fibrillization?",
            "answers": {
                "answer_start": 17,
                "text": "LQVVR"
            }
        },
        {
            "context": "Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors. Inactivating mutations in the MEN1 gene predisposing to the multiple endocrine neoplasia type 1 (MEN1) syndrome can also cause sporadic pancreatic endocrine tumors. MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3). The importance of menin-dependent H3K4me3 in normal and transformed pancreatic endocrine cells is unclear. To study the role of menin-dependent H3K4me3, we performed in vitro differentiation of wild-type as well as menin-null mouse embryonic stem cells (mESCs) into pancreatic islet-like endocrine cells (PILECs). Gene expression analysis and genome-wide H3K4me3 ChIP-Seq profiling in wild-type and menin-null mESCs and PILECs revealed menin-dependent H3K4me3 at the imprinted Dlk1-Meg3 locus in mESCs, and all four Hox loci in differentiated PILECs. Specific and significant loss of H3K4me3 and gene expression was observed for genes within the imprinted Dlk1-Meg3 locus in menin-null mESCs and the Hox loci in menin-null PILECs. Given that the reduced expression of genes within the DLK1-MEG3 locus and the HOX loci is associated with MEN1-like sporadic tumors, our data suggests a possible role for menin-dependent H3K4me3 at these genes in the initiation and progression of sporadic pancreatic endocrine tumors. Furthermore, our investigation also demonstrates that menin-null mESCs can be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null mESC-derived specialized cell types for genome-wide high-throughput studies.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 446,
                "text": "H3K4"
            }
        },
        {
            "context": "Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL) Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most common progressive encephalopathy of childhood, is caused by mutations in a novel lysosomal membrane protein (CLN3) with unknown function. In this study, we have confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by co-localizing it with soluble and membrane-associated lysosomal proteins. We have analysed the intracellular processing and localization of two mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the classical JNCL, and E295K [corrected], which is a rare missense mutation associated with an atypical form of JNCL. Pulse-chase labelling and immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461-677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 polypeptide. Transient expression of the two mutants in BHK cells showed that 461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected] was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wild-type CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutant was arrested in the cell soma. Interestingly, co-localization of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle marker indicates that the CLN3 protein might participate in synaptic vesicle transport/transmission. The data presented here provide clear evidence for a cellular distinction between classical and atypical forms of Batten disease both in neural and non-neural cells.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 106,
                "text": "juvenile-onset neuronal ceroid lipofuscinosis"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 676,
                "text": "SIP-1"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 717,
                "text": "tyr"
            }
        },
        {
            "context": "A bivalent chromatin structure marks key developmental genes in embryonic stem cells. The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed \"bivalent domains,\" consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 211,
                "text": "development"
            }
        },
        {
            "context": "Approaches for the Development of Drugs for Treatment of Obesity and Metabolic Syndrome. Obesity and metabolic syndrome (MS) are risk factors for diabetes, cancer, some cardiovascular and musculoskeletal diseases. Pharmacotherapy should be used when the body mass index (BMI) exceeds 30 kg/m² or 27 kg/m² with comorbidity. Efficacy and safety of pharmacotherapy depend on the mechanism of action of drugs. In this context, drugs affecting the central and peripheral mediator systems such as cannabinoid receptor antagonists (Rimonabant), neuronal reuptake inhibitor of NE and 5 HT (Sibutramine), neuronal reuptake inhibitor of NE 5-HT DA (Tesofensine), agonist of 5 HT 2C receptors (Lorcaserin) have a high risk of side effects on the central nervous and cardiovascular systems when used for a long period. Apparently, the drugs design targeting obesity should screen safer drugs that affect fat absorption (Orlistat), activate energy metabolism (Adipokines), inhibit MetAP2 (Beloranib) and other peripheral metabolic processes. The use of synergies of anti-obesity drugs with different mechanisms of action is an effective approach for developing new combined pharmaceutical compositions (Contrave®, EmpaticTM, Qsymia et al). The purpose of this article is to review the currently available anti-obesity drugs and some new promising trends in development of anti-obesity therapy.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 1058,
                "text": "obesity"
            }
        },
        {
            "context": "Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome. Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32_-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 190,
                "text": "fibrillin 1 gene"
            }
        },
        {
            "context": "Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 814,
                "text": "orally"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1726,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Pharmaceutical approval update. Duavee, an oral contraceptive; riociguat (Adempas) for two types of pulmonary hypertension; and macitentan (Opsumit) for pulmonary arterial hypertension.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 63,
                "text": "riociguat"
            }
        },
        {
            "context": "JAMM: a peak finder for joint analysis of NGS replicates. MOTIVATION: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets. RESULTS: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy. AVAILABILITY AND IMPLEMENTATION: JAMM is available for free and can run on Linux machines through the command line: http://code.google.com/p/jamm-peak-finder.",
            "question": "Which peak calling algorithm employs mixture model clustering under the hood?",
            "answers": {
                "answer_start": 649,
                "text": "JAMM"
            }
        },
        {
            "context": "Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect. Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.",
            "question": "How is myotonic dystrophy inherited?",
            "answers": {
                "answer_start": 413,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "[Dermatoglyphics of homo- and heterozygotes for Wilson's disease (hepatolenticular degeneration) (author's transl)]. Dermatoglyphics of 11 patients with Wilson's disease and 16 of their clinically asymptomatic relatives of first degree were investigated; 11 of the latter ones were heterozygous in agreement with the turn over rates of Cu-67, 12 under the assumption of autosomal recessive inheritance. On the finger tips the Mb. Wilson patients showed 52.7% whorls, their heterozygous relatives about 40%; compared with our controls (males 33.16%, females 28.82%, Aue-Hauser, 1970) that means a strong increase of this pattern type. On the palm the high frequency of hypothenar patterns in homo- and heterozygotes for Wilson's disease and of loops with accessory triradius in the 4th interdigitum of the patients with Wilson's disease was striking.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 370,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. The Philadelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein kinases were thought to be poor therapeutic targets because of their ubiquitous nature and crucial role in many normal physiologic processes. However, the advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer kinase inhibitors could be specific. This agent has shown striking activity in chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell factor receptor) and platelet-derived growth factor receptor. In addition, it has shown similar impressive responses, with little host toxicity, in gastrointestinal stromal tumors, which harbor activating Kit mutations, and in tumors with activated platelet-derived growth factor receptor. The studies of imatinib mesylate provide proof-of-principle for using aberrant kinases as a therapeutic target and are a model for the promise of molecular therapeutics. This paper reviews the current knowledge on the function of Bcr-Abl and its normal counterparts (Bcr and Abl), as well as the impact of this knowledge on the development of a remarkably successful targeted therapy approach.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 231,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 405,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 496,
                "text": "xa"
            }
        },
        {
            "context": "Parallel overexpression of seven kallikrein genes in ovarian cancer. Recent evidence suggests that many members of the human kallikrein (KLK) gene family are differentially regulated in ovarian cancer and have potential as diagnostic and/or prognostic markers. We used the serial analysis of gene expression and expressed sequence tag databases of the Cancer Genome Anatomy Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines. We found that seven KLK genes (KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, and KLK14) are up-regulated in ovarian cancer. Probing 2 normal and 10 ovarian cancer serial analysis of gene expression libraries with gene-specific tags for each KLK indicated that whereas no expression was detected in any normal libraries (with the exception of KLK10 and KLK11), these KLKs were found to be expressed with moderate densities (103-408 tags per million) in 40-60% of the ovarian cancer libraries analyzed. These data were verified by screening the expressed sequence tag databases, where 78 of 79 mRNA clones isolated for these genes were from ovarian cancer libraries. X-profiler comparison of the pools of normal and cancerous ovaries identified a significant difference in expression levels for six of the seven KLKs. We experimentally verified the overexpression of six KLK proteins in cancer versus normal or benign tissues with highly sensitive and specific immunofluorometric assays. A statistically significant stepwise increase in protein levels was found among normal, benign, and cancerous ovarian tissues. The expression of five KLKs showed a strong degree of correlation at the protein level, suggesting the existence of a common mechanism or pathway that controls the expression of this group of adjacent genes during ovarian cancer progression.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 445,
                "text": "15"
            }
        },
        {
            "context": "Defining the sequence requirements for the positioning of base J in DNA using SMRT sequencing. Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. This highly restricted distribution must be co-determined by the thymidine hydroxylases (JBP1 and JBP2) that catalyze the initial step in J synthesis. To determine the DNA sequences recognized by JBP1/2, we used SMRT sequencing of DNA segments inserted into plasmids grown in Leishmania tarentolae. We show that SMRT sequencing recognizes base J in DNA. Leishmania DNA segments that normally contain J also picked up J when present in the plasmid, whereas control sequences did not. Even a segment of only 10 telomeric (GGGTTA) repeats was modified in the plasmid. We show that J modification usually occurs at pairs of Ts on opposite DNA strands, separated by 12 nucleotides. Modifications occur near G-rich sequences capable of forming G-quadruplexes and JBP2 is needed, as it does not occur in JBP2-null cells. We propose a model whereby de novo J insertion is mediated by JBP2. JBP1 then binds to J and hydroxylates another T 13 bp downstream (but not upstream) on the complementary strand, allowing JBP1 to maintain existing J following DNA replication.",
            "question": "Where is base J found in the genome of Leishmania tarentolae?",
            "answers": {
                "answer_start": 200,
                "text": "telomeric repeats"
            }
        },
        {
            "context": "Red hair is the null phenotype of MC1R. The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible for production of the darker eumelanin pigment and the tanning response. The MC1R gene has many polymorphisms, some of which have been linked to variation in pigmentation phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and p.D294 H alleles have been strongly associated with red hair, fair skin and increased skin cancer risk. These red hair colour (RHC) variants are relatively well described and are thought to result in altered receptor function, while still retaining varying levels of signaling ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W and p.D294 H alleles were able to partially rescue this phenotype, leading to the question of what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null alleles in human populations, they have only been found in the heterozygous state until now. We report here the first case of a homozygous MC1R null individual, phenotypic analysis indicates that red hair and fair skin is found in the absence of MC1R function.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 34,
                "text": "MC1R"
            }
        },
        {
            "context": "In vivo Bacillus anthracis gene expression requires PagR as an intermediate effector of the AtxA signalling cascade. Transcription of the major Bacillus anthracis virulence genes is triggered by CO2, a signal mimicking the host environment. A 182-kb plasmid, pXO1, carries the anthrax toxin genes and the genes responsible for their regulation of transcription, namely atxA and, pagR, the second gene of the pag operon. AtxA has major effects on the physiology of B. anthracis. It coordinates the transcription activation of the toxin genes with that of the capsule biosynthetic enzyme operon, located on the second virulence plasmid, pXO2. In rich medium, B. anthracis synthesises alternatively two S-layer proteins (Sap and EA1). An exponential phase \"Sap-layer\" is subsequently replaced by a stationary phase \"EA1-layer\". S-layer gene transcription is controlled by alternative sigma factors and by Sap acting as a transcriptional repressor of eag. Furthermore, in vitro in presence of CO2 and in vivo, AtxA is part of the sap and eag regulatory network. Only eag is significantly expressed in these conditions and this is due to AtxA activating eag and repressing sap transcription. PagR, and not AtxA itself, is the direct effector of this regulation by binding to sap and eag promoter regions. Therefore, PagR mediates the effect of AtxA on eag and sap and is the most downstream element of a signalling cascade initiated by AtxA. Taken together, these results indicate that the B. anthracis transcriptional regulator AtxA is controlling the synthesis of the three toxin components and of the surface elements (capsule and S-layer). Thus, AtxA is a master regulator that coordinates the response to host signals by orchestrating positive and negative controls over genes located on all genetic elements.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 989,
                "text": "CO2"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 426,
                "text": "methylKit"
            }
        },
        {
            "context": "Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria. Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 404,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Anesthetic efficacy of the inferior alveolar nerve block in red-haired women. INTRODUCTION: The exact reasons for failure of the inferior alveolar nerve (IAN) block are not completely known, but red hair could play a role. The genetic basis for red hair involves specific mutations, red hair color (RHC) alleles, in the melanocortin-1 receptor (MC1R) gene. The purpose of this prospective randomized study was to investigate a possible link between certain variant alleles of the MC1R gene or its phenotypic expression of red hair and the anesthetic efficacy of the IAN block in women. MATERIALS: One-hundred twenty-four adult female subjects (62 red haired and 62 dark haired) participated in this study. Dental anxiety was determined in each subject using the Corah Dental Anxiety Questionnaire. The subjects were given 2 cartridges of 2% lidocaine with 1:100,000 epinephrine via the IAN block. Pulpal anesthesia was measured in the posterior and anterior teeth in 4-minute cycles for 60 minutes using an electric pulp tester. The MC1R alleles were genotyped for each subject from cheek cells containing DNA collected using buccal swabs. RESULTS: Women with red hair and women with 2 RHC alleles reported significantly higher levels of dental anxiety compared with women with dark hair or women with 0 RHC alleles. No significant differences in anesthetic success were found between any of the groups for any of the teeth. CONCLUSIONS: Red hair and the MC1R gene were significantly linked to higher levels of dental anxiety but were unrelated to success rates of the IAN block in women with healthy pulps.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 345,
                "text": "MC1R"
            }
        },
        {
            "context": "deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, DeltaNp73, is upregulated in breast and gynecological cancers. We further showed that DeltaNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of DeltaNp73, this can only be directly shown in primary cells. We report here that DeltaNp73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. DeltaNp73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, DeltaNp73 rescues Ras-induced senescence. Moreover, DeltaNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of DeltaNp73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of DeltaNp73. Taken together, DeltaNp73 behaves as an oncogene that targets p53 that might explain why DeltaNp73 upregulation may be selected for during tumorigenesis of human cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 535,
                "text": "7"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 1810,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Size matters: versatile use of PiggyBac transposons as a genetic manipulation tool. Transposons have been promising elements for gene integration, and the Sleeping Beauty (SB) system has been the major one for many years, although there have been several other transposon systems available, for example, Tol2. However, recently another system known as PiggyBac (PB) has been introduced and developed for fulfilling the same purposes, for example, mutagenesis, transgenesis and gene therapy and in some cases with improved transposition efficiency and advantages over the Sleeping Beauty transposon system, although improved hyperactive transposase has highly increased the transposition efficacy for SB. The PB systems have been used in many different scientific research fields; therefore, the purpose of this review is to describe some of these versatile uses of the PiggyBac system to give readers an overview on the usage of PiggyBac system.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 352,
                "text": "PiggyBac"
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 1854,
                "text": "Slc9a6"
            }
        },
        {
            "context": "Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.",
            "question": "What do nerve-associated peripheral glial progenitors give rise to?",
            "answers": {
                "answer_start": 18,
                "text": "Parasympathetic neurons"
            }
        },
        {
            "context": "Mechanism of start site selection by RNA polymerase II: interplay between TFIIB and Ssl2/XPB helicase subunit of TFIIH. TFIIB is essential for transcription initiation by RNA polymerase II. TFIIB also cross-links to terminator regions and is required for gene loops that juxtapose promoter-terminator elements in a transcription-dependent manner. The Saccharomyces cerevisiae sua7-1 mutation encodes an altered form of TFIIB (E62K) that is defective for both start site selection and gene looping. Here we report the isolation of an ssl2 mutant, encoding an altered form of TFIIH, as a suppressor of the cold-sensitive growth defect of the sua7-1 mutation. Ssl2 (Rad25) is orthologous to human XPB and is a member of the SF2 family of ATP-dependent DNA helicases. The ssl2 suppressor allele encodes an arginine replacement of the conserved histidine residue (H508R) located within the DEVH-containing helicase domain. In addition to suppressing the TFIIB E62K growth defect, Ssl2 H508R partially restores both normal start site selection and gene looping. Moreover, Ssl2, like TFIIB, associates with promoter and terminator regions, and the diminished association of TFIIB E62K with the PMA1 terminator is restored by the Ssl2 H508R suppressor. These results define a novel, functional interaction between TFIIB and Ssl2 that affects start site selection and gene looping.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1306,
                "text": "TFIIB"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1270,
                "text": "53BP1"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 912,
                "text": "L-dopa"
            }
        },
        {
            "context": "Arabidopsis homologs of components of the SWR1 complex regulate flowering and plant development. The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes. We compared the phenotype of mutants in the homologs of SWR1C components in Arabidopsis thaliana. Mutations in Arabidopsis SWC6 (AtSWC6), SUPPRESSOR OF FRIGIDA 3 (SUF3) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1), homologs of SWC6, ARP6 and SWR1, respectively, caused similar developmental defects, including leaf serration, weak apical dominance, flowers with extra petals and early flowering by reduction in expression of FLOWERING LOCUS C (FLC), a strong floral repressor. Chromatin immunoprecipitation assays showed that AtSWC6 and SUF3 bind to the proximal region of the FLC promoter, and protoplast transfection assays showed that AtSWC6 colocalizes with SUF3. Protein interaction analyses suggested the formation of a complex between PIE1, SUF3, AtSWC6 and AtSWC2. In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2. Finally, knockdown of the H2AZ genes by RNA interference or artificial microRNA caused a phenotype similar to that of atswc6 or suf3. Our results strongly support the presence of an SWR1C-like complex in Arabidopsis that ensures proper development, including floral repression through full activation of FLC.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 101,
                "text": "SWR1"
            }
        },
        {
            "context": "RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia. Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 897,
                "text": "RANKL"
            }
        },
        {
            "context": "Borderline oxacillin-resistant Staphylococcus aureus (BORSA) - a more common problem than expected? Borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a quite poorly understood and inadequately defined phenotype of methicillin resistance. BORSA strains show low, borderline resistance to penicillinase-resistant penicillins (PRPs), with oxacillin MICs typically equal to 1-8 µg ml, and in contrast to methicillin-resistant S. aureus (MRSA), do not have an altered penicillin-binding protein, PBP2a, encoded by the mecA or mecC gene. Their resistance is typically associated with hyperproduction of beta-lactamases or, in some cases, point mutations in PBP genes. BORSA cannot be classified as either truly methicillin-resistant or truly methicillin-susceptible strains. However, they are frequently misidentified, which poses an obvious epidemiological and therapeutic threat. BORSA strains are commonly isolated from humans and animals, and are found both in hospitals and in a community setting. The epidemiology and clinical presentation of BORSA infections seem to be similar to those for MRSA; these infections are usually more severe than those caused by methicillin-sensitive S. aureus (MSSA). Treatment of severe infections caused by BORSA may be ineffective, even with larger doses of oxacillin. The available evidence suggests that BORSA represent a frequently neglected problem, and their emergence in new environments implies that they need to be monitored and accurately distinguished from MSSA and MRSA.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 0,
                "text": "Borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers. Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 474,
                "text": "chordomas"
            }
        },
        {
            "context": "Flumazenil: a new benzodiazepine antagonist. Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects of benzodiazepines. It acts by binding CNS benzodiazepine receptors and competitively blocking benzodiazepine activation of inhibitory GABAergic synapses. Animal studies and some human studies appear to demonstrate that flumazenil has weak intrinsic agonist activity; on the other hand, studies are inconclusive in demonstrating any inverse agonist effects of this agent. Evidence available suggests that flumazenil is well tolerated in human beings over a broad range of doses when given either orally or parenterally and does not produce serious adverse effects. In the setting of isolated benzodiazepine overdose, flumazenil is capable of completely reversing coma within one to two minutes, with this effect lasting between one and five hours. Repeat doses can be given safely to reverse recurrent effects of longer-acting benzodiazepines. Flumazenil is undergoing further evaluation by the Food and Drug Administration; should this drug receive approval, it is likely to be used in emergency departments as well as in a variety of other clinical settings. First, it could be used to effect rapid reversal of benzodiazepine-induced sedation that has been administered to facilitate medical, orthopedic, and surgical procedures, particularly in the event of inadvertent respiratory depression. Second, flumazenil might have a therapeutic role in the management of patients who have taken benzodiazepine overdoses. Although most of these patients can be managed successfully with supportive therapy alone, it is possible that the use of flumazenil may obviate the need for intubation and respiratory support in such patients and eliminate the possible adverse effects of even short-term endotracheal intubation. Finally, flumazenil could have both diagnostic and therapeutic value in patients with acute alterations of mental status of unknown etiology, particularly when possible drug overdose is a consideration. Because flumazenil appears to be specific in its antagonism of benzodiazepine-induced respiratory and CNS depression, it could be used empirically to confirm or exclude a role of benzodiazepines in the generation of mental status changes in the setting of overdose or coma of unknown origin. This in turn might obviate the need for further expensive (eg, computed tomography) and sometimes invasive (eg, lumbar puncture) diagnostic modalities. This might be particularly useful because there is nothing about benzodiazepine-induced coma that clearly distinguishes it from other causes of coma; thus, there are no signs or symptoms that may reasonably allow benzodiazepine overdose to be confirmed or eliminated on clinical grounds. Further studies will continue to define the ultimate use of this new agent.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 742,
                "text": "flumazenil"
            }
        },
        {
            "context": "Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 162,
                "text": "FSHD"
            }
        },
        {
            "context": "Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles.",
            "question": "Cytochrome p450 CYP3A is induced by rifampicin  and compounds used to treat what virus?",
            "answers": {
                "answer_start": 253,
                "text": "HIV"
            }
        },
        {
            "context": "Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 179,
                "text": "7"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 815,
                "text": "factor Xa"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1270,
                "text": "53BP1"
            }
        },
        {
            "context": "Human caspases: activation, specificity, and regulation. Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation. Activation of caspases occurs by a conserved mechanism subject to strict cellular regulation. Once activated by a specific stimulus, caspases execute limited proteolysis of downstream substrates to trigger a cascade of events that culminates in the desired biological response. Much has been learned of the mechanisms that govern the activation and regulation of caspases, and this minireview provides an update of these areas. We also delineate substantial gaps in knowledge of caspase function, which can be approached by techniques and experimental paradigms that are currently undergoing development.",
            "question": "What is the function of caspases?",
            "answers": {
                "answer_start": 57,
                "text": "Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation."
            }
        },
        {
            "context": "Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage. OBJECTIVE: To evaluate gender differences in score on 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) and Signals Of Functional Impairment (SOFI) and to relate these scores to radiographic joint destruction. METHODS: In all, 549 patients with early RA (62% women) from the BARFOT (for \"Better Anti-Rheumatic FarmacOTherapy\") study were included. At baseline, 1, 2 and 5 years DAS28, HAQ and SOFI scoring, and radiographs of hands and feet were performed. The radiographs were scored using the van der Heijde-Sharp score. RESULTS: In women the DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were rated significantly higher in women. The SOFI score was worse in men during the first 2 years, depending on higher upper limb scores. Total Sharp score (TotSharp), erosion score and joint space narrowing score did not differ between the sexes at any time point. The DAS28 area under the curve (AUC) correlated significantly with TotSharp at 5 years in both genders (r = 0.316, r = 0.313) mainly owing to swollen joints and erythrocyte sedimentation rate (ESR). The SOFI AUC correlated significantly with TotSharp in women (r = 0.135 to 0.220) but not in men. CONCLUSIONS: Despite a similar degree of radiographic joint destruction women had, compared with men, worse scores for DAS28 and HAQ, possibly due to higher pain perception and less muscular strength and perhaps because men overestimate their functional capacity.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 878,
                "text": "women"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy (SUDEP): don't ask, don't tell? BACKGROUND: The National Institute for Clinical Excellence in the UK has issued guidelines stating all individuals with epilepsy be given information about sudden unexpected death in epilepsy (SUDEP). METHODS: We conducted a survey of current practice among UK neurologists, using a questionnaire sent to all practising neurologists in the UK listed on the Association of British Neurologists database, asking under what circumstances they told patients about SUDEP. RESULTS: Of the validated respondents, 5% discussed SUDEP with all patients, 26% with a majority, 61% with a few, and 7.5% with none. The commonest reasons for SUDEP to be discussed were the patient asking about it and the neurologist counselling people with known risk factors for SUDEP. CONCLUSIONS: The variation we found, although not necessarily in tune with the guidelines, reflects the variation in patients' need for knowledge about their condition.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 0,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The RTS,S vaccine candidate for malaria. Malaria continues to be a worldwide leading cause of morbidity and mortality, and the development of an effective malaria vaccine remains a research imperative. Of the multiple approaches that have been pursued, the RTS,S/AS01 vaccine candidate represents the most developed and clinically validated malaria vaccine formulation. Throughout its development, increasingly more effective adjuvants have been key in improving the potency of the vaccine. RTS,S-based vaccine formulations have been demonstrated to be safe, well tolerated, immunogenic, and to confer partial efficacy in both malaria-naive and -experienced adults as well as children. Further research to optimize and improve vaccine efficacy is ongoing.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 341,
                "text": "malaria"
            }
        },
        {
            "context": "Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 332,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Role of the Q-tip test in evaluating stress urinary incontinence. The Q-tip test was applied on 105 patients. Fifty-one had stress urinary incontinency (SUI), 28 had bladder instability by clinical and urodynamic criteria, and 36 had mild or moderate pelvic relaxation without urinary pathology. More than 90% of the patients with SUI and no previous surgery had a positive Q-tip test, with 90% test sensitivity in this group. More than one-third of the patients with bladder instability and almost one-half of the patients with pelvic relaxation and no urinary incontinence had a positive Q-tip test, for low test specificity. The Q-tip test is a simple clinical tool for diagnosing pelvic relaxation, which at times leads to SUI. Almost all patients with primary SUI have pelvic relaxation. The Q-tip test alone does not stand as a diagnostic test. When it is positive, the diagnosis of genuine stress incontinence is possible although not absolute. A negative test should cause one to question the diagnosis of genuine stress incontinence, and sophisticated and more expensive tests should be ordered before establishing a final diagnosis.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 37,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Panton-Valentine leukocidin-positive Staphylococcus aureus osteomyelitis of the tibia in a 10-year-old child. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing in prevalence among asymptomatic carriers and in cases of paediatric soft-tissue infections alike. CA-MRSA may express virulence factors such as Panton-Valentine leukocidin, which makes soft-tissue and hard-tissue infections due to such organisms challenging to treat. We report a case of osteomyelitis of the proximal tibia in a 10-year-old boy and discuss its management in what is to the authors' knowledge the first case report of Panton-Valentine leukocidin-positive CA-MRSA osteomyelitis in a child in the UK.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 179,
                "text": "MRSA"
            }
        },
        {
            "context": "McEnhancer: predicting gene expression via semi-supervised assignment of enhancers to target genes. Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.",
            "question": "Which method has been developed for assignment of enhancers to target genes?",
            "answers": {
                "answer_start": 318,
                "text": "McEnhancer"
            }
        },
        {
            "context": "Analysis of the 5' flanking region of the human galactocerebrosidase (GALC) gene. Galactocerebrosidase (GALC) is the lysosomal enzyme deficient in human and certain animal species with globoid cell leukodystrophy (GLD) or Krabbe disease. It catalyzes the hydrolysis of specific galactolipids including galactosylceramide and psychosine. The GALC protein is found in very low amounts in all tissues, which delayed its purification and the subsequent cloning of its cDNA and gene. We previously published the exon-intron organization of the human gene, but did not functionally analyze the 5' flanking region. We now provide a description of this GC-rich region which includes one potential YY1 element and one potential SP1 binding site. There are 13 GGC trinucleotides within the first 150 bp preceding the initiation codon. The 5' end of intron 1 contains six potential Sp1 binding sites, one AP1 binding site, and eight AP2 binding sites. A construct containing nucleotides -176 to -24 had the strongest promoter activity using a vector containing the chloramphenicol acetyltransferase reporter gene. We also provide evidence for the presence of inhibitory sequences located immediately upstream of the promoter region, and within the first 234 nucleotides of intron 1. These elements together with a suboptimal nucleotide at position +4 may explain the low level of GALC protein in all cell types.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 82,
                "text": "Galactocerebrosidase"
            }
        },
        {
            "context": "iLIR database: A web resource for LIR motif-containing proteins in eukaryotes. Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.",
            "question": "Which web resource for LIR motif-containing proteins in eukaryotes has been developed?",
            "answers": {
                "answer_start": 1491,
                "text": "the iLIR database"
            }
        },
        {
            "context": "Nivolumab in the treatment of malignant melanoma: review of the literature. Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma.",
            "question": "Which is the target protein of the drug nivolumab?",
            "answers": {
                "answer_start": 133,
                "text": "programmed death receptor-1"
            }
        },
        {
            "context": "Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 556,
                "text": "XK"
            }
        },
        {
            "context": "The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 1074,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Impact of DNA repair pathways on the cytotoxicity of piperlongumine in chicken DT40 cell-lines. Piperlongumine is a naturally-occurring small molecule with various biological activities. Recent studies demonstrate that piperlongumine selectively kills various types of transformed cells with minimal toxicity to non-transformed cells by inducing a high level of reactive oxygen species (ROS). ROS generates various types of DNA lesions, including base modifications and single strand breaks. In order to examine the contribution of ROS-induced DNA damage to the cytotoxicity by piperlongumine, various DNA repair-deficient chicken DT40 cell-lines with a single DNA repair gene deletion were tested for cellular sensitivity to piperlongumine. The results showed that cell lines defective in homologous recombination (HR) display hyper-sensitivity to piperlongumine, while other cell lines with a deficiency in non-homologous end joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER), Fanconi anemia (FA) pathway, or translesion DNA synthesis (TLS) polymerases, show no sensitivity to piperlongumine. The results strongly implicate that double strand breaks (DSBs) generated by piperlongumine are major cytotoxic DNA lesions. Furthermore, a deletion of 53BP1 or Ku70 in the BRCA1-deficient cell line restored cellular resistance to piperlongumine. This strongly supports the idea that piperlongumine induces DSB- mediated cell death. Interestingly, piperlongumine makes the wild type DT40 cell line hypersensitive to a PARP-inhibitor, Olaparib. The results implicate that piperlongumine inhibits HR. Further analysis with cell-based HR assay and the kinetic study of Rad51 foci formation confirmed that piperlongumine suppresses HR activity. Altogether, we revealed novel mechanisms of piperlongumine-induced cytotoxicity.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 1540,
                "text": "PARP"
            }
        },
        {
            "context": "In vivo analysis of Cajal body movement, separation, and joining in live human cells. Cajal bodies (also known as coiled bodies) are subnuclear organelles that contain specific nuclear antigens, including splicing small nuclear ribonucleoproteins (snRNPs) and a subset of nucleolar proteins. Cajal bodies are localized in the nucleoplasm and are often found at the nucleolar periphery. We have constructed a stable HeLa cell line, HeLa(GFP-coilin), that expresses the Cajal body marker protein, p80 coilin, fused to the green fluorescent protein (GFP-coilin). The localization pattern and biochemical properties of the GFP-coilin fusion protein are identical to the endogenous p80 coilin. Time-lapse recordings on 63 nuclei of HeLa(GFP-coilin) cells showed that all Cajal bodies move within the nucleoplasm. Movements included translocations through the nucleoplasm, joining of bodies to form larger structures, and separation of smaller bodies from larger Cajal bodies. Also, we observed Cajal bodies moving to and from nucleoli. The data suggest that there may be at least two classes of Cajal bodies that differ in their size, antigen composition, and dynamic behavior. The smaller size class shows more frequent and faster rates of movement, up to 0.9 microm/min. The GFP-coilin protein is dynamically associated with Cajal bodies as shown by changes in their fluorescence intensity over time. This study reveals an unexpectedly high level of movement and interactions of nuclear bodies in human cells and suggests that these movements may be driven, at least in part, by regulated mechanisms.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 551,
                "text": "coilin"
            }
        },
        {
            "context": "Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that resulted in 655,000 deaths and 216 million clinical cases in 2010 alone. Recent phase 3 trials with malaria vaccine candidate RTS,S/AS01 (RTS,S) in children has demonstrated modest efficacy against clinical and severe malaria. RTS,S targets the pre-erythrocytic phase of the disease and induces high antibody titers against the P. falciparum circumsporozoite protein (CSP) and a moderate CD4(+) T cell response. The individual contribution of these adaptive immune responses to protection from infection remains unknown. Here, we found that prophylactic administration of anti-CSP mAbs derived from an RTS,S-vaccinated recipient fully protected mice with humanized livers from i.v.- and mosquito bite - delivered P. falciparum sporozoite challenge. Titers of anti-CSP that conveyed full protection were within the range observed in human RTS,S vaccine recipients. Increasing anti-CSP titers resulted in a dose-dependent reduction of the liver parasite burden. These data indicate that RTS,S-induced antibodies are protective and provide sterilizing immunity against P. falciparum infection when reaching or exceeding a critical plasma concentration.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 310,
                "text": "malaria"
            }
        },
        {
            "context": "Diversity and evolution of multiple orc/cdc6-adjacent replication origins in haloarchaea. BACKGROUND: While multiple replication origins have been observed in archaea, considerably less is known about their evolutionary processes. Here, we performed a comparative analysis of the predicted (proved in part) orc/cdc6-associated replication origins in 15 completely sequenced haloarchaeal genomes to investigate the diversity and evolution of replication origins in halophilic Archaea. RESULTS: Multiple orc/cdc6-associated replication origins were predicted in all of the analyzed haloarchaeal genomes following the identification of putative ORBs (origin recognition boxes) that are associated with orc/cdc6 genes. Five of these predicted replication origins in Haloarcula hispanica were experimentally confirmed via autonomous replication activities. Strikingly, several predicted replication origins in H. hispanica and Haloarcula marismortui are located in the distinct regions of their highly homologous chromosomes, suggesting that these replication origins might have been introduced as parts of new genomic content. A comparison of the origin-associated Orc/Cdc6 homologs and the corresponding predicted ORB elements revealed that the replication origins in a given haloarchaeon are quite diverse, while different haloarchaea can share a few conserved origins. Phylogenetic and genomic context analyses suggested that there is an original replication origin (oriC1) that was inherited from the ancestor of archaea, and several other origins were likely evolved and/or translocated within the haloarchaeal species. CONCLUSION: This study provides detailed information about the diversity of multiple orc/cdc6-associated replication origins in haloarchaeal genomes, and provides novel insight into the evolution of multiple replication origins in Archaea.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 1697,
                "text": "multiple"
            }
        },
        {
            "context": "Subviral pathogens of plants: the viroids. Research during the last 15 years has conclusively shown that viroids are not only fundamentally different from viruses at the molecular level, but that they are most likely not directly related to viruses in an evolutionary sense. Today, viroids are among the most thoroughly studied biological macromolecules. Their molecular structures have been elucidated to a large extent, but much needs to be learned regarding the correlation between molecular structure and biological function. The availability of the tools of recombinant DNA technology in viroid research promises rapid progress in these areas of inquiry.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 34,
                "text": "viroids"
            }
        },
        {
            "context": "Selexipag for the treatment of pulmonary arterial hypertension. INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 31,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "The wrist hyperflexion and abduction of the thumb (WHAT) test: a more specific and sensitive test to diagnose de Quervain tenosynovitis than the Eichhoff's Test. De Quervain's disease has different clinical features. Different tests have been described in the past, the most popular test being the Eichhoff's test, often wrongly named as the Finkelstein's test. Over the years, a misinterpretation has occurred between these two tests, the latter being confused with the first. To compare the Eichhoff's test with a new test, the wrist hyperflexion and abduction of the thumb test, we set up a prospective study over a period of three years for a cohort of 100 patients (88 women, 12 men) presenting spontaneous pain over the radial side of the styloid of the radius (de Quervain tendinopathy). The purpose of the study was to compare the accuracy of the Eichhoff's test and wrist hyperflexion and abduction of the thumb test to diagnose correctly de Quervain's disease by comparing clinical findings using those tests with the results on ultrasound. The wrist hyperflexion and abduction of the thumb test revealed greater sensitivity (0.99) and an improved specificity (0.29) together with a slightly better positive predictive value (0.95) and an improved negative predictive value (0.67). Moreover, the study showed us that the wrist hyperflexion and abduction of the thumb test is very valuable in diagnosing dynamic instability after successful decompression of the first extensor compartment. Our results support that the wrist hyperflexion and abduction of the thumb test is a more precise tool for the diagnosis of de Quervain's disease than the Eichhoff's test and thus could be adopted to guide clinical diagnosis in the early stages of de Quervain's tendinopathy.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 162,
                "text": "De Quervain's disease"
            }
        },
        {
            "context": "First case of X-linked dystonia-parkinsonism (\"Lubag\") to demonstrate a response to bilateral pallidal stimulation. \"Lubag\" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 14,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. Alpha interferon (IFN-α) controls homeostasis of hematopoietic stem cells, regulates antiviral resistance, inhibits angiogenesis, and suppresses tumor growth. This cytokine is often used to treat cancers and chronic viral infections. The extent of cellular responses to IFN-α is limited by the IFN-induced ubiquitination and degradation of the IFN-α/β receptor chain 1 (IFNAR1) chain of the cognate receptor. IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand. Here we report identification of protein kinase D2 (PKD2) as a kinase that mediates the ligand-inducible phosphorylation of IFNAR1 degron and enables binding of βTrcp to the receptor. Treatment of cells with IFN-α induces catalytic activity of PKD2 and stimulates its interaction with IFNAR1. Expression and kinase activity of PKD2 are required for the ligand-inducible stimulation of IFNAR1 ubiquitination and endocytosis and for accelerated proteolytic turnover of IFNAR1. Furthermore, inhibition or knockdown of PKD2 robustly augments intracellular signaling induced by IFN-α and increases the efficacy of its antiviral effects. The mechanisms of the ligand-inducible elimination of IFNAR1 are discussed, along with the potential medical significance of this regulation.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 547,
                "text": "βTrcp"
            }
        },
        {
            "context": "Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.",
            "question": "What is the drug target for Simtuzumab?",
            "answers": {
                "answer_start": 557,
                "text": "LOXL2"
            }
        },
        {
            "context": "Nuclear gems and Cajal (coiled) bodies in fetal tissues: nucleolar distribution of the spinal muscular atrophy protein, SMN. SMN, the affected protein in spinal muscular atrophy (SMA), is a cytoplasmic protein that also occurs in nuclear structures called \"gems\" and is involved in snRNP maturation. Coilin-p80 is a marker protein for nuclear Cajal bodies (coiled bodies; CBs) which are also involved in snRNP maturation, storage or transport. We now show that gems and CBs are present in all fetal tissues, even those that lack gems/CBs in the adult. Most gems and CBs occur as separate nuclear structures in fetal tissues, but their colocalization increases with fetal age and is almost complete in the adult. In adult tissues, up to half of all gems/CBs are inside the nucleolus, whereas in cultured cells they are almost exclusively nucleoplasmic. The nucleolar SMN is often more diffusely distributed, compared with nucleoplasmic gems. Up to 30% of cells in fetal tissues have SMN distributed throughout the nucleolus, instead of forming gems in the nucleoplasm. The results suggest a function for gems distinct from Cajal bodies in fetal nuclei and a nucleolar function for SMN. Spinal cord, the affected tissue in SMA, behaves differently in several respects. In both fetal and adult motor neurons, many gems/CBs occur as larger bodies closely associated with the nucleolar perimeter. Uniquely in motor neurons, gems/CBs are more numerous in adult than in fetal stages and colocalization of gems and CBs occurs earlier in development. These unusual features of motor neurons may relate to their special sensitivity to reduced SMN levels in SMA patients.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 300,
                "text": "Coilin"
            }
        },
        {
            "context": "Cardiac conduction disorders in children. Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy, Arrhythmogenic right ventricular dysplasia, Isolated noncompaction of the left ventricle, Long QT syndrome (LQTS) and Brugada syndrome, are all well described. Congenital short QT syndrome is a new familial primary electrical disease of the heart, which is characterized by abnormally short QT interval and paroxysmal atrial and ventricular tachyarrhythmias, including sudden cardiac death. An autosomal dominant mode of inheritance has been suggested. Catecholaminergic polymorphic ventricular tachycardia is an inherited disease and occurs in the absence of structural heart disease or known associated syndromes. Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.",
            "question": "What is the mode of inheritance of short QT syndrome?",
            "answers": {
                "answer_start": 535,
                "text": "autosomal dominant mode of inheritance"
            }
        },
        {
            "context": "Classification schemes of cranial dural arteriovenous fistulas. The clinical presentation of dural arteriovenous fistulas (DAVFs), in particular the associated risk of intracranial hemorrhage, shows a strong correlation with their pattern of venous drainage. The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage. A revised classification that grades DAVFs through a combination of angiographic and clinical features has also been proposed. This article offers a review of these various classification schemes, and discusses their application to treatment decision making.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 310,
                "text": "DAVF"
            }
        },
        {
            "context": "Microbiome and metabolic disease: revisiting the bacterial phylum Bacteroidetes. Bacterial species composition in the gut has emerged as an important factor in obesity and its related metabolic diseases such as type 2 diabetes. Out of thousands of bacterial species-level phylotypes inhabiting the human gut, the majority belong to two dominant phyla, the Bacteroidetes and Firmicutes. Members of the Bacteroidetes in particular have been associated with human metabolic diseases. However, their associations with disease are not always consistent between studies. Delving deeper into the diversity within the Bacteroidetes reveals a vast diversity in genomes and capacities, which partly explain how not all members respond equally to similar environmental conditions in their hosts. Here, we discuss the Bacteroidetes phylum, associations of its members with metabolic phenotypes, and efforts to characterize functionally their interactions with their hosts. Harnessing the Bacteroidetes to promote metabolic health will require a nuanced understanding of how specific strains interact with their microbial neighbors and their hosts under various conditions.",
            "question": "Which are the two main bacterial phyla in human gut?",
            "answers": {
                "answer_start": 356,
                "text": "Bacteroidetes and Firmicutes"
            }
        },
        {
            "context": "New directions in antiarrhythmic drug therapy for atrial fibrillation. Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and has a significant impact on morbidity and mortality. Current antiarrhythmic drugs for AF suffer from limited safety and efficacy, probably because they were not designed based on specific pathological mechanisms. Recent research has provided important insights into the mechanisms contributing to AF and highlighted several potential novel antiarrhythmic strategies. In this review, we highlight the main pathological mechanisms of AF, discuss traditional and novel aspects of atrial antiarrhythmic drugs in relation to these pathological mechanisms, and present potential novel therapeutic approaches including structure-based modulation of atrial-specific cardiac ion channels, restoring abnormal Ca(2+) handling in AF and targeting atrial remodeling.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 92,
                "text": "AF"
            }
        },
        {
            "context": "A protein complex containing the conserved Swi2/Snf2-related ATPase Swr1p deposits histone variant H2A.Z into euchromatin. The conserved histone variant H2A.Z functions in euchromatin to antagonize the spread of heterochromatin. The mechanism by which histone H2A is replaced by H2A.Z in the nucleosome is unknown. We identified a complex containing 13 different polypeptides associated with a soluble pool of H2A.Z in Saccharomyces cerevisiae. This complex was designated SWR1-Com in reference to the Swr1p subunit, a Swi2/Snf2-paralog. Swr1p and six other subunits were found only in SWR1-Com, whereas six other subunits were also found in the NuA4 histone acetyltransferase and/or the Ino80 chromatin remodeling complex. H2A.Z and SWR1 were essential for viability of cells lacking the EAF1 component of NuA4, pointing to a close functional connection between these two complexes. Strikingly, chromatin immunoprecipitation analysis of cells lacking Swr1p, the presumed ATPase of the complex, revealed a profound defect in the deposition of H2A.Z at euchromatic regions that flank the silent mating type cassette HMR and at 12 other chromosomal sites tested. Consistent with a specialized role for Swr1p in H2A.Z deposition, the majority of the genome-wide transcriptional defects seen in swr1Delta cells were also found in htz1Delta cells. These studies revealed a novel role for a member of the ATP-dependent chromatin remodeling enzyme family in determining the region-specific histone subunit composition of chromatin in vivo and controlling the epigenetic state of chromatin. Metazoan orthologs of Swr1p (Drosophila Domino; human SRCAP and p400) may have analogous functions.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 502,
                "text": "Swr1"
            }
        },
        {
            "context": "Oligomeric interactions between phospholamban molecules regulate Ca-ATPase activity in functionally reconstituted membranes. Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, and functions as an endogenous inhibitor of Ca-ATPase transport activity. To identify whether oligomeric interactions between PLB molecules are involved in regulating Ca-ATPase transport activity, we have investigated functional interactions between PLB and the Ca-ATPase in proteoliposomes of purified PLB functionally co-reconstituted with the SERCA2a isoform of the Ca-ATPase isolated from cardiac sarcoplasmic reticulum (SR). The calcium sensitivity of this reconstituted preparation and functional stimulation by cAMP-dependent protein kinase (PKA) are virtually identical to those of the Ca-ATPase in cardiac SR microsomes, ensuring the functional relevance of this reconstituted preparation. Interactions between PLB molecules were measured following covalent modification of the single lysine (i.e., Lys(3)) in PLB isolated from cardiac SR membranes with fluorescein isothiocyanate (FITC) prior to co-reconstitution with the Ca-ATPase. FITC modification of PLB does not interfere with the ability of PLB to inhibit the Ca-ATPase, since FITC-PLB co-reconstituted with the Ca-ATPase exhibits a similar calcium dependence of Ca-ATPase activation to that observed in native SR membranes. Thus, the functional arrangement of PLB with the Ca-ATPase is not modified by FITC modification. Using changes in the anisotropy of FITC-PLB resulting from fluorescence resonance energy transfer (FRET) between proximal PLB molecules to measure the average size and spatial arrangement of FITC chromophores, we find that PLB self-associates to form oligomers whose spatial arrangement with respect to one another is in agreement with earlier suggestions that PLB exists predominantly as a homopentamer. The inability of PKA to activate PLB following covalent modification with FITC permits functional interactions between PLB molecules associated with the Ca-ATPase activation to be identified. A second-order loss of Ca-ATPase activation by PKA is observed as a function of the fractional contribution of FITC-PLB, indicating that PKA-dependent activation of two PLB molecules within a quaternary complex containing the Ca-ATPase is necessary for activation of the Ca-ATPase. We suggest that the requirement for activation of two PLB molecules by PKA represents a physiological mechanism to ensure that activation of the Ca-ATPase following beta-adrenergic stimulation in the heart only occurs above a threshold level of PKA activation.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 125,
                "text": "Phospholamban"
            }
        },
        {
            "context": "Sushi.R: flexible, quantitative and integrative genomic visualizations for publication-quality multi-panel figures. Interpretation and communication of genomic data require flexible and quantitative tools to analyze and visualize diverse data types, and yet, a comprehensive tool to display all common genomic data types in publication quality figures does not exist to date. To address this shortcoming, we present Sushi.R, an R/Bioconductor package that allows flexible integration of genomic visualizations into highly customizable, publication-ready, multi-panel figures from common genomic data formats including Browser Extensible Data (BED), bedGraph and Browser Extensible Data Paired-End (BEDPE). Sushi.R is open source and made publicly available through GitHub (https://github.com/dphansti/Sushi) and Bioconductor (http://bioconductor.org/packages/release/bioc/html/Sushi.html).",
            "question": "Which R/bioconductor package is used for integrative genomics visualizations?",
            "answers": {
                "answer_start": 0,
                "text": "Sushi.R"
            }
        },
        {
            "context": "Monitoring twenty-six chronic myeloid leukemia patients by BCR-ABL mRNA level in bone marrow:a single hospital experience. Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 295,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 72,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519. The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator. We examined the modulatory effect of JTV-519 on the antitumor activity of several platinum compounds (cisplatin, carboplatin, and nedaplatin) in a human cancer cell line resistant to cisplatin (PC-14 / CDDP) in vitro. PC-14 / CDDP cells showed 8-fold resistance to cisplatin compared with the parental PC-14 cells as determined by dye formation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] assay. In PC-14 / CDDP, but not PC-14 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 mM) of JTV-519 was combined with the platinum compounds. Increased intracellular cisplatin accumulation was observed in PC-14 / CDDP cells in the presence of JTV-519 as measured by atomic absorption assay. Therefore, increased cisplatin accumulation was considered to be a possible mechanism underlying the reversing effect of JTV-519 on cisplatin resistance. These results suggest that JTV-519 is a potent agent reversing cisplatin resistance.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 85,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy. Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 346,
                "text": "FSHD"
            }
        },
        {
            "context": "Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms. The chronic myeloproliferative neoplasms (MPNs), are characterized by a Janus Kinase (JAK)-2 V617F point mutation but this molecular abnormality does not explain by itself the pathogenesis of these disorders, or the phenotypic diversity associated with essential thrombocythemia, polycythemia vera (PV), and myelofibrosis. Beyond the JAK/signal transducer and activator of transcription network, a wide number of molecular alterations were described in MPN including the fosfatidilinositolo-3-chinasi (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway constitutive activation. Several pathway inhibitors were developed, including everolimus, up to the latest class of catalytic inhibitors such as BKM120 and BEZ235. In this review, we present some clinical and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent a therapeutic target in MPNs. In in vitro studies, everolimus has been shown to inhibit cell proliferation and clonogenic potential in human and murine JAK2 V617F mutated cell lines. Patients with PV and primary myelofibrosis hematopoietic progenitors were significantly more sensitive to everolimus compared with healthy control subjects. Of much interest, a combination of everolimus and the JAK1/2 inhibitor, ruxolitinib, showed strong synergism in inducing cell cycle arrest and blockade of cell proliferation. Similar data were obtained using a dual PI3K/mTOR inhibitor, BEZ235, with activity that was also shown in preclinical murine models. A multicenter phase I/II trial with everolimus in myelofibrosis documented a well tolerated clinical efficiency in terms of spleen size reduction and resolution of systemic symptoms and pruritus. These observations indicate that the PI3K/Akt/mTOR pathway might represent a novel target for treatment in MPN. The synergism demonstrated in vitro with JAK2 inhibitors could open additional therapeutic possibilities based on concurrent targeting of different pathways that might optimize efficacy and reduce toxicity in patients.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 614,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1131,
                "text": "53BP1"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 839,
                "text": "Xa"
            }
        },
        {
            "context": "Evaluation of the safety and efficacy of isradipine in elderly patients with essential hypertension. The British Isradipine Hypertension Group. One hundred eighteen patients, aged between 65 and 87 years with mild-to-moderate hypertension were given placebo or isradipine (1.25 to 5 mg twice daily, or 2.5 to 10 mg once daily) following a three-week placebo period to evaluate its safety and efficacy in elderly patients. Dosage step-up was at three-week intervals. Blood pressure measurements were taken immediately before the morning dose (12 to 24 hours after the previous dose). At the end of the study, both supine and standing diastolic blood pressures were significantly lower with isradipine than with placebo. A 10-mm Hg reduction in supine diastolic blood pressure was achieved with once-daily isradipine in 65 percent and with twice-daily isradipine in 52 percent of patients, indicating sustained blood pressure control over the dose interval (12 to 24 hours). Adverse events were usually mild, transient, and typical for vasodilators. Isradipine did not produce more laboratory, clinical, or electrocardiographic abnormalities than did placebo. In conclusion, isradipine either once or twice daily at doses between 2.5 and 10 mg is an effective and well-tolerated treatment for mild-to-moderate hypertension in elderly patients.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 87,
                "text": "hypertension"
            }
        },
        {
            "context": "Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 194,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case. Speech and language disorders are some of the most common referral reasons to child development centers accounting for approximately 40% of cases. Stuttering is a disorder in which involuntary repetition, prolongation, or cessation of the sound precludes the flow of speech. About 5% of individuals in the general population have a stuttering problem, and about 80% of the affected children recover naturally. The causal factors of stuttering remain uncertain in most cases; studies suggest that genetic factors are responsible for 70% of the variance in liability for stuttering, whereas the remaining 30% is due to environmental effects supporting a complex cause of the disorder. The use of high-resolution genome wide array comparative genomic hybridization has proven to be a powerful strategy to narrow down candidate regions for complex disorders. We report on a case with a complex set of speech and language difficulties including stuttering who presented with a 10 Mb deletion of chromosome region 7q33-35 causing the deletion of several genes and the disruption of CNTNAP2 by deleting the first three exons of the gene. CNTNAP2 is known to be involved in the cause of language and speech disorders and autism spectrum disorder and is in the same pathway as FOXP2, another important language gene, which makes it a candidate gene for causal studies speech and language disorders such as stuttering.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 1378,
                "text": "FOXP2"
            }
        },
        {
            "context": "Preventing deaths from cryptococcal meningitis: from bench to bedside. Cryptococcal meningitis (CM), a fungal disease caused by Cryptococcus spp., is the most common form of meningitis and a leading cause of death among persons with HIV/AIDS in sub-Saharan Africa. Detection of cryptococcal antigen, which is present several weeks before overt signs of meningitis develop, provides an opportunity to detect infection early. Screening persons with HIV for cryptococcal infection when they access healthcare can identify asymptomatic infected patients allowing for prompt treatment and prevention of death. A newly developed point-of-care assay for cryptococcal antigen, as well as growing evidence supporting the utility and cost-effectiveness of screening, are further reasons to consider broad implementation of cryptococcal screening in countries with a high burden of cryptococcal disease.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 233,
                "text": "HIV"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 295,
                "text": "TYR"
            }
        },
        {
            "context": "Inhibitory Effect of Algal Extracts on Mycelial Growth of the Tomato-Wilt Pathogen, Fusarium oxysporum f. sp. lycopersici. The present study was undertaken to explore the inhibitory effect of cyanobacterial extracts of Nostoc commune FA-103 against the tomato-wilt pathogen, Fusarium oxysporum f. sp. lycopersici. In an optimal medium, cell growth, antifungal activity, and antifungal compound production could be increased 2.7-fold, 4.1-fold, and 13.4-fold, respectively. A crude algal extract had a similar effect as mancozeb at the recommended dose, both in laboratory and pot tests. In vitro and in vivo fungal growth, spore sporulation and fungal infection of wilt pathogen in tomato seeds were significantly inhibited by cyanobacterial extracts. Nostoc commune FA-103 extracts have potential for the suppression of Fusarium oxysporum f. sp. lycopersici.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 253,
                "text": "tomato"
            }
        },
        {
            "context": "Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations. Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1497,
                "text": "xa"
            }
        },
        {
            "context": "Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia. OBJECTIVE: To review the efficacy, safety, and pharmacology data available for suvorexant and determine its role in therapy as compared with other agents available for the treatment of insomnia. DATA SOURCES: A PubMed search using the terms suvorexant and MK-4305 (the original name given to suvorexant during early trials) was conducted in December 2014 to identify initial literature sources. No time frame was used for exclusion of older trials. STUDY SELECTION AND DATA EXTRACTION: Animal studies and trials written in a language other than English were excluded. Abstracts of the remaining trials were evaluated for determination of relevance to this review. References from these studies along with suvorexant prescriber information were used to identify additional literature. DATA SYNTHESIS: Three randomized, double-blind, placebo-controlled clinical trials were identified showing suvorexant to be safe, effective, and tolerable for the treatment of insomnia. After 4 weeks of therapy, relative to placebo, the 10- and 20-mg doses improved subjective total sleep time (22.3 and 49.9 minutes, respectively), wake after sleep onset (-21.4 and -28.1 minutes), and latency to persistent sleep (-2.3 and -22.3 minutes). CONCLUSION: Suvorexant is the first dual orexin receptor antagonist approved for the treatment of insomnia. Clinical trials have shown that it is relatively safe and effective for the treatment of both sleep onset and sleep maintenance at doses of 20 mg or less. Higher doses were studied but not approved because of concerns for next-day somnolence and effects on driving. Further studies are needed to assess this medication in patients with a history of addiction, because they were excluded from clinical trials, as well as to compare suvorexant with other insomnia medications available because no head-to-head studies have yet been conducted. However, its novel mechanism of action and theoretically lower addiction liability make suvorexant an appealing new option.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 19,
                "text": "orexin"
            }
        },
        {
            "context": "Profiling the RNA editomes of wild-type C. elegans and ADAR mutants. RNA editing increases transcriptome diversity through post-transcriptional modifications of RNA. Adenosine deaminases that act on RNA (ADARs) catalyze the adenosine-to-inosine (A-to-I) conversion, the most common type of RNA editing in higher eukaryotes. Caenorhabditis elegans has two ADARs, ADR-1 and ADR-2, but their functions remain unclear. Here, we profiled the RNA editomes of C. elegans at different developmental stages of wild-type and ADAR mutants. We developed a new computational pipeline with a \"bisulfite-seq-mapping-like\" step and achieved a threefold increase in identification sensitivity. A total of 99.5% of the 47,660 A-to-I editing sites were found in clusters. Of the 3080 editing clusters, 65.7% overlapped with DNA transposons in noncoding regions and 73.7% could form hairpin structures. The numbers of editing sites and clusters were highest at the L1 and embryonic stages. The editing frequency of a cluster positively correlated with the number of editing sites within it. Intriguingly, for 80% of the clusters with 10 or more editing sites, almost all expressed transcripts were edited. Deletion of adr-1 reduced the editing frequency but not the number of editing clusters, whereas deletion of adr-2 nearly abolished RNA editing, indicating a modulating role of ADR-1 and an essential role of ADR-2 in A-to-I editing. Quantitative proteomics analysis showed that adr-2 mutant worms altered the abundance of proteins involved in aging and lifespan regulation. Consistent with this finding, we observed that worms lacking RNA editing were short-lived. Taken together, our results reveal a sophisticated landscape of RNA editing and distinct modes of action of different ADARs.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 246,
                "text": "A-to-I"
            }
        },
        {
            "context": "Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1547,
                "text": "flumazenil"
            }
        },
        {
            "context": "The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.",
            "question": "Which type of GTPases is required for amino acid-dependent activation of mTORC1?",
            "answers": {
                "answer_start": 193,
                "text": "Heterodimeric Rag GTPases"
            }
        },
        {
            "context": "Incidence of Community-associated Methicillin-resistant Staphylococcus aureus Infections in a Regional Hospital. BACKGROUND AND OBJECTIVE: Since the early 2000s, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections among the community of people lacking known healthcare risk factors has increased. This MRSA infection is referred to as community-associated MRSA (CA-MRSA) infection and is distinct from hospital-associated MRSA (HA-MRSA) infection, which occurs among people with known healthcare risk factors. Understanding the epidemiology of CA-MRSA infections is critical; however, this has not been investigated in detail in Japan. Our objective was to investigate the incidence of CA-MRSA infections in a regional hospital. PATIENTS AND METHODS: We investigated CA-MRSA isolates and infections in a rural regional hospital by reviewing medical records of one year. Infections were classified as CA-MRSA if no established risk factors were identified. RESULTS: During 2008, 31 Staphylococcus aureus (S. aureus) isolates were detected in 29 unique patients, with 1 methicillin-sensitive S. aureus (MSSA) isolates obtained from 19 patients (66%) and MRSA obtained from 10 patients (34%). In the 10 patients with MRSA, the number of HA-MRSA and CA-MRSA cases were nine (32% of patients with S. aureus isolates) and one (3%), respectively. The patient with CA-MRSA was diagnosed with cellulitis due to CA-MRSA. All nine patients with HA-MRSA exhibited colonization. CONCLUSION: We observed a CA-MRSA case in a regional hospital in Japan, suggesting that incidence trends of CA-MRSA should be considered in future research and treatment.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 224,
                "text": "MRSA"
            }
        },
        {
            "context": "Skin layer-specific transcriptional profiles in normal and recessive yellow (Mc1re/Mc1re) mice. The melanocortin 1 receptor (Mc1r) plays a central role in cutaneous biology, but is expressed at very low levels by a small fraction of cells in the skin. In humans, loss-of-function MC1R mutations cause fair skin, freckling, red hair, and increased predisposition to melanoma; in mice, Mc1r loss-of-function is responsible for the recessive yellow mutation, associated with pheomelanic hair and a decreased number of epidermal melanocytes. To better understand how Mc1r signaling affects different cutaneous phenotypes, we examined large-scale patterns of gene expression in different skin components (whole epidermal sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and recessive yellow mice, starting with a 26K mouse cDNA microarray. From c. 17 000 genes whose levels could be accurately measured in neonatal skin, we identified 883, 2097 and 552 genes that were uniquely expressed in the suprabasal epidermis, basal epidermis and dermis, respectively; specific biologic roles could be assigned for each class. Comparison of normal and recessive yellow mice revealed 69 differentially expressed genes, of which the majority had not been previously implicated in Mc1r signaling. Surprisingly, many of the Mc1r-dependent genes are expressed in cells other than melanocytes, even though Mc1r expression in the skin is confined almost exclusively to epidermal melanocytes. These results reveal new targets for Mc1r signaling, and point to a previously unappreciated role for a Mc1r-dependent paracrine effect of melanocytes on other components of the skin.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 384,
                "text": "Mc1r"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 733,
                "text": "Xa"
            }
        },
        {
            "context": "A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome. Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 21,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 734,
                "text": "TYR"
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 969,
                "text": "PD-L1"
            }
        },
        {
            "context": "Regulation of the Ets-1 transcription factor by sumoylation and ubiquitinylation. Sumoylation and ubiquitinylation reversibly regulate the activity of transcription factors through covalent attachment to lysine residues of target proteins. We examined whether the Ets-1 transcription factor is modified by sumoylation and/or ubiquitinylation. Among four potential SUMO motifs in Ets-1, we identified lysines 15 and 227 within the LK(15)YE and IK(227)QE motifs, as being the sumoylation acceptor sites. Using transfection of Ets-1 wildtype (WT) or its sumoylation deficient version (Ets-1 K15R/K227R), as well as WT or mutant proteins of the SUMO pathway, we further demonstrated that the E2 SUMO-conjugating enzyme Ubc9 and a E3 SUMO ligase, PIASy, can enhance Ets-1 sumoylation, while a SUMO protease, SENP1, can desumoylate Ets-1. We also found that Ets-1 is modified by K48-linked polyubiquitinylation independently of the sumoylation acceptor sites and is degraded through the 26S proteasome pathway, while sumoylation of Ets-1 does not affect its stability. Finally, sumoylation of Ets-1 leads to reduced transactivation and we demonstrated that previously identified critical lysine residues in Synergistic Control motifs are the sumoylation acceptor sites of Ets-1. These data show that Ets-1 can be modified by sumoylation and/or ubiquitinylation, with sumoylation repressing transcriptional activity of Ets-1 and having no clear antagonistic action on the ubiquitin-proteasome degradation pathway.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 691,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "Bone involvement in adult patients affected with Ehlers-Danlos syndrome. UNLABELLED: The Ehlers-Danlos syndrome is characterized by abnormal connective tissue but bone involvement is debated. We found a reduced BMD and bone quality and increased prevalence of asymptomatic vertebral fractures in eugonadal patients with Ehlers-Danlos syndrome. These findings suggest the need of a bone health evaluation in these patients. INTRODUCTION: The Ehlers-Danlos (EDS) syndrome is characterized by abnormalities of the connective tissue leading to ligamentous laxity and skin and tissue fragility. We evaluated the bone metabolism, bone mineral density (BMD) and bone quality (measured by trabecular bone score, TBS), and the prevalence of vertebral fractures (VFx) in a group of eugonadal adult EDS patients. METHODS: Fifty consecutive Caucasian patients, aged 30-50 years (36 females, 14 males) with classical or hypermobility EDS and 50 age-, gender-, and body mass index (BMI)-matched control subjects were enrolled. In all subjects' calcium-phosphorous metabolism, bone turnover, BMD at the lumbar spine (LS) and femur (femoral neck, FN and total femur, FT) and TBS by dual-energy X-ray absorptiometry, and the VFx presence by spine radiograph were assessed. RESULTS: Patients showed reduced BMD (Z-scores LS -0.45 ± 1.00, FN -0.56 ± 1.01, FT -0.58 ± 0.92) and TBS (1.299 ± 0.111) and increased prevalence of morphometric VFx (32 %) than controls (Z-scores LS 0.09 ± 1.22, FN 0.01 ± 0.97, FT 0.08 ± 0.89; TBS 1.382 ± 0.176; VFx 8 %, p <0.05 for all comparisons), while vitamin D levels, calcium-phosphorous metabolism, and bone turnover were comparable. Fractured EDS patients showed lower TBS values than non-fractured ones (1.245 ± 0.138 vs 1.325 ± 0.086, p < 0.05), despite comparable BMD. In EDS patients, the VFx presence was significantly associated with TBS even after adjusting for sex, age, BMD, EDS type, and falls frequency. CONCLUSIONS: EDS patients have reduced BMD and bone quality (as measured by TBS) and increased prevalence of VFx.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 141,
                "text": "connective tissue"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1006,
                "text": "Xa"
            }
        },
        {
            "context": "Remission of ulcerated necrobiosis lipoidica diabeticorum after bariatric surgery. A 32-year-old woman with type 2 diabetes mellitus suffering from morbid obesity with BMI 45,14 kg/m(2) was operated on. Not only the type 2DM but also one of its complication known as necrobiosis lipoidica diabeticorum remitted postoperatively. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals but an epidemic that threatens global well-being. It causes or exacerbates many health problems, and in particular, it is associated with the type 2 diabetes. Necrobiosis lipoidica is a granulomatous skin disease of unknown etiology, associated mainly with diabetes mellitus. We presented in this paper a morbid obese case of necrobiosis lipoidica diabeticorum with dramatic good response to bariatric surgery.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 115,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and > 10 years) and baseline mobility testing passing level (pass at > 125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 10 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.",
            "question": "Which retinal dystrophy related gene is targeted by the AAV2-hRPE65v2 drug?",
            "answers": {
                "answer_start": 780,
                "text": "RPE65"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 196,
                "text": "MRSA"
            }
        },
        {
            "context": "A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 87,
                "text": "FBN1"
            }
        },
        {
            "context": "The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca(2+)-activated K(+) channels. Atrial fibrillation (AF) is associated with increased morbidity and is in addition the most prevalent cardiac arrhythmia. Compounds used in pharmacological treatment has traditionally been divided into Na(+) channel inhibitors, β-blockers, K(+) channel inhibitors, and Ca(2+) channel inhibitors, whereas newer multichannel blockers such as amiodarone and ranolazine have been introduced later. This study was devoted to the evaluation of an acute pacing-induced in vivo model of AF in rats. Antiarrhythmic effects of well-known compounds such as lidocaine, dofetilide, and ranolazine were confirmed in this model. In addition, antiarrhythmic effects of different inhibitors of Ca(2+)-activated small conductance K(+) (SK) channels were demonstrated. Intravenous application of 5 mg/kg of the negative SK channel modulator NS8593 reduced AF duration by 64.5%, and the lowest significantly effective dose was 1.5 mg/kg. A dose-effect relationship was established based on 6 different dose groups. Furthermore, it was demonstrated that the antiarrhythmic effect of NS8593 and other tested drugs was associated with an increase in atrial effective refractory period. The functional role of SK channels was confirmed by 2 other SK channel inhibitors, UCL1684 and apamin, thereby confirming the hypothesis that these channels might constitute a new promising target for antiarrhythmic treatment.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 158,
                "text": "AF"
            }
        },
        {
            "context": "PPADS, a P2X receptor antagonist, as a novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger in guinea pig airway smooth muscle. The Na(+)/Ca(2+)exchanger (NCX) principal function is taking 1 Ca(2+) out of the cytoplasm and introducing 3 Na(+). The increase of cytoplasmic Na(+) concentration induces the NCX reverse mode (NCX(REV)), favoring Ca(2+) influx. NCX(REV) can be inhibited by: KB-R7943 a non-specific compound that blocks voltage-dependent and store-operated Ca(2+) channels; SEA0400 that appears to be selective for NCX(REV), but difficult to obtain and SN-6, which efficacy has been shown only in cardiomyocytes. We found that PPADS, a P2X receptor antagonist, acts as a NCX(REV) inhibitor in guinea pig tracheal myocytes. In these cells, we characterized the NCX(REV) by substituting NaCl and NaHCO(3) with LiCl, resulting in the increase of the intracellular Ca(2+) concentration ([Ca(2+)]i) using fura 2-AM. We analyzed 5 consecutive responses of the NCX(REV) every 10 min, finding no differences among them. To evaluate the effect of different NCX(REV) blockers, concentration response curves to KB-R7943 (1, 3.2 and 10 μM), and SN-6 (3.2, 10 and 30 μM) were constructed, whereas PPADS effect was characterized as time- and concentration-dependent (1, 3.2, 10 and 30 μM). PPADS had similar potency and efficacy as KB-R7943, whereas SN-6 was the least effective. Furthermore, KCl-induced contraction, sensitive to D600 and nifedipine, was blocked by KB-R7943, but not by PPADS. KCl-induced [Ca(2+)]i increment in myocytes was also significantly decreased by KBR-7943 (10 μM). Our results demonstrate that PPADS can be used as a reliable pharmacological tool to inhibit NCX(REV), with the advantage that it is more specific than KB-R7943 because it does not affect L-type Ca(2+) channels.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 331,
                "text": "NCX"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 344,
                "text": "NCX"
            }
        },
        {
            "context": "Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. We report on maternal first cousins with bilateral microtia, micrognathia, cleft palate and hematologic findings of Diamond-Blackfan anemia (DBA). The similarity of findings shared between our cases and a female reported by Hasan and Inoue [1993] suggests that this is a distinctive syndrome, rather than a chance association. DBA is a heterogeneous disorder, caused in about 25% of cases by heterozygous mutations in the RPS19 gene (DBA1). Mutation analysis in our cases did not show an RPS19 mutation, and 2 alleles were present in each. Segregation analysis for DBA1 on chromosome 19 and DBA2 on 8p23 was not consistent with linkage. We conclude that this syndrome of microtia, cleft palate and DBA is not allelic to known DBA loci.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 511,
                "text": "DBA"
            }
        },
        {
            "context": "The Roles of Arabidopsis CDF2 in Transcriptional and Posttranscriptional Regulation of Primary MicroRNAs. The precise regulation of microRNA (miRNA) transcription and processing is important for eukaryotic development. Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1). We identified a cycling DOF transcription factor, CDF2, which interacts with DCL1 and regulates the accumulation of a population of miRNAs. CDF2 binds directly to the promoters of some miRNAs and works as a transcription activator or repressor for these miRNA genes. CDF2 binds preferentially to the pri-miRNAs regulated by itself and affects DCL1-mediated processing of these pri-miRNAs. Genetically, CDF2 works in the same pathway as miR156 or miR172 to control flowering. We conclude that CDF2 regulates a group of pri-miRNAs at both the transcriptional and posttranscriptional levels to maintain proper levels of their mature miRNAs to control plant development.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 298,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "McLeod syndrome: life-long neuropsychiatric disorder due to a novel mutation of the XK gene. A 50-year-old man presented with worsening, virtually lifelong, chorea and progressive behavioural disturbance, involving disinhibition and hoarding, over 10 years. Clinical assessment revealed chorea, dysarthria, areflexia, an inappropriately jovial, impulsive manner and neuropsychological evidence of frontosubcortical dysfunction. Investigation results included an elevated creatine kinase, caudate atrophy and hypoperfusion, acanthocytes in the peripheral blood and the McLeod phenotype. DNA studies demonstrated a single-base deletion at position 172 in exon 1 of the XK gene, giving rise to a premature stop codon at position 129 in exon 2.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 84,
                "text": "XK"
            }
        },
        {
            "context": "p63 protein expression in high risk diffuse large B-cell lymphoma. BACKGROUND: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. AIMS: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high-intermediate and high risk DLBCL populations. METHODS: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high-intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. RESULTS: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01). CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 218,
                "text": "7"
            }
        },
        {
            "context": "Determination of the critical concentration required for desmin assembly. The critical concentration required for filament assembly in vitro from highly purified desmin was determined by both turbidity and centrifugation assays. Assembly was done in the presence of 2 mM-Ca2+, 2 mM-Mg2+ or 150 mM-Na+ at 2, 22 and 37 degrees C. Similar values for critical concentration were obtained by both assays. As temperature increased, critical concentration decreased for each cation. The critical concentration was lowest in the presence of Ca2+ at 2, 22 and 37 degrees C, but was highest in the presence of 150 mM-Na+ at 2 degrees C. Negative staining showed that supernatants from the centrifugation assays contained protofilaments, protofibrils and short particles (less than 300 nm), but pellets contained long filaments (greater than 1 micron) with an average diameter of 10 nm. As the temperature increased, both the average diameter and average length of particles in the supernatant increased. Thermodynamic analysis indicated that hydrophobic interactions were dominant during desmin assembly, but that ionic interactions might also be involved. Our results demonstrated that the specific cation and temperature and temperature-cation interactions all are important in assembly of desmin intermediate filaments.",
            "question": "What is the average diameter of intermediate filaments?",
            "answers": {
                "answer_start": 869,
                "text": "10 nm"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L.) 11. Molecular cloning and expression of alfalfa isoflavone reductase, a key enzyme of isoflavonoid phytoalexin biosynthesis. The major phytoalexin in alfalfa is the isoflavonoid (-)-medicarpin (or 6aR, 11aR)-medicarpin. Isoflavone reductase (IFR), the penultimate enzyme in medicarpin biosynthesis, is responsible for introducing one of two chiral centers in (-)-medicarpin. We have isolated a 1.18 kb alfalfa cDNA (pIFRalf1) which, when expressed in Escherichia coli, converts 2'-hydroxyformononetin stereospecifically to (3R)-vestitone, as would be predicted for IFR from alfalfa. The calculated molecular weight of the polypeptide (35,400) derived from the 954 bp open reading frame compares favorably to estimated Mrs determined for IFR proteins purified from other legumes. The transcript (1.4 kb) is highly induced in elicited alfalfa cell cultures. The kinetics of induction are consistent with the appearance of IFR activity, the accumulation of medicarpin, and the observed induction of other enzymes in the pathway. Low levels of IFR transcripts were found in healthy plant parts (roots and nodules) which accumulate low levels of a medicarpin glucoside. IFR appears to be encoded by a single gene in alfalfa. The cloning of IFR opens up the possibility of genetic manipulation of phytoalexin biosynthesis in alfalfa by altering isoflavonoid stereochemistry.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 257,
                "text": "medicarpin"
            }
        },
        {
            "context": "Alternative transcripts and 3'UTR elements govern the incorporation of selenocysteine into selenoprotein S. Selenoprotein S (SelS) is a 189 amino acid trans-membrane protein that plays an important yet undefined role in the unfolded protein response. It has been proposed that SelS may function as a reductase, with the penultimate selenocysteine (Sec(188)) residue participating in a selenosulfide bond with cysteine (Cys(174)). Cotranslational incorporation of Sec into SelS depends on the recoding of the UGA codon, which requires a Selenocysteine Insertion Sequence (SECIS) element in the 3'UTR of the transcript. Here we identify multiple mechanisms that regulate the expression of SelS. The human SelS gene encodes two transcripts (variants 1 and 2), which differ in their 3'UTR sequences due to an alternative splicing event that removes the SECIS element from the variant 1 transcript. Both transcripts are widely expressed in human cell lines, with the SECIS-containing variant 2 mRNA being more abundant. In vitro experiments demonstrate that the variant 1 3'UTR does not allow readthrough of the UGA/Sec codon. Thus, this transcript would produce a truncated protein that does not contain Sec and cannot make the selenosulfide bond. While the variant 2 3'UTR does support Sec insertion, its activity is weak. Bioinformatic analysis revealed two highly conserved stem-loop structures, one in the proximal part of the variant 2 3'UTR and the other immediately downstream of the SECIS element. The proximal stem-loop promotes Sec insertion in the native context but not when positioned far from the UGA/Sec codon in a heterologous mRNA. In contrast, the 140 nucleotides downstream of the SECIS element inhibit Sec insertion. We also show that endogenous SelS is enriched at perinuclear speckles, in addition to its known localization in the endoplasmic reticulum. Our results suggest the expression of endogenous SelS is more complex than previously appreciated, which has implications for past and future studies on the function of this protein.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 571,
                "text": "SECIS"
            }
        },
        {
            "context": "The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. For cytosine (C) demethylation of vertebrate DNA, it is known that the TET proteins could convert 5-methyl C (5-mC) to 5-hydroxymethyl C (5-hmC). However, DNA dehydroxymethylase(s), or enzymes able to directly convert 5-hmC to C, have been elusive. We present in vitro evidence that the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B, but not the maintenance enzyme DNMT1, are also redox-dependent DNA dehydroxymethylases. Significantly, intactness of the C methylation catalytic sites of these de novo enzymes is also required for their 5-hmC dehydroxymethylation activity. That DNMT3A and DNMT3B function bidirectionally both as DNA methyltransferases and as dehydroxymethylases raises intriguing and new questions regarding the structural and functional aspects of these enzymes and their regulatory roles in the dynamic modifications of the vertebrate genomes during development, carcinogenesis, and gene regulation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 499,
                "text": "DNMT1"
            }
        },
        {
            "context": "The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene. The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as judged by electro-cardiographic investigation. LQTS is a genetically heterogeneous disease with four loci having been identified to date: chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3) and 4q25-26 (LQT4). The corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2) and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized by six transmembrane domains (S1-S6), a pore region situated between the S5 and S6 domains and a C-terminal domain accounting for approximately 60% of the channel. This domain is thought to be co-associated with another protein, viz. minK (minimal potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype (syncopes and occurrence of sudden death). Most affected individuals had considerable prolongations of QT(c). By using haplotyping with a set of markers covering the four LQT loci, strong linkage was established to the LQT1 locus, whereas the other loci (LQT2, LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism analysis and direct sequencing were used to screen the KVLQT1 gene for mutations in the S1-S6 region, including the pore domain. We identified a Gly-216-Arg substitution in the S6 transmembrane domain of KVLQT1. The mutation was present in all affected family members but absent in normal control individuals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this family. The mutated KVLQT1-gene product thus probably results in a dominant negative suppression of channel activity.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 132,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13. Empagliflozin, (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon-13 and carbon-14 labeled empagliflozin. Carbon-13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α-D-glucose-[(13)C6]. For the radiosynthesis, the carbon-14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon-14 D-(+)-gluconic acid δ-lactone was used to prepare specifically labeled empagliflozin in carbon-1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon-14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon-14 uniformly labeled phenol was used to give [(14)C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 321,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia. The function of the recently isolated FACC (Fanconi anemia group C complementing) gene for a subset of this disorder is not yet known. The notion that FACC plays a direct role in DNA repair would predict that the polypeptide should reside in the nucleus. In this study, a polyclonal antiserum raised against FACC was used to determine the subcellular location of the polypeptide. Immunofluorescence and subcellular fractionation studies of human cell lines as well as COS-7 cells transiently expressing human FACC showed that the protein was localized primarily to the cytoplasm under steady-state conditions, transit through the cell cycle, and exposure to crosslinking or cytotoxic agents. However, placement of a nuclear localization signal from the simian virus 40 large tumor antigen at the amino terminus of FACC directed the hybrid protein to the nuclei of transfected COS-7 cells. These observations suggest an indirect role for FACC in regulating DNA repair in this group of Fanconi anemia.",
            "question": "What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?",
            "answers": {
                "answer_start": 247,
                "text": "Fanconi anemia"
            }
        },
        {
            "context": "Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 135,
                "text": "FSHD"
            }
        },
        {
            "context": "MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 765,
                "text": "MC1R"
            }
        },
        {
            "context": "Expression of heme oxygenase-1 in human leukemic cells and its regulation by transcriptional repressor Bach1. Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or gamma-interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 505,
                "text": "repressor"
            }
        },
        {
            "context": "Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene. The export of certain nuclear proteins is involved in the regulation of various nuclear functions, including transcription. In some cases, the export of target proteins is induced upon environmental or cellular cues, resulting in conditional gene expression. The small Maf proteins appear to be critical regulators of heme oxygenase (HO)-1, an anti-oxidant defense enzyme that degrades heme into iron, carbon monoxide, and biliverdin. Although ho-1 is repressed by Bach1/small Maf heterodimers, it is activated by Nrf2/small Maf heterodimers, indicating that Bach1 and Nrf2 compete with each other. We anticipated that the nuclear concentration of Bach1 might be regulated to ensure that the entire system effectively responds to various stimuli. We carried out detailed domain analysis of Bach1 in an effort to understand how various inducers of HO-1 inactivate Bach1. We show here that cadmium, a strong inducer of HO-1, activates the nuclear export of Bach1. This cadmium-induced export of Bach1 was mediated in trans by its C-terminal region that is conserved between Bach1 and Bach2. The nuclear export of Bach2 was also induced by cadmium, indicating that the cadmium responsibility is shared between Bach1 and Bach2. The nuclear export of Bach1 was dependent on Crm1/Exportin-1 as well as the extracellular signal-regulated kinase-1/2 (ERK1/2) activity. These results indicate that the nuclear export of Bach1 constitutes an important regulatory mechanism to relieve the Bach1-mediated repression of genes such as ho-1.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 59,
                "text": "repressor"
            }
        },
        {
            "context": "Amyotrophic lateral sclerosis model derived from human embryonic stem cells overexpressing mutant superoxide dismutase 1. The generation of amyotrophic lateral sclerosis (ALS) disease models is an important subject for investigating disease mechanisms and pharmaceutical applications. In transgenic mice, expression of a mutant form of superoxide dismutase 1 (SOD1) can lead to the development of ALS that closely mimics the familial type of ALS (FALS). Although SOD1 mutant mice show phenotypes similar to FALS, dissimilar drug responses and size differences limit their usefulness to study the disease mechanism(s) and identify potential therapeutic compounds. Development of an in vitro model system for ALS is expected to help in obtaining novel insights into disease mechanisms and discovery of therapeutics. We report the establishment of an in vitro FALS model from human embryonic stem cells overexpressing either a wild-type (WT) or a mutant SOD1 (G93A) gene and the evaluation of the phenotypes and survival of the spinal motor neurons (sMNs), which are the neurons affected in ALS patients. The in vitro FALS model that we developed mimics the in vivo human ALS disease in terms of the following: (a) selective degeneration of sMNs expressing the G93A SOD1 but not those expressing the WT gene; (b) susceptibility of G93A SOD1-derived sMNs to form ubiquitinated inclusions; (c) astrocyte-derived factor(s) in the selective degeneration of G93A SOD1 sMNs; and (d) cell-autonomous, as well as non-cell-autonomous, dependent sMN degeneration. Thus, this model is expected to help unravel the disease mechanisms involved in the development of FALS and also lead to potential drug discoveries based on the prevention of neurodegeneration.",
            "question": "Which type of cells is affected in Amyotrophic Lateral Sclerosis?",
            "answers": {
                "answer_start": 1032,
                "text": "motor neurons"
            }
        },
        {
            "context": "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways. The transition between a unicellular yeast form to multicellular filaments is crucial for budding yeast foraging and the pathogenesis of many fungal pathogens such as Candida albicans. Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation. Overexpression of either ECM22 or UPC2 leads to increased filamentation, whereas cells lacking both ECM22 and UPC2 do not exhibit filamentous growth. Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes. These genes all play a positive role in filamentous growth, and their expression is upregulated during filamentation in an Ecm22/Upc2-dependent manner. Furthermore, ergosterol content increases during filamentous growth. UPC2 expression also increases during filamentation and is inhibited by the transcription factors Sut1 and Sut2. The expression of SUT1 and SUT2 in turn is under negative control of the transcription factor Ste12. We suggest that during filamentation Ste12 becomes activated and reduces SUT1/SUT2 expression levels. This would result in increased UPC2 levels and as a consequence to transcriptional activation of FHN1, NPR1, PRR2 and sterol biosynthesis genes. Higher ergosterol levels in combination with the proteins Fhn1, Npr1 and Prr2 would then mediate the transition to filamentous growth.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 35,
                "text": "Ecm22"
            }
        },
        {
            "context": "The tomato wilt fungus Fusarium oxysporum f. sp. lycopersici shares common ancestors with nonpathogenic F. oxysporum isolated from wild tomatoes in the Peruvian Andes. Fusarium oxysporum is an ascomycetous fungus that is well-known as a soilborne plant pathogen. In addition, a large population of nonpathogenic F. oxysporum (NPF) inhabits various environmental niches, including the phytosphere. To obtain an insight into the origin of plant pathogenic F. oxysporum, we focused on the tomato (Solanum lycopersicum) and its pathogenic F. oxysporum f. sp. lycopersici (FOL). We collected F. oxysporum from wild and transition Solanum spp. and modern cultivars of tomato in Chile, Ecuador, Peru, Mexico, Afghanistan, Italy, and Japan, evaluated the fungal isolates for pathogenicity, VCG, mating type, and distribution of SIX genes related to the pathogenicity of FOL, and constructed phylogenies based on ribosomal DNA intergenic spacer sequences. All F. oxysporum isolates sampled were genetically more diverse than FOL. They were not pathogenic to the tomato and did not carry SIX genes. Certain NPF isolates including those from wild Solanum spp. in Peru were grouped in FOL clades, whereas most of the NPF isolates were not. Our results suggested that the population of NPF isolates in FOL clades gave rise to FOL by gaining pathogenicity.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 486,
                "text": "tomato"
            }
        },
        {
            "context": "Medulloblastoma metastatic to the marrow. Report of four cases and review of the literature. Medulloblastoma is a malignant cerebellar tumor seen primarily in the pediatric age group that has a known ability to metastasize extraneurally. The skeleton is the most common site of extraneural metastases, but metastases to the bone marrow can also occur. Four cases of medulloblastoma metastatic to the marrow are reported. In addition, 31 cases from the medical literature are reviewed. Clinical features include bone tenderness, cytopenias and elevated serum alkaline phosphatase and lactic dehydrogenase levels. Skeletal involvement, especially of the pelvic bones, is frequently seen radiographically. Weight loss, soft tissue masses and a requirement for blood transfusion are also associated features. Marrow biopsy specimens are characterized by the presence of a small cell tumor often with fibrosis, necrosis and osteoblastic activity. The symptomatic response to chemotherapy is rapid, but chemotherapy resistance appears quickly. Only 1 in 4 cases diagnosed antemortem in this review lived for more than a year. We conclude that marrow aspiration and biopsy are indicated in the evaluation of patients with medulloblastoma and may serve to diagnose the cause of cytopenias, to verify extraneural spread and to provide prognostic information.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 93,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 360,
                "text": "7"
            }
        },
        {
            "context": "Defective Proteasome Delivery of Polyubiquitinated Proteins by Ubiquilin-2 Proteins Containing ALS Mutations. Ubiquilin proteins facilitate delivery of ubiquitinated proteins to the proteasome for degradation. Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which the mutations cause ALS are not known. Here we report on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations in affecting proteasome-mediated degradation. We found that overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations slow degradation of Myc, a prototypic proteasome substrate. Examination of coprecipitating proteins indicated that the mutant proteins are generally capable of binding polyubiquitinated proteins, but defective in binding the proteasome. GST-pulldown studies revealed that many of the mutants bind weaker to the S5a subunit of the proteasome, compared with wild type (WT) ubiquilin-2 protein. The results suggest the mutant proteins are unable to deliver their captured cargo to the proteasome for degradation, which presumably leads to toxicity. Quantification of cell death is consistent with this idea. Measurement of protein turnover further indicated the mutant proteins have longer half-lives than WT ubiquilin-2. Our studies provide novel insight into the mechanism by which ALS-linked mutations in UBQLN2 interfere with protein degradation.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 332,
                "text": "amyotrophic lateral sclerosis"
            }
        },
        {
            "context": "The Subviral RNA Database: a toolbox for viroids, the hepatitis delta virus and satellite RNAs research. BACKGROUND: Viroids, satellite RNAs, satellites viruses and the human hepatitis delta virus form the 'brotherhood' of the smallest known infectious RNA agents, known as the subviral RNAs. For most of these species, it is generally accepted that characteristics such as cell movement, replication, host specificity and pathogenicity are encoded in their RNA sequences and their resulting RNA structures. Although many sequences are indexed in publicly available databases, these sequence annotation databases do not provide the advanced searches and data manipulation capability for identifying and characterizing subviral RNA motifs. DESCRIPTION: The Subviral RNA database is a web-based environment that facilitates the research and analysis of viroids, satellite RNAs, satellites viruses, the human hepatitis delta virus, and related RNA sequences. It integrates a large number of Subviral RNA sequences, their respective RNA motifs, analysis tools, related publication links and additional pertinent information (ex. links, conferences, announcements), allowing users to efficiently retrieve and analyze relevant information about these small RNA agents. CONCLUSION: With its design, the Subviral RNA Database could be considered as a fundamental building block for the study of these related RNAs. It is freely available via a web browser at the URL: http://subviral.med.uottawa.ca.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 117,
                "text": "Viroids"
            }
        },
        {
            "context": "Direct evidence of allele-specific binding of CTCF and MeCP2 to Tsix in a HPRT-deficient female F₁ hybrid mouse cell line. Mammalian dosage compensation requires silencing of one of the two X chromosomes in females and is controlled by the X inactivation center (Xic). Xic contains many of the regulatory elements for the mutual interplay of X-inactive specific transcript (Xist) and Tsix, the antisense counterpart of Xist. The regulatory elements control X chromosome inactivation (XCI) via the formation of DNA-DNA and DNA-protein complexes with cis- and trans-acting factors. However, the process-dependent regulation of Xist/Tsix by these elements in each XCI process remains largely unknown. In this study, a 6-thioguanine-resistant female F(1) hybrid mouse cell line (designated HOBMSKI2) was constructed from a cross between a female HPRT-deficient transgenic mouse (designated BM3) and a male wild type Mus spretus mouse (designated MS), which enabled the direct discrimination of both allele-specific expression of X-linked genes and allele-specific binding of proteins associated with XCI due to DNA polymorphisms between BM3 and MS. Using this cell line, we found that Tsix on the active X chromosome (Xa) was not expressed in somatic cells despite the fact that CTCF, which ensures Tsix expression in embryonic stem cells, was still bound to the 5' end of Tsix on Xa, implying that CTCF may function differently during each XCI process and its trans-activating activity for Tsix expression may be lost in the maintenance process. In addition, the monoallelic expression of Tsix on Xa was inhibited by epigenetic modification of the chromatin in the maintenance process, which was mediated by protein complexes recruited by MeCP2. The results indicate the value of HOBMSKI2 in directly detecting the allele-specific binding of CTCF and MeCP2 to the 5' end of Tsix. The HOBMSKI2 mouse line is a versatile and useful resource for studying the molecular mechanism of the XCI process.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 374,
                "text": "Xist"
            }
        },
        {
            "context": "Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. PURPOSE: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies. EXPERIMENTAL DESIGN: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes. RESULTS: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment. CONCLUSIONS: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 90,
                "text": "PD-1"
            }
        },
        {
            "context": "Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study. BACKGROUND AND OBJECTIVES: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS: Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses > 2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS: Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01955720.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1728,
                "text": "dabigatran"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 466,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide. Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.",
            "question": "Which is the defective protein causing the lysosomal storage disease Fabry?",
            "answers": {
                "answer_start": 225,
                "text": "alpha-galactosidase A"
            }
        },
        {
            "context": "Hungarian Isradipine Study (HIS): long-term (3-year) effects on blood pressure and plasma lipids. These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 429,
                "text": "hypertension"
            }
        },
        {
            "context": "Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review. BACKGROUND: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene. CASE PRESENTATION: We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data. CONCLUSIONS: Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 1065,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance. Acromicric dysplasia is a rare bone dysplasia characterised by short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and characteristic x ray abnormalities of the hands. Only a very small number of children with this condition have been reported so far. Here we report on a series of 22 patients including 10 boys and 12 girls with acromicric dysplasia. Length was normal at birth and height fell progressively off the centiles postnatally. The mean adult height was 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs were short and OFC was normal. Intelligence was normal and mild dysmorphic features were noted. Other occasional features included well developed muscles, a hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complication, and spine abnormalities. Long term follow up showed that facial dysmorphism was less obvious in adults and that carpal tunnel syndrome was frequent in older patients. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x ray abnormalities. No major complications, such as cardiac disease or major orthopaedic problems, occurred in the course of the disease. The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance.",
            "question": "What is the mode of inheritance of Acromicric dysplasia?",
            "answers": {
                "answer_start": 1556,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 0,
                "text": "methylKit"
            }
        },
        {
            "context": "Low alpha-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease. Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 88,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 355,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 99,
                "text": "2"
            }
        },
        {
            "context": "Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction. Results are presented of a comparison of the amino acid (AA) δ(13)C values obtained by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) and liquid chromatography-isotope ratio mass spectrometry (LC/IRMS). Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ(13)C values are required. We compare LC/IRMS with the most up-to-date GC/C/IRMS method using N-acetyl methyl ester (NACME) AA derivatives. This comparison involves the analysis of standard AAs and hydrolysates of archaeological human bone collagen, which have been previously investigated as N-trifluoroacetyl isopropyl esters (TFA/IP). It was observed that, although GC/C/IRMS analyses required less sample, LC/IRMS permitted the analysis of a wider range of AAs, particularly those not amenable to GC analysis (e.g. arginine). Accordingly, reconstructed bulk δ(13)C values based on LC/IRMS-derived δ(13)C values were closer to the EA/IRMS-derived δ(13)C values than those based on GC/C/IRMS values. The analytical errors for LC/IRMS AA δ(13)C values were lower than GC/C/IRMS determinations. Inconsistencies in the δ(13)C values of the TFA/IP derivatives compared with the NACME- and LC/IRMS-derived δ(13)C values suggest inherent problems with the use of TFA/IP derivatives, resulting from: (i) inefficient sample combustion, and/or (ii) differences in the intra-molecular distribution of δ(13)C values between AAs, which are manifested by incomplete combustion. Close similarities between the NACME AA δ(13)C values and the LC/IRMS-derived δ(13)C values suggest that the TFA/IP derivatives should be abandoned for the natural abundance determinations of AA δ(13)C values.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 181,
                "text": "collagen"
            }
        },
        {
            "context": "PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 0,
                "text": "PD-1"
            }
        },
        {
            "context": "Specificity of Dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain. The maintenance methylation of hemimethylated CpG sites by the DNA methyltransferase Dnmt1 is the molecular basis of the inheritance of DNA methylation patterns. Based on structural data and kinetics obtained with a truncated form of Dnmt1, an autoinhibition model for the specificity of Dnmt1 was proposed in which unmethylated DNA binds to Dnmt1's CXXC domain, which prevents its methylation. We have prepared CXXC domain variants that lost DNA binding. Corresponding full-length Dnmt1 variants did not display a reduction in specificity, indicating that the autoinhibition model does not apply in full-length Dnmt1. Furthermore, we show that the Dnmt1 M1235S variant, which carries an exchange in the catalytic domain of the enzyme, has a marked reduction in specificity, indicating that the recognition of the hemimethylated state of target sites resides within the catalytic domain.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 15,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. This article discusses the infection control and public health measures taken whilst managing a case of laboratory-confirmed rabies, and the challenges faced in implementing these measures. Case management requires intensive multi-disciplinary co-ordination. The Milwaukee protocol, which to date has five reported human rabies survivors associated with its use, has been suggested as a potential management pathway for human rabies. Consensus among hospital and public health clinicians would aid future deployment of this approach in selected cases.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 26,
                "text": "rabies"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 1598,
                "text": "AD"
            }
        },
        {
            "context": "A revised six-kingdom system of life. A revised six-kingdom system of life is presented, down to the level of infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi, Plantae and Chromista. Intermediate high level categories (superkingdom, subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are extensively used to avoid splitting organisms into an excessive number of kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms, Protozoa and Animalia, are subject to the International Code of Zoological Nomenclature, the kingdom Bacteria to the International Code of Bacteriological Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to the International Code of Botanical Nomenclature. Circumscriptions of the kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20 classes; fungal classification at the rank of subclass and above is comprehensively revised. The kingdoms Protozoa and Animalia are modified in the light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not Protozoa, and that mesozoans are related to bilaterian animals. Animalia are divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa, Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other phyla). Several new higher level groupings are made in the animal kingdom including three new phyla: Acanthognatha (rotifers, acanthocephalans, gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not as a separate kingdom. The recently revised phylum Rhizopoda is modified further by adding more flagellates and removing some 'rhizopods' and is therefore renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa and Archamoebae (both now infraphyla) as a new subphylum Conosa within the phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the (formerly microsporidian) metchnikovellids are now both placed within the phylum Sporozoa. These changes make a total of only 13 currently recognized protozoan phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is modified in circumscription by adding the Discicristata, a new infrakingdom comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in relation to the principles of megasystematics, here defined as systematics that concentrates on the higher levels of classes, phyla, and kingdoms. These principles also make it desirable to rank Archaebacteria as an infrakingdom of the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising all bacteria bounded by a single membrane. The bacterial subkingdom Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides in the outer leaflet of the outer membrane and phospholipids in its inner leaflet. (ABSTRACT TRUNCATED)",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 965,
                "text": "Fungi"
            }
        },
        {
            "context": "Validation of a Portuguese version of the STOP-Bang questionnaire as a screening tool for obstructive sleep apnea: Analysis in a sleep clinic. INTRODUCTION: Screening methods have become increasingly important owing to the growing number of patients suspected of obstructive sleep apnea (OSA) being referred for sleep consultation. The STOP-Bang questionnaire has been validated as a screening tool for OSA in surgical patients. OBJECTIVES: To evaluate the performance of a Portuguese version of the STOP-Bang questionnaire for the diagnosis of OSA in a sleep clinic. METHODS: Prospectively, for 2 months, all patients referred to our clinic for clinical evaluation completed a translated version of the STOP-Bang questionnaire in Portuguese and underwent a sleep study. RESULTS: We observed 216 patients and 215 (99.5%) were included. Age was 53.63±13.10 years, 63.3% were male patients, neck circumference was 40.4±44.11 cm and BMI was 29.41 [26.85; 33.06] kg/m(2). OSA was present in 78% of the patients, of whom, 33% had moderate and 37% had severe OSA. A STOP-Bang score > 3 had a sensitivity and positive predictive value (PPV) for OSA of 93.4% and 86.6%, respectively. Each increase in the STOP-Bang score was associated with an increase in the probability of OSA and severe OSA; reaching a 95% OSA probability, for a score of 6, and a 73% severe OSA probability, for a score of 8. A score of 3 and 2 had a negative predictive value for moderate/severe OSA of 85.3% and 91.7%, respectively. CONCLUSIONS: The STOP-Bang questionnaire showed high sensitivity and PPV for OSA with the probability of severe OSA steadily increasing, the higher the scores. Furthermore, a low score showed high predictive value for the exclusion of moderate/severe OSA. The STOP-Bang questionnaire can be a powerful tool for stratifying patients in the diagnosis of OSA.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 90,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Idarucizumab, a Humanized, Monoclonal Antibody Fragment for Immediate Reversal of Dabigatran. OBJECTIVE: To evaluate the role of idarucizumab, a humanized monoclonal antibody fragment, as a specific reversal agent for the anticoagulant activity of dabigatran and to review the pharmacology, pharmacokinetic properties, efficacy, and safety of this agent. METHODS: A literature search was conducted consisting of a PubMed database using the MeSH term idarucizumab and the key word dabigatran antidote. Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of idarucizumab for the reversal of the anticoagulant activity of dabigatran were included. RESULTS: Idarucizumab represents a novel treatment option as it is the only humanized, monoclonal antibody fragment that specifically binds to dabigatran. Studies evaluating reversal of dabigatran-induced anticoagulation have demonstrated immediate, complete, and sustained effects with idarucizumab. Idarucizumab did not overcorrect thrombin generation. Additionally, evaluations have shown that dabigatran can be safely reinitiated 24 hours after the administration of idarucizumab. The United States Food and Drug Administration granted priority review for the biologic license application and accelerated approval for idarucizumab. CONCLUSION: Idarucizumab represents an encouraging development in the reversal of dabigatran. Its novel mechanism of action, pharmacokinetics, tolerability, and lack of thrombotic events contribute positively to its use in patients who experience bleeding or for those who require emergent surgery or procedures.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 248,
                "text": "dabigatran"
            }
        },
        {
            "context": "Dasatinib treatment for imatinib resistant or intolerant patients with chronic myeloid leukaemia. Chronic myeloid leukaemia (CML) is a genetically associated malignancy of haematopoietic stem cells, characterized by a t(9;22) translocation that forms the Philadelphia chromosome and creates a novel fusion gene, BCR-ABL. Treatment with molecular-targeted therapy is usually initiated with imatinib, an inhibitor of BCR-ABL tyrosine kinase. Imatinib resistance is, however, observed in some CML patients, especially in those with advanced disease. Through computerized literature searches, a systematic analysis was conducted to examine the efficacy and benefits of dasatinib therapy for imatinib resistant or intolerant CML patients in the chronic phase (CP), accelerated phase (AP) and fatal blast crisis phase (BC). In terms of major haematological and cytogenetic responses, this meta-analysis showed no significant differences in dasatinib treatment between myeloid BC-CML and lymphoid BC-CML patients with imatinib resistance or intolerance. Dasatinib therapy was, however, significantly more effective in improving major haematological and cytogenetic responses for CP-CML patients than for AP-CML patients with imatinib resistance or intolerance.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 312,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (ref. 1). A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes. We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA. A test for the mutant allele based on amplification of DNA by the 'polymerase chain rection and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations. The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 165,
                "text": "HEXA"
            }
        },
        {
            "context": "A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mutations of the fibrillin gene (FBN1) are known to cause classical Marfan's syndrome, ectopia lentis and neonatal Marfan's syndrome. We have identified a novel missense mutation in exon 28 of the FBN1 gene (R1170H) which is responsible for an atypical marfanoid phenotype characterised by dolichostenomelia and arachnodactyly.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 107,
                "text": "FBN1"
            }
        },
        {
            "context": "Antibodies to both terminal and internal B-cell epitopes of Francisella tularensis O-polysaccharide produced by patients with tularemia. Francisella tularensis, the Gram-negative bacterium that causes tularemia, is considered a potential bioterrorism threat due to its low infectivity dose and the high morbidity and mortality from respiratory disease. We previously characterized two mouse monoclonal antibodies (MAbs) specific for the O-polysaccharide (O antigen [OAg]) of F. tularensis lipopolysaccharide (LPS): Ab63, which targets a terminal epitope at the nonreducing end of OAg, and Ab52, which targets a repeating internal OAg epitope. These two MAbs were protective in a mouse model of respiratory tularemia. To determine whether these epitope types are also targeted by humans, we tested the ability of each of 18 blood serum samples from 11 tularemia patients to inhibit the binding of Ab63 or Ab52 to F. tularensis LPS in a competition enzyme-linked immunosorbent assay (ELISA). Although all serum samples had Ab63- and Ab52-inhibitory activities, the ratios of Ab63 to Ab52 inhibitory potencies varied 75-fold. However, the variation was only 2.3-fold for sequential serum samples from the same patient, indicating different distributions of terminal- versus internal-binding antibodies in different individuals. Western blot analysis using class-specific anti-human Ig secondary antibodies showed that both terminal- and internal-binding OAg antibodies were of the IgG, IgM, and IgA isotypes. These results support the use of a mouse model to discover protective B-cell epitopes for tularemia vaccines or prophylactic/therapeutic antibodies, and they present a general strategy for interrogating the antibody responses of patients and vaccinees to microbial carbohydrate epitopes that have been characterized in experimental animals.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 137,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 764,
                "text": "FBN1"
            }
        },
        {
            "context": "Ultrasound: a noninvasive screening test for detrusor instability. OBJECTIVE: To determine whether transvaginal ultrasound measurement of bladder wall thickness can be used as a screening test for detrusor instability in women with urinary symptoms. DESIGN: A blinded prospective study. SETTING: A London teaching hospital. PARTICIPANTS: One hundred and eight-four symptomatic women presenting to a urodynamic clinic. MAIN OUTCOME MEASURE: The detection of detrusor instability by means of videocystourethrography (VCU) and ambulatory urodynamics in women with a mean bladder wall thickness of greater than 5 mm measured by transvaginal ultrasound. RESULTS: One hundred and eight women had a mean bladder wall thickness of greater than 5 mm. Ninety-four percent (102) of these women had detrusor instability either when undergoing VCU or ambulatory urodynamics. Seventeen women had a bladder wall thickness of less than 3.5 mm of whom three were found to have detrusor instability on VCU. CONCLUSION: The measurement of a mean bladder wall thickness greater than 5 mm with transvaginal ultrasound is a sensitive screening method for diagnosing detrusor instability in symptomatic women without outflow obstruction.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 112,
                "text": "ultrasound"
            }
        },
        {
            "context": "False positivity of monospot test in an immunocompetent elderly woman with acute cytomegalovirus infection. A 75-year-old woman presented with altered mental status, septic picture, and influenza-like symptoms. Initial investigations revealed atypical lymphocytosis, thrombocytopenia, elevated liver enzymes, and a positive monospot test result. Further investigation showed the Epstein-Barr virus viral capsid antibody IgM/IgG and Epstein-Barr virus DNA by polymerase chain reaction to be negative; however, interestingly her cytomegalovirus (CMV) IgM and IgG were positive, suggesting that her mononucleosis-like syndrome was due to acute CMV infection. Herein, we report the first case of a heterophile-positive mononucleosis syndrome caused by acute CMV infection in an elderly immunocompetent woman. This case conveys that monospot test can yield false-positive result in the setting of acute CMV infection.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 379,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Trends in inulinase production--a review. This article highlights the research work carried out in the production of inulinases from various inulin substrates using strains of bacteria, yeast and fungi. Inulin is one of the numerous polysaccharides of plant origin that contains glucose or fructose. It is used as a substrate in industrial fermentation processes and in food industries due to its relatively cheap and abundant source for the microbiological production of high-fructose syrups, ethanol and acetone-butanol. The various oligosaccharides derived from inulin also find their application in the medical and dietary sector. The inulinase acts on the beta-(2,1)-D-fructoside links in inulin releasing D-fructose. Hence, this article illustrates the capability of various microbes in hydrolyzing the carbon at its optimum nutrient concentration and operating condition towards inulinase production.",
            "question": "What is the substrate of the microbial enzyme inulinase?",
            "answers": {
                "answer_start": 635,
                "text": "The inulinase acts on the beta-(2,1)-D-fructoside links in inulin releasing D-fructose."
            }
        },
        {
            "context": "Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study. OBJECTIVE: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects. MATERIALS AND METHODS: This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 x 200 μg tablets (reference: A) or 1 x 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated. RESULTS: 80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 μg b.i.d. TREATMENTS: The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCτ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679. CONCLUSIONS: Bioequivalence was demonstrated between 8 x 200 μg and 1 x 1,600 μg selexipag at steady state.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 277,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. AIMS: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). RESULTS: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0 -∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. CONCLUSIONS: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 98,
                "text": "SGLT2"
            }
        },
        {
            "context": "Ultrasound estimated bladder weight in asymptomatic adult females. PURPOSE: To estimate the bladder weight by automated ultrasound method (BladderScan BVM 9500) in adult females without lower urinary tract symptoms and to assess both the intra-observer and interobserver reproducibility of this method. MATERIALS AND METHODS: Healthy volunteers were recruited in King Khalid University Hospital from hospital staff and patients attending the gynecological clinic over a period of six months. All women were screened for any lower urinary tract symptoms using a validated short version of Urinary Distress Inventory questionnaire. BladderScan BVM 9500 device (Diagnostic Ultrasound, Bothell, WA) was used to measure bladder wall thickness, bladder volume, and calculated bladder weight. RESULTS: Eighty-five women were included in the study. The mean age was 37.5 years (± 11.1). Mean bladder wall thickness (BWT) was 1.68 mm (95% confidence interval: 1.61 to 1.75) and the mean ultrasound-estimated bladder weight (UEBW) was 32.25 g (95% confidence interval: 31.7 to 32.8). The UEBW intra-observer (ICC: 0.81) and interobserver (ICC: 0.8) reproducibility were excellent while intra-observer (ICC: 0.55) and interobserver (ICC: 0.6) reproducibility for BWT were moderate. No correlation was found between UEBW and age, height, body weight, or bladder volume. CONCLUSION: The estimated bladder weight by automated ultrasound device in asymptomatic adult females yields reproducible measurements and can be used as a reference for future understanding of the changes in bladder weight related to different types of urinary incontinence or voiding disorders.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 670,
                "text": "Ultrasound"
            }
        },
        {
            "context": "A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. STUDY OBJECTIVE: To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated. SETTING: Sixteen emergency departments in the United States. POPULATION: Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose. INTERVENTIONS: Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered. MEASUREMENTS AND MAIN RESULTS: Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ. CONCLUSION: Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1621,
                "text": "flumazenil"
            }
        },
        {
            "context": "Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating enzyme inhibitor, MLN4924, using AlphaScreen. Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct. The inhibited enzyme can no longer transfer Nedd8 downstream to modify and activate the E3 cullin-RING ligases. This results in the stabilization of proteins regulated by the proteasome, leading to cell death. These studies monitored the endogenous cellular changes to NAE∼Nedd8 thioester, the formation of the Nedd8-MLN4924 adduct, and the reduction in the Cul1-Nedd8. Lysates derived from MLN4924-treated HCT116 cells showed that whereas the β-subunit of NAE remained constant, reductions of both NAE∼Nedd8 thioester and Cul1-Nedd8 levels occurred with a concomitant rise of the adduct. Moreover, the formation of the Nedd8-MLN4924 adduct was approximately stoichiometric with the concentration of NAEβ. Higher density 384-well cell-based assays illustrated the kinetics of enzyme inactivation across a wider range of MLN4924 concentrations, showing a rapid loss of NAE∼Nedd8 thioester and Cul1-Nedd8. The reduction of NAE∼Nedd8 thioester precedes the loss of Cul1-Nedd8 at twice the rate. Finally, these results clearly demonstrate the utility of the homogeneous assay for quantitative assessment of these endogenous cellular components in a 384-well plate in response to inhibition of NAE by MLN4924.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 143,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Transvaginal ultrasound measurement of bladder wall thickness: a more reliable approach than transperineal and transabdominal approaches. OBJECTIVES To validate transperineal, transabdominal and transvaginal ultrasound (US) techniques to measure bladder wall thickness (BWT). SUBJECTS AND METHODS Women underwent US measurement of BWT at three different anatomical sites: anterior wall, dome and trigone of the bladder by two 'blinded' operators using transabdominal, transperineal and transvaginal approaches at separate visits and by a single operator using transabdominal and transperineal techniques. Bland-Altman analysis was used to determine interobserver reliability for all three techniques and intraobserver reliability for transabdominal and transperineal methods. RESULTS In all, 25 women were scanned. The transperineal US had a high interobserver mean difference when measuring the anterior BWT (-0.34) and a high intraobserver mean difference when measuring the anterior (0.54) and dome BWT (0.33). Transabdominal US had a high interobserver mean difference for all measurements of BWT, and a high intraobserver mean difference when measuring the trigonal thickness (0.56). Transvaginal US had a consistent interobserver mean difference for all three measurements. The transperineal and transabominal approaches had the widest intraobserver and interobserver 95% confidence intervals of the mean difference when compared with the transvaginal approach. CONCLUSIONS Transabdominal and transperineal US for measuring BWT did not have good intraobserver and interobserver reliability for measurement of the three anatomical sites to determine mean BWT. Transvaginal US had good interobserver reliability, thus mean BWT is best measured using the transvaginal approach.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 13,
                "text": "ultrasound"
            }
        },
        {
            "context": "Thyroid anomalies in Williams syndrome: investigation of 95 patients. Thyroid involvement in Williams syndrome (WS) was recently reported in two small groups of patients, both showing an increased prevalence of elevation of TSH serum concentration; in one of the two reports, 70% of the patients demonstrated a hypoplasia of thyroid gland as well. In our institution, we currently follow a large population of WS patients who periodically undergo a multispecialist clinical evaluation that includes ultrasound evaluation of the thyroid gland, and levels of FT3, FT4, TSH, and anti-thyroid antibodies. Here, we report on the prevalence of thyroid structural and functional anomalies, in a population of 95 WS patients, half of them followed for more than 5 years. Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample) and thyroid gland hypoplasia (74.7%). Moreover, we demonstrated that TSH elevation declines with age. For this reason, we suggest that a complete thyroid evaluation be performed in every patient with WS, and that this medical complication should be periodically searched for in follow-up visits.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 70,
                "text": "Thyroid"
            }
        },
        {
            "context": "A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype. Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 726,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 151,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "A new database for ribosomal protein genes which are mutated in Diamond-Blackfan Anemia. Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 19,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. METHODS: We conducted an electronic search for randomized controlled trials (RCTs) involving DPP-4 inhibitors through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more and reported the proportion of patients reaching the HbA1c target of <7%. RESULTS: A total of 43 RCTs reporting 52 comparisons met the selection criteria, which included 19 101 study participants evaluated for the primary endpoint, 10 467 treated with a DPP-4 inhibitor and 8634 treated with placebo or a comparator drug. DPP-4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40% of participants achieved the HbA1c goal of <7%: this was associated with weight neutrality and no greater hypoglycaemia. The reduction of the HbA1c level and the rate of HbA1c goal attainment was not different from comparator drugs, with similar hypoglycaemia, and different effect on weight owing to the nature of comparator (metformin, sulfonylurea or glitazones). Baseline HbA1c was the best predictor for achievement of A1C target (overall weighted r(2) value = 0.410, p < 0.001). CONCLUSIONS: A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with DPP-4 inhibitors compared to placebo, with no weight gain, and no hypoglycaemic risk when used alone; DPP-4 inhibitors were not different from comparator drugs.",
            "question": "What are 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin'?",
            "answers": {
                "answer_start": 158,
                "text": "dipeptidyl peptidase-4 (DPP-4) inhibitors"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 38,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Differential effects of diverse p53 isoforms on TAp73 transcriptional activity and apoptosis. The p53 activities are due, at least in part, to its ability to form oligomers that bind to specific DNA sequences and activate transcription. Since some mutant p53 proteins and ΔNp73 isoforms form heterocomplexes with TAp73, we asked whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73. Moreover, it has already been found that some isoforms form complex with wtp53 and some of them inhibit p53 tumor-suppressor functions. Therefore, we studied the complex formation and co-immunoprecipitation assays show that all six p53 isoforms examined can form complexes with TAp73β, whereas only Δ133p53α/β/γ isoforms form complex with TAp73α. All p53 isoforms counteract TAp73β transactivation function but with different efficiency and in a promoter-dependent manner. Furthermore, apoptotic activity of TAp73β was augmented by coexpression of p53β, whereas Δ133p53α and β inhibit its apoptotic activity most efficiently. We have determined the half-life of different p53 isoforms: p53γ isoform has the shortest half-life, whereas Δ133p53γ has the longest half-life. Inhibitory interactions of two proteins in complex often lead to their stabilization. However, only three isoforms (Δ133p53α, Δ133p53β and Δ40p53α) stabilize TAp73β. We are convinced that defining the interactions between p53/p73 would give a new insight into how the p53 isoforms modulate the p73 functions in tumorigenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 275,
                "text": "7"
            }
        },
        {
            "context": "A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China. BACKGROUND: The mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. METHODS: Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. RESULTS: A novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. CONCLUSION: This study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 136,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Idarucizumab: Clinical Role of a Novel Reversal Agent for Dabigatran. Atrial fibrillation (AF), a common cardiac arrhythmia associated with increased risk of heart failure, thromboembolic phenomena and death, is a leading cause of hospitalization of adults. A major complication of AF is an increased risk of ischemic stroke leading to long-term disability and in severe cases, death. Historically, Coumadin has been the drug of choice for chronic anticoagulation and stroke prevention in AF patients however, given the need for constant monitoring and multiple drug interactions, newer anticoagulants have been developed. One such drug is dabigatran, with the promise of less frequent monitoring and decreased bleeding tendencies as compared to Coumadin. The main disadvantage of dabigatran has been the lack of a reversal agent in case of severe bleeding or emergent surgical intervention. This was until the recent The Food and Drug Administration approval of idarucizumab, a potential reversal agent for dabigatran. In this article, we discuss the evidence addressing idarucizumab safety, tolerability and its efficacy for reversing effect of dabigatran.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1008,
                "text": "dabigatran"
            }
        },
        {
            "context": "Programmed death 1 pathway inhibition in metastatic renal cell cancer and prostate cancer. Programmed death 1 (PD-1) is a T cell co-inhibitory receptor with two ligands, PD-L1 and PD-L2. In cancer, this pathway plays a major role in immune resistance in the tumor environment. Blockade of this pathway can enhance antitumor immune responses. This review discusses the preclinical rationale for PD-1 pathway inhibition in advanced renal cell carcinoma and prostate cancer, in addition to the clinical activity and toxicity of the anti-PD-L1 antibody BMS-936559, as well as anti-PD-1 antibodies MK-3475 and BMS-936558.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 577,
                "text": "PD-1"
            }
        },
        {
            "context": "[Gaucher's disease uncovered late]. Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta glucocerebrosidase. This disease is usually diagnosed in the first or second decade of life with the arising of bone pains, splenomegaly and hemorragic manifestations due to thrombocytopenia. When the enlarged spleen is not evident, or after splenectomy, patients may be mis-identified as having Gaucher's disease. We present here two cases of elderly patients aged 70 and 46 years respectively, in whom the disease was a surprising finding of bone marrow examination, during check up for pancytopenia.",
            "question": "Which enzyme is deficient in Gaucher's disease?",
            "answers": {
                "answer_start": 157,
                "text": "beta glucocerebrosidase"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 916,
                "text": "CO2"
            }
        },
        {
            "context": "Stress Responses in Alfalfa (Medicago sativa L.) : V. Constitutive and Elicitor-Induced Accumulation of Isoflavonoid Conjugates in Cell Suspension Cultures. The isoflavonoid conjugates medicarpin-3-O-glucoside-6''-O-malonate (MGM), afrormosin-7-O-glucoside (AG), and afrormosin-7-O-glucoside-6''-O-malonate (AGM) were isolated and characterized from cell suspension cultures of alfalfa (Medicago sativa L.), where they were the major constitutive secondary metabolites. They were also found in alfalfa roots but not in other parts of the plant. The phytoalexin medicarpin accumulated rapidly in suspension cultured cells treated with elicitor from Colletotrichum lindemuthianum, and this was subsequently accompanied by an increase in the levels of MGM. In contrast, net accumulation of afrormosin conjugates was not affected by elicitor treatment. Labeling studies with [(14)C]phenylalanine indicated that afrormosin conjugates were the major de novo synthesized isoflavonoid products in unelicited cells. During elicitation, [(14)C]phenylalanine was incorporated predominantly into medicarpin, although a significant proportion of the newly synthesized medicarpin was also conjugated. Treatment of (14)C-labeled, elicited cells with l-alpha-aminooxy-beta-phenylpropionic acid, a potent inhibitor of PAL activity in vivo, resulted in the initial appearance of labeled medicarpin of very low specific activity, suggesting that the phytoalexin could be released from a preformed conjugate under these conditions. Our data draw attention to the involvement of isoflavone hydroxylases during the constitutive and elicitor-induced accumulation of isoflavonoids and their conjugates in alfalfa cell cultures.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 185,
                "text": "medicarpin"
            }
        },
        {
            "context": "The many faces of oxytocin: implications for psychiatry. Oxytocin is known as the 'love hormone' due its role in promoting mother-child and pair bonding. More recent research indicates that oxytocin may have broader pro-social effects on behavior and cognition, which points towards oxytocin's potential as an agent to help improve social cognition and functioning in psychiatric disorders such as schizophrenia and autism. However, new research on oxytocin has also uncovered a 'darker side', including oxytocin's possible role in social out-grouping and envy. Instead of a simple view of oxytocin as 'good' or 'bad', a more accurate depiction of oxytocin's role in social processing likely involves the presence of moderating factors. We review moderation effects in oxytocin and their implications for psychiatry. One implication is that, across diagnostic categories, oxytocin administration may have positive effects for patients with social cognitive deficits but negative effects for patients with social cognitive bias. We conclude that future intervention studies should use methods such as signal detection to measure both deficit and bias parameters of social cognition and to evaluate potential individual and contextual moderators both within and between psychiatric diagnoses in order to determine for whom oxytocin treatment may be beneficial and for whom it may actually be harmful.",
            "question": "Which is the \"bonding hormone\"?",
            "answers": {
                "answer_start": 57,
                "text": "Oxytocin"
            }
        },
        {
            "context": "Single amino acid radiocarbon dating of Upper Paleolithic modern humans. Archaeological bones are usually dated by radiocarbon measurement of extracted collagen. However, low collagen content, contamination from the burial environment, or museum conservation work, such as addition of glues, preservatives, and fumigants to \"protect\" archaeological materials, have previously led to inaccurate dates. These inaccuracies in turn frustrate the development of archaeological chronologies and, in the Paleolithic, blur the dating of such key events as the dispersal of anatomically modern humans. Here we describe a method to date hydroxyproline found in collagen (~10% of collagen carbon) as a bone-specific biomarker that removes impurities, thereby improving dating accuracy and confidence. This method is applied to two important sites in Russia and allows us to report the earliest direct ages for the presence of anatomically modern humans on the Russian Plain. These dates contribute considerably to our understanding of the emergence of the Mid-Upper Paleolithic and the complex suite of burial behaviors that begin to appear during this period.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 152,
                "text": "collagen"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 1618,
                "text": "Huntington disease"
            }
        },
        {
            "context": "[Cryptococcal meningitis]. BACKGROUND: Cryptococcus neoformans causes systemic disease in patients with immunodeficiency. The incidence of cryptococcal meningitis has increased in parallel with that of HIV infection. Cancer is also a known predisposing factor. MATERIAL AND METHODS: We present two case reports and a review of the literature concerning the epidemiology, diagnostics and treatment of cryptococcal meningitis. RESULTS: The incidence of cryptococcal meningitis in Scandinavia seems to be lower than in other parts of the world. Clinical signs and symptoms are often uncharacteristic. Detection of antigen in spinal fluid is a sensitive and fast test. INTERPRETATION: Cryptococcal meningitis is a rare disease, often with uncharacteristic symptoms. Patients with haematological malignancies have a higher risk of contracting this disease. It is a differential diagnosis when neurological symptoms occur in these patients.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 202,
                "text": "HIV"
            }
        },
        {
            "context": "Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 99,
                "text": "dabigatran"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi. BACKGROUND: Microsporidia is one of the taxa that have experienced the most dramatic taxonomic reclassifications. Once thought to be among the earliest diverging eukaryotes, the fungal nature of this group of intracellular pathogens is now widely accepted. However, the specific position of microsporidia within the fungal tree of life is still debated. Due to the presence of accelerated evolutionary rates, phylogenetic analyses involving microsporidia are prone to methodological artifacts, such as long-branch attraction, especially when taxon sampling is limited. RESULTS: Here we exploit the recent availability of six complete microsporidian genomes to re-assess the long-standing question of their phylogenetic position. We show that microsporidians have a similar low level of conservation of gene neighborhood with other groups of fungi when controlling for the confounding effects of recent segmental duplications. A combined analysis of thousands of gene trees supports a topology in which microsporidia is a sister group to all other sequenced fungi. Moreover, this topology received increased support when less informative trees were discarded. This position of microsporidia was also strongly supported based on the combined analysis of 53 concatenated genes, and was robust to filters controlling for rate heterogeneity, compositional bias, long branch attraction and heterotachy. CONCLUSIONS: Altogether, our data strongly support a scenario in which microsporidia is the earliest-diverging clade of sequenced fungi.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1146,
                "text": "fungi"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 825,
                "text": "xa"
            }
        },
        {
            "context": "The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 561,
                "text": "orally"
            }
        },
        {
            "context": "Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome. Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32_-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 208,
                "text": "FBN1"
            }
        },
        {
            "context": "From the circumsporozoite protein to the RTS, S/AS candidate vaccine. The RTS,S/AS01(E) malaria vaccine candidate has recently entered Phase 3 testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline and partners and collaborators. The vaccine has been developed to protect young children and infants living in Sub-Saharan Africa against clinical and severe disease caused by Plasmodium falciparum infection. Over the past 9 years, RTS,S/AS has been evaluated in multiple Phase 2 studies. The vaccine was shown to have a favorable safety profile and to be well tolerated in all age groups in which it was tested, including the intended target population of infants and young children in Sub-Saharan Africa. Data obtained so far suggest that RTS,S/AS can be co-administered with other vaccines included in the routine Expanded Program of Immunization (EPI). In Phase 2 testing, the vaccine candidate was shown to confer significant protection against P. falciparum infection and clinical disease, including severe malaria. Furthermore, a trend towards an indirect beneficial effect of the vaccine on non-malarial morbidities has been observed in several trials. In this paper, we will describe the genesis of the RTS,S/AS concept, including the rationale for selecting the circumsporozoite protein (CSP) as the target antigen. Early development history of the vaccine will be briefly described. We will present the most salient results from recent Phase 2 studies conducted in the target pediatric population, which have led to the decision to progress RTS,S/AS to Phase 3 testing. If the Phase 3 results confirm the observations made during Phase 2 testing, the RTS,S/AS vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in Sub-Saharan Africa.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 88,
                "text": "malaria"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 40,
                "text": "Spinal Muscular Atrophy"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 935,
                "text": "XK"
            }
        },
        {
            "context": "DNA binding by Sgf11 protein affects histone H2B deubiquitination by Spt-Ada-Gcn5-acetyltransferase (SAGA). The yeast Spt-Ada-Gcn5-acetyltransferase (SAGA) complex is a transcription coactivator that contains a histone H2B deubiquitination activity mediated by its Ubp8 subunit. Full enzymatic activity requires the formation of a quaternary complex, the deubiquitination module (DUBm) of SAGA, which is composed of Ubp8, Sus1, Sgf11, and Sgf73. The crystal structures of the DUBm have shed light on the structure/function relationship of this complex. Specifically, both Sgf11 and Sgf73 contain zinc finger domains (ZnF) that appear essential for the DUBm activity. Whereas Sgf73 N-terminal ZnF is important for DUBm stability, Sgf11 C-terminal ZnF appears to be involved in DUBm function. To further characterize the role of these two zinc fingers, we have solved their structure by NMR. We show that, contrary to the previously reported structures, Sgf73 ZnF adopts a C2H2 coordination with unusual tautomeric forms for the coordinating histidines. We further report that the Sgf11 ZnF, but not the Sgf73 ZnF, binds to nucleosomal DNA with a binding interface composed of arginine residues located within the ZnF α-helix. Mutational analyses both in vitro and in vivo provide evidence for the functional relevance of our structural observations. The combined interpretation of our results leads to an uncommon ZnF-DNA interaction between the SAGA DUBm and nucleosomes, thus providing further functional insights into SAGA's epigenetic modulation of the chromatin structure.",
            "question": "What does the SAGA complex acronym stands for?",
            "answers": {
                "answer_start": 118,
                "text": "Spt-Ada-Gcn5-acetyltransferase"
            }
        },
        {
            "context": "Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. BACKGROUND AND OBJECTIVES: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone. METHODS: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose. RESULTS: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments. CONCLUSION: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 176,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 339,
                "text": "webSDA"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 1343,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. BACKGROUND: Diamond-Blackfan anemia is a rare, clinically heterogeneous, congenital red cell aplasia: 40% of patients have congenital abnormalities. Recent studies have shown that in western countries, the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes in about 50% of patients. There have been no studies to determine the incidence of these mutations in Asian patients with Diamond-Blackfan anemia. DESIGN AND METHODS: We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A. RPS14 was also examined due to its implied involvement in 5q- syndrome. RESULTS: Mutations in RPS19, RPL5, RPL11 and RPS17 were identified in five, four, two and one of the probands, respectively. In total, 12 (27%) of the Japanese Diamond-Blackfan anemia patients had mutations in ribosomal protein genes. No mutations were detected in RPS14, RPS24 or RPL35A. All patients with RPS19 and RPL5 mutations had physical abnormalities. Remarkably, cleft palate was seen in two patients with RPL5 mutations, and thumb anomalies were seen in six patients with an RPS19 or RPL5 mutation. In contrast, a small-for-date phenotype was seen in five patients without an RPL5 mutation. CONCLUSIONS: We observed a slightly lower frequency of mutations in the ribosomal protein genes in patients with Diamond-Blackfan anemia compared to the frequency reported in western countries. Genotype-phenotype data suggest an association between anomalies and RPS19 mutations, and a negative association between small-for-date phenotype and RPL5 mutations.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 1033,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. Activation of the non-phagocytic superoxide-producing NADPH oxidase Nox1, complexed with p22(phox) at the membrane, requires its regulatory soluble proteins Noxo1 and Noxa1. However, the role of the small GTPase Rac remained to be clarified. Here we show that Rac directly participates in Nox1 activation via interacting with Noxa1. Electropermeabilized HeLa cells, ectopically expressing Nox1, Noxo1, and Noxa1, produce superoxide in a GTP-dependent manner, which is abrogated by expression of a mutant Noxa1(R103E), defective in Rac binding. Superoxide production in Nox1-expressing HeLa and Caco-2 cells is decreased by depletion or sequestration of Rac; on the other hand, it is enhanced by expression of the constitutively active Rac1(Q61L), but not by that of a mutant Rac1 with the A27K substitution, deficient in binding to Noxa1. We also demonstrate that Nox1 activation requires membrane recruitment of Noxa1, which is normally mediated via Noxa1 binding to Noxo1, a protein tethered to the Nox1 partner p22(phox): the Noxa1-Noxo1 and Noxo1-p22(phox) interactions are both essential for Nox1 activity. Rac likely facilitates the membrane localization of Noxa1: although Noxa1(W436R), defective in Noxo1 binding, neither associates with the membrane nor activates Nox1, the effects of the W436R substitution are restored by expression of Rac1(Q61L). The Rac-Noxa1 interaction also serves at a step different from the Noxa1 localization, because the binding-defective Noxa1(R103E), albeit targeted to the membrane, does not support superoxide production by Nox1. Furthermore, a mutant Noxa1 carrying the substitution of Ala for Val-205 in the activation domain, which is expected to undergo a conformational change upon Rac binding, fully localizes to the membrane but fails to activate Nox1.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 173,
                "text": "Nox1"
            }
        },
        {
            "context": "Inhibition of CaM kinase II activation and force maintenance by KN-93 in arterial smooth muscle. Ca(+)/calmodulin-dependent protein kinase II (CaM kinase II) has been implicated in the regulation of smooth muscle contractility. The goals of this study were to determine: 1) to what extent CaM kinase II is activated by contractile stimuli in intact arterial smooth muscle, and 2) the effect of a CaM kinase II inhibitor (KN-93) on CaM kinase II activation, phosphorylation of myosin regulatory light chains (MLC(20)), and force. Both histamine (1 microM) and KCl depolarization activated CaM kinase II with a time course preceding maximal force development, and suprabasal CaM kinase II activation was sustained during tonic contractions. CaM kinase II activation was inhibited by KN-93 pretreatment (IC(50) approximately 1 microM). KN-93 inhibited histamine-induced tonic force maintenance, whereas early force development and MLC(20) phosphorylation responses during the entire time course were unaffected. Both force development and maintenance in response to KCl were inhibited by KN-93. Rapid increases in KCl-induced MLC(20) phosphorylation were also inhibited by KN-93, whereas steady-state MLC(20) phosphorylation responses were unaffected. In contrast, phorbol 12,13-dibutyrate (PDBu) did not activate CaM kinase II and PDBu-stimulated force development was unaffected by KN-93. Thus KN-93 appears to target a step(s) essential for force maintenance in response to physiological stimuli, suggesting a role for CaM kinase II in regulating tonic contractile responses in arterial smooth muscle. Pharmacological activation of protein kinase C bypasses the KN-93 sensitive step.",
            "question": "Which kinase is inhibited by the small molecule KN-93?",
            "answers": {
                "answer_start": 739,
                "text": "CaM kinase II"
            }
        },
        {
            "context": "Quantitative real-time PCR for detection of neurotoxin genes of Clostridium botulinum types A, B and C in equine samples. Botulism in horses in the USA is attributed to Clostridium botulinum types A, B or C. In this study, a duplex quantitative real-time PCR (qPCR) for detection of the neurotoxin genes of C. botulinum types A and B, and a singleplex qPCR for detection of the neurotoxin gene of C. botulinum type C, were optimized and validated for equine gastrointestinal, faecal and feed samples. The performance of these assays was evaluated and compared to the standard mouse bioassay (MBA) using 148 well-characterized samples, most of which were acquired from a repository of veterinary diagnostic samples from cases of botulism: 106 samples positive for C. botulinum (25 type A, 27 type B, 28 type C, 1 type D and 25 type E) and 42 negative samples. The sensitivities of the qPCR assays were 89%, 86% and 96% for C. botulinum types A, B and C, respectively. The overall sensitivity of the mouse bioassay for types A, B and C was 81%. The specificities of the qPCR assays were 99-100% and the specificity of the mouse bioassay was 95%.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 169,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies. BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks. OBJECTIVE: We sought to further characterize the safety and efficacy of ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies. METHODS: An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age > 10 years) received 30 mg of subcutaneous ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). RESULTS: Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (ecallantide [mean ± SD], -0.97 ± 0.78; placebo, -0.47 ± 0.71; P < .001) and a significantly greater increase in TOSs at 4 hours (ecallantide, 55.5 ± 46.5; placebo, 20.0 ± 58.9; P < .001). Significantly greater symptomatic improvement over placebo occurred through 24 hours after dosing (MSCS score, P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups. CONCLUSIONS: This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 0,
                "text": "Ecallantide"
            }
        },
        {
            "context": "Human alpha-galactosidase A: high plasma activity expressed by the -30G-->A allele. Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). An unusally elevated level of plasma alpha-Gal A activity (> 2.5 times the normal mean) was detected in two unrelated normal males and the elevated activities were inherited as X-linked traits in their families. Sequencing of the alpha-Gal A coding region, intron/exon boundaries and 5'-flanking region from the proband identified a single mutation, a G-->A transition 30 nt upstream from the initiation of translation codon in exon 1. The -30G-->A mutation occurred in a putative NF kappa B/Ets consensus binding site that was recently shown to inhibit protein binding to the 5'-untranslated region of the gene, providing a possible explanation for its high activity. To further characterize the mutation, the mRNA and protein expressed by this variant allele were studied. Purified plasma and lymphoblast alpha-Gal A activity from individuals with the -30G-->A mutation had normal physical and kinetic properties. In vitro translation of mRNAs from the cloned normal and high plasma activity alleles resulted in similar levels of alpha-Gal A protein, indicating that this mutation did not enhance translation. These findings suggest that the -30G-->A mutation in the 5'-untranslated region of the alpha-Gal A gene enhances transcription, presumably by interfering with the binding of negatively-acting transcription factors which normally decrease alpha-Gal A expression in various cells. Preliminary studies of the frequency of the -30G-->A mutation in 395 unrelated normal males of mixed ancestry revealed two additional unrelated individuals who had high plasma enzymatic activity and the mutation, confirming the effect of this mutation on enzyme expression and suggesting that about 0.5% of normal individuals have high plasma alpha-Gal A activity due to this variant allele.",
            "question": "Which is the defective protein causing the lysosomal storage disease Fabry?",
            "answers": {
                "answer_start": 90,
                "text": "alpha-galactosidase A"
            }
        },
        {
            "context": "Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR? Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter's syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 160,
                "text": "insulin receptor"
            }
        },
        {
            "context": "GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvβ3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFβ signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 325,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Developmental and cell type-specific expression of thyroid hormone transporters in the mouse brain and in primary brain cells. Cellular thyroid hormone uptake and efflux are mediated by transmembrane transport proteins. One of these, monocarboxylate transporter 8 (MCT8) is mutated in Allan-Herndon-Dudley syndrome, a severe mental retardation associated with abnormal thyroid hormone constellations. Since mice deficient in Mct8 exhibit a milder neurological phenotype than patients, we hypothesized that alternative thyroid hormone transporters may compensate in murine brain cells for the lack of Mct8. Using qPCR, Western Blot, and immunocytochemistry, we investigated the expression of three different thyroid hormone transporters, i.e., Mct8 and L-type amino acid transporters Lat1 and Lat2, in mouse brain. All three thyroid hormone transporters are expressed from corticogenesis and peak around birth. Primary cultures of neurons and astrocytes express Mct8, Lat1, and Lat2. Microglia specifically expresses Mct10 and Slco4a1 in addition to high levels of Lat2 mRNA and protein. As in vivo, a brain microvascular endothelial cell line expressed Mct8 and Lat1. 158N, an oligodendroglial cell line expressed Mct8 protein, consistent with delayed myelination in MCT8-deficient patients. Functional T(3)- and T(4)-transport assays into primary astrocytes showed K(M) values of 4.2 and 3.7 μM for T(3) and T(4). Pharmacological inhibition of L-type amino acid transporters by BCH and genetic inactivation of Lat2 reduced astrocytic T(3) uptake to the same extent. BSP, a broad spectrum inhibitor, including Mct8, reduced T(3) uptake further suggesting the cooperative activity of several T(3) transporters in astrocytes.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 369,
                "text": "thyroid"
            }
        },
        {
            "context": "New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Although the triptan drugs provide effective relief from migraine for many patients, a substantial number of affected individuals are unresponsive to these compounds, and such therapy can also lead to a range of adverse effects. Telcagepant represents a new class of antimigraine drug-the calcitonin gene-related peptide receptor blockers. This compound exerts its effects by blocking receptors for the calcitonin-gene-related peptide at several sites in the trigeminal and central nervous systems, resulting in pain relief. Telcagepant does not cause vasoconstriction, a major limitation in the use of triptans. Comparisons with triptans in clinical trials for acute treatment of migraine attacks revealed clinical effects similar to those of triptans but better than those of placebo. Telcagepant might provide hope for those who have a poor response to, or are unable to use, older drugs. In patients who need prophylaxis because of frequent attacks of migraine, topiramate is a first-line drug for migraine prevention in many countries; it is generally safe and reasonably well tolerated. Data suggest that topiramate could aid reversion of chronic migraine to episodic migraine.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 366,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Proton pump inhibitors and pain. There may be a relationship between proton pump inhibitors (PPIs) and iron absorption. PPIs may decrease the amount of iron absorbed gastrointestinally specifically due to alteration of the pH in the duodenum. Restless legs syndrome (RLS) is a sensorimotor disorder that includes an urge to move legs, accompanied or caused by uncomfortable and unpleasant sensations in the legs; the urge to move begins or worsens during periods of rest or inactivity, the urge to move is partially or totally relieved by movement, and the urge is worse or only occurs at night. In the majority of the restless leg syndrome population, the sensation is deep seated, often described as being in the shin bones, and most commonly felt between the knee and ankle. It may be described as a creepy, shock-like, tense, electric, buzzing, itchy, or even numb sensation. A subpopulation of this restless leg syndrome patient population experiences restless leg syndrome associated pain (RLSAP) that has been described as a deep \"achy pain.\" This pain has not been found to be relieved by many of the typical over the counter analgesics. Often, constant movement of the legs appears to be the only remedy, as these sensations usually appear during periods of rest. Furthermore, there appears to be an association between iron deficiency and those suffering from Restless Leg Syndrome (RLS). The authors theorize that there may be a possible correlation between PPIs and the symptoms (e.g. pain) associated with RLS. The authors propose that PPIs, such as omeprazole, may interfere with iron absorption in certain patients and that a subpopulation of patients who develop significant iron deficiency characterized by low serum ferritin levels while on PPIs may also develop RLS-like symptoms (including RLSAP). While there is no robust direct evidence to support any associations of PPIs and iron deficiency or PPIs associated with RLS-like symptoms (including RLSAP), it is hoped that this manuscript may spark research efforts on this issue.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1594,
                "text": "iron"
            }
        },
        {
            "context": "Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 13,
                "text": "Poly(ADP-ribose) Polymerase"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1566,
                "text": "53BP1"
            }
        },
        {
            "context": "Targeting CDK4/6 in patients with cancer. The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 1408,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Monitoring plasma levels of factor Xa inhibitors: how, why and when? New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed. Several available anti-FXa assays are used for monitoring anticoagulant activity of heparins and fondaparinux. They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). The use of calibrators (lyophilized plasma with a known concentration of drug) allows an expression of the results in ng per ml of plasma. Two categories of assays - endogenous and exogenous assays are available. Endogenous assays are useful in pharmaceutical research, while exogenous assays are used in clinical laboratories. The preferred anti-FXa assay is a specific method in contrast to prothrombin time and activated partial thromboplastin time, but it is not available everywhere at any time. A specific measurement of direct FXa inhibitors is feasible with the use of a new test developed by the authors' group. The physicians must be aware of the possibility to measure the plasma concentration of FXa inhibitors in patients at high risk of bleeding and in several other special clinical situations.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 656,
                "text": "xa"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 749,
                "text": "ADAR"
            }
        },
        {
            "context": "Treatment of suicidal and deliberate self-harming patients with borderline personality disorder using dialectical behavioral therapy: the patients' and the therapists' perceptions. The aim was to investigate patients and therapists perception of receiving and giving dialectical behavioral therapy (DBT). Ten deliberate self-harm patients with borderline personality disorder and four DBT-therapists were interviewed. The interviews were analyzed with qualitative content analysis. The patients unanimously regard the DBT-therapy as life saving and something that has given them a bearable life situation. The patients and the therapists are concordant on the effective components of the therapy: the understanding, respect, and confirmation in combination with the cognitive and behavioral skills. The experienced effectiveness of DBT is contrasted by the patient's pronouncedly negative experiences from psychiatric care before entering DBT.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 64,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 386,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 436,
                "text": "flumazenil"
            }
        },
        {
            "context": "Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Inheritance of epigenetic information encoded by cytosine DNA methylation patterns is crucial for mammalian cell survival, in large part through the activity of the maintenance DNA methyltransferase (DNMT1). Here, we show that SET7, a known histone methyltransferase, is involved in the regulation of protein stability of DNMT1. SET7 colocalizes and directly interacts with DNMT1 and specifically monomethylates Lys-142 of DNMT1. Methylated DNMT1 peaks during the S and G(2) phases of the cell cycle and is prone to proteasome-mediated degradation. Overexpression of SET7 leads to decreased DNMT1 levels, and siRNA-mediated knockdown of SET7 stabilizes DNMT1. These results demonstrate that signaling through SET7 represents a means of DNMT1 enzyme turnover.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 291,
                "text": "DNMT1"
            }
        },
        {
            "context": "Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 830,
                "text": "xa"
            }
        },
        {
            "context": "Hemorheological alterations in sickle cell anemia and their clinical consequences - The role of genetic modulators. Sickle cell anemia (SCA) is an autosomal recessive disease caused by the HBB:c.20A>T mutation that leads to hemoglobin S synthesis. The disease presents with high clinical heterogeneity characterized by chronic hemolysis, recurrent episodes of vaso-oclusion and infection. This work aimed to characterize by in silico studies some genetic modulators of severe hemolysis and stroke risk in children with SCA, and understand their consequences at the hemorheological level.Association studies were performed between hemolysis biomarkers as well as the degree of cerebral vasculopathy and the inheritance of several polymorphic regions in genes related with vascular cell adhesion and vascular tonus in pediatric SCA patients. In silico tools (e.g. MatInspector) were applied to investigate the main variant consequences.Variants in vascular adhesion molecule-1 (VCAM1) gene promoter and endothelial nitric oxide synthase (NOS3) gene were significantly associated with higher degree of hemolysis and stroke events. They potentially modify transcription factor binding sites (e.g. VCAM1 rs1409419_T allele may lead to an EVI1 gain) or disturb the corresponding protein structure/function. Our findings emphasize the relevance of genetic variation in modulating the disease severity due to their effect on gene expression or modification of protein biological activities related with sickled erythrocyte/endothelial interactions and consequent hemorheological abnormalities.",
            "question": "What gene is mutated in Sickle Cell Anemia?",
            "answers": {
                "answer_start": 189,
                "text": "HBB"
            }
        },
        {
            "context": "Regulation of neuronal differentiation by proteins associated with nuclear bodies. Nuclear bodies are large sub-nuclear structures composed of RNA and protein molecules. The Survival of Motor Neuron (SMN) protein localizes to Cajal bodies (CBs) and nuclear gems. Diminished cellular concentration of SMN is associated with the neurodegenerative disease Spinal Muscular Atrophy (SMA). How nuclear body architecture and its structural components influence neuronal differentiation remains elusive. In this study, we analyzed the effects of SMN and two of its interaction partners in cellular models of neuronal differentiation. The nuclear 23 kDa isoform of Fibroblast Growth Factor - 2 (FGF-2(23)) is one of these interacting proteins - and was previously observed to influence nuclear bodies by destabilizing nuclear gems and mobilizing SMN from Cajal bodies (CBs). Here we demonstrate that FGF-2(23) blocks SMN-promoted neurite outgrowth, and also show that SMN disrupts FGF-2(23)-dependent transcription. Our results indicate that FGF-2(23) and SMN form an inactive complex that interferes with neuronal differentiation by mutually antagonizing nuclear functions. Coilin is another nuclear SMN binding partner and a marker protein for Cajal bodies (CBs). In addition, coilin is essential for CB function in maturation of small nuclear ribonucleoprotein particles (snRNPs). The role of coilin outside of Cajal bodies and its putative impacts in tissue differentiation are poorly defined. The present study shows that protein levels of nucleoplasmic coilin outside of CBs decrease during neuronal differentiation. Overexpression of coilin has an inhibitory effect on neurite outgrowth. Furthermore, we find that nucleoplasmic coilin inhibits neurite outgrowth independent of SMN binding revealing a new function for coilin in neuronal differentiation.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1166,
                "text": "Coilin"
            }
        },
        {
            "context": "Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 1255,
                "text": "HIV"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 0,
                "text": "MARS"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 533,
                "text": "tyrosinase"
            }
        },
        {
            "context": "[Regulation of inflammation through JAK3-Stat6 pathway in dendritic cells]. Dendritic cells (DCs) is the cell that act as source of the immune response by exquisitely presenting antigens to acquired immunity such as the T cells. Janus kinase (JAK) is a tyrosine kinase that is activated immediately after the cytokine binds to its unique receptor expressed on the cell surface. Among the JAKs, expression of JAK3 is limited on haematopoietic cells and is indispensable for lymphocyte development and proliferation. We have demonstrated that JAK3-deficient DCs normally develop, uptake antigens, produce inflammatory cytokines and function as an antigen-presenting cell, although they over-produce IL-10. Among the transcription factors that are known to be activated by JAK3, we explored the phenotype of Stat6-deficient DCs which is a transcription factor specifically activated by JAK3. Interestingly, development, function and inflammatory cytokine production was normal with over-production of IL-10 which was in line with the JAK3-deficient DCs. IL-4 is well known to activate JAK3-Stat6 in the cytoplasm and has been reported to be produced in the synovial fluid of rheumatoid arthritis patients. Hence the suppression of IL-10 production by IL-4 can be considered as one of the inflammatory process of arthritis. Moreover, induction of IL-10 production by DCs can be one mechanism of action of the JAK inhibitor (tofacitinib) which have shown high efficiency on active rheumatoid arthritis in clinical trials.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1420,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 163,
                "text": "Nox1"
            }
        },
        {
            "context": "WRAP53 is essential for Cajal body formation and for targeting the survival of motor neuron complex to Cajal bodies. The WRAP53 gene gives rise to a p53 antisense transcript that regulates p53. This gene also encodes a protein that directs small Cajal body-specific RNAs to Cajal bodies. Cajal bodies are nuclear organelles involved in diverse functions such as processing ribonucleoproteins important for splicing. Here we identify the WRAP53 protein as an essential factor for Cajal body maintenance and for directing the survival of motor neuron (SMN) complex to Cajal bodies. By RNA interference and immunofluorescence we show that Cajal bodies collapse without WRAP53 and that new Cajal bodies cannot be formed. By immunoprecipitation we find that WRAP53 associates with the Cajal body marker coilin, the splicing regulatory protein SMN, and the nuclear import receptor importinβ, and that WRAP53 is essential for complex formation between SMN-coilin and SMN-importinβ. Furthermore, depletion of WRAP53 leads to accumulation of SMN in the cytoplasm and prevents the SMN complex from reaching Cajal bodies. Thus, WRAP53 mediates the interaction between SMN and associated proteins, which is important for nuclear targeting of SMN and the subsequent localization of the SMN complex to Cajal bodies. Moreover, we detect reduced WRAP53-SMN binding in patients with spinal muscular atrophy, which is the leading genetic cause of infant mortality worldwide, caused by mutations in SMN1. This suggests that loss of WRAP53-mediated SMN trafficking contributes to spinal muscular atrophy.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 949,
                "text": "coilin"
            }
        },
        {
            "context": "Post-translational modifications of p53 tumor suppressor: determinants of its functional targets. Tumor suppressor p53 functions as a \"guardian of the genome\" to prevent cells from transformation. p53 is constitutively ubiquitinated and degradated in unstressed conditions, thereby suppressing the expression. However, cellular stimuli enable p53 to escape from the negative regulation, and then stably expressed p53 transactivates its target genes to induce cell cycle arrest, DNA repair, or apoptosis. Promoter preference of target genes is determined by modification status of p53. Because p53 has two critical roles in the decision of cell fate, stopping cell cycle to repair damaged DNA or induction of apoptotic cell death in response to DNA damage, elucidation of switching mechanisms on p53 functions is of particular importance. Here we review recent evidence how several post-translational modifications of p53 including methylation, phosphorylation, acetylation, and ubiquitination, affect the functions of p53 in response to cellular stress.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 197,
                "text": "p53"
            }
        },
        {
            "context": "Alpha-synuclein is not a requisite component of synaptic boutons in the adult human central nervous system. It is increasingly clear that the normal protein alpha-synuclein is in some manner closely associated with presynaptic components of select neuronal types within the adult human central nervous system (CNS) and, in addition, that in its pathologically altered state alpha-synuclein aggregates selectively in the form of filamentous inclusion bodies during certain progressive neurodegenerative disorders, such as familial and sporadic Parkinson's disease. By having the antibody AFshp raised specifically to alpha-synuclein to label Parkinson disease-specific Lewy bodies and Lewy neurites as well as synaptic boutons containing the unaltered protein, an initial attempt is made to map the overall distribution pattern and describe the staining behavior of the immunoreactive punctae in select regions of the prosencephalon. Neocortical immunolabeling is most prominent in the prodigious, but incompletely myelinated, association fields and faintest in the heavily myelinated primary motor and primary sensory fields, with the premotor and first order sensory association areas occupying an intermediate position. Of the thalamic grays evaluated, those containing powerfully myelinated fiber tracts (e.g. centrum medianum, habenular complex) show the weakest immunolabeling, whereas, less sturdily myelinated structures are highly immunoreactive. The fact that the immunostaining spectrum for normal alpha-synuclein is so broad, together with the fact that some thalamic sites actually are immunonegative leads to the following conclusions (1) alpha-synuclein, although present in the synaptic boutons of many nerve cells in the adult human CNS, is by no means ubiquitous there, and (2) neuronal types lacking the normal protein cannot generate the Parkinson's disease-specific filamentous pathology.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 616,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 273,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Association between the neutrophil-to-lymphocyte ratio, a new marker of systemic inflammation, and restless legs syndrome. INTRODUCTION: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is characterised by abnormal sensations in the legs as well as dysaesthesia. Although the aetiology of RLS has not yet been determined, it may be associated with systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) is a new and simple marker indicating systemic inflammation. The present study aimed to investigate the relationship between systemic inflammation and RLS through the use of the NLR. METHODS: A total of 75 newly diagnosed patients with RLS and 56 healthy control subjects were included in the study. Baseline NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The NLRs of the two groups were compared. RESULTS: There were no significant differences in gender and age between the two groups. The NLR was 1.96 ± 0.66 in the patient group and 1.67 ± 0.68 in the control group (p = 0.005). Receiver operating characteristic analysis was performed to determine the cut-off value of NLR to predict RLS. The NLR was predictive at 1.58 with a 64% sensitivity and 50% specificity (95% confidence interval 0.55-0.74, area under curve 0.648 ± 0.05). The NLR was found to be statistically higher in patients with RLS and may be used to predict RLS. CONCLUSION: The aetiology of RLS remains undetermined. The present study showed that systemic inflammation may play a role in RLS. However, RLS could also be associated with systemic inflammatory diseases. This relationship is supported by high NLR values, which are related to chronic systemic inflammation.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 137,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Designing calcium release channel inhibitors with enhanced electron donor properties: stabilizing the closed state of ryanodine receptor type 1. New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 561,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Hypoleptinaemia in patients with anorexia nervosa and in elite gymnasts with anorexia athletica. Leptin, the product of the ob-gene, is specifically released by adipocytes. In addition to its metabolic function it seems to affect the feedback-mechanisms of the hypothalamic-pituitary-gonadal-axis. We studied 13 female juvenile elite gymnasts with anorexia athletica (AA) and 9 female patients with anorexia nervosa (AN) regarding the relation between leptin, fat stores, and the reproductive hormone levels. Leptin levels in females with anorexia nervosa (Tanner stage B4 [median]; mean age: 17.8 +/- 1.7 years) were low (2.9 +/- 2.7 microg/L), and were related to body mass index (BMI) (r = 0.71; p = 0.03) and percentage body fat mass (r = 0.78; p = 0.01). Leptin levels of the elite gymnasts were even more decreased (1.2 +/- 0.8 microg/L) caused by the low amount of fat stores. Leptin correlated with BMI (r= 0.77; p = 0.004) and the percentage body fat mass (r = 0.6; p = 0.04). In elite gymnasts leptin levels correlated with CA showing an age-dependent increase (r= 0.59; p = 0.04). Oestradiol was secreted at a low level in both groups (AN: 25.6 +/- 17.4 microg/L; AA: 24.4 +/- 13.5 microg/L). A delay in menarche and a retarded bone maturation occurred in AA. Our results clearly show that leptin levels are low in restrained eaters. Leptin levels represent the fat stores in the body and play a permissive role for female pubertal development. There is evidence that the mechanisms leading to a dysregulation of the reproductive-axis in patients with AN are comparable with those leading to delayed puberty in juvenile elite gymnasts with AA. This implies that AN and AA are overlapping groups and AA can lead to the development of AN.",
            "question": "What is the name for anorexia in gymnasts?",
            "answers": {
                "answer_start": 348,
                "text": "anorexia athletica"
            }
        },
        {
            "context": "SUMO and Parkinson's disease. Parkinson's disease (PD) is one of the most common degenerative disorders of the central nervous system that produces motor and non-motor symptoms. The majority of cases are idiopathic and characterized by the presence of Lewy bodies containing fibrillar α-synuclein. Small ubiquitin-related modifier (SUMO) immunoreactivity was observed among others in cases with PD. Key disease-associated proteins are SUMO-modified, linking this posttranslational modification to neurodegeneration. SUMOylation and SUMO-mediated mechanisms have been intensively studied in recent years, revealing nuclear and extranuclear functions for SUMO in a variety of cellular processes, including the regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress. This points to a role for SUMO more than just an antagonist to ubiquitin and proteasomal degradation. The identification of risk and age-at-onset gene loci was a breakthrough in PD and promoted the understanding of molecular mechanisms in the pathology. PD has been increasingly linked with mitochondrial dysfunction and impaired mitochondrial quality control. Interestingly, SUMO is involved in many of these processes and up-regulated in response to cellular stress, further emphasizing the importance of SUMOylation in physiology and disease.",
            "question": "Which disease of the central nervous system is characterized by the presence of Lewy bodies?",
            "answers": {
                "answer_start": 30,
                "text": "Parkinson's disease (PD)"
            }
        },
        {
            "context": "Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies. Estrogen and selective estrogen receptor modulator (SERM) treatments for acromegaly have received limited attention since the development of newer pharmacologic therapies. There has been ongoing research evidence suggesting their utility in the biochemical control of acromegaly. Therefore, the aim of this meta-analysis was to synthesise current evidence with a view to determining to what extent and in which acromegalic patient subsets do estrogen and SERMs reduce IGF-1 levels. A literature search was conducted (finished December 2012), which included all studies pertaining to estrogen or SERM treatment and IGF-1. Seven patient subsets were identified from six published observational studies, and were pooled using meta-analytic methods. Overall, the pooled mean loss in IGF-1 was -29.09 nmol/L (95 % CI -37.23 to -20.95). A sensitivity analysis indicated that women receiving estrogen had a substantially greater reduction in IGF-1 levels compared with women receiving SERMs, with a weighted mean loss in IGF-1 of -38.12 nmol/L (95 % CI -46.78 to -29.45) compared with -22.91 nmol/L (95 % CI -32.73 to -13.09). There was a trend that did not reach statistical significance for men receiving SERM treatment at -11.41 nmol/L (95 % CI -30.14 to 7.31). It was concluded that estrogen and SERMs are a low cost and effective treatment to achieve control of IGF-1 levels in acromegalic women either as concomitant treatment for refractory disease, or where access to conventional therapy is restricted. Their use in men requires further study.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 13,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 973,
                "text": "xa"
            }
        },
        {
            "context": "Regulation of NF-κB by ubiquitination and degradation of the IκBs. The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3, β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have been worked out, the development of β-TrCP inhibitors might be a feasible therapeutic approach for NF-κB-associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β-TrCP in vivo.",
            "question": "Which is the E3 ubiquitin ligase which ubiquitinates IkB leading to its proteasomal degradation?",
            "answers": {
                "answer_start": 975,
                "text": "SCF(β-TrCP)"
            }
        },
        {
            "context": "Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Although most eukaryotic genomes lack operons, they contain some physical clusters of genes that are related in function despite being unrelated in sequence. How these clusters are formed during evolution is unknown. The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. We show here that the DAL cluster was assembled, quite recently in evolutionary terms, through a set of genomic rearrangements that happened almost simultaneously. Six of the eight genes involved in allantoin degradation, which were previously scattered around the genome, became relocated to a single subtelomeric site in an ancestor of S. cerevisiae and Saccharomyces castellii. These genomic rearrangements coincided with a biochemical reorganization of the purine degradation pathway, which switched to importing allantoin instead of urate. This change eliminated urate oxidase, one of several oxygen-consuming enzymes that were lost by yeasts that can grow vigorously in anaerobic conditions. The DAL cluster is located in a domain of modified chromatin involving both H2A.Z histone exchange and Hst1-Sum1-mediated histone deacetylation, and it may be a coadapted gene complex formed by epistatic selection.",
            "question": "Which is the largest metabolic gene cluster in yeast?",
            "answers": {
                "answer_start": 289,
                "text": "The DAL cluster"
            }
        },
        {
            "context": "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.",
            "question": "Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?",
            "answers": {
                "answer_start": 1001,
                "text": "TBC1D7"
            }
        },
        {
            "context": "Assessing serotonin receptor mRNA editing frequency by a novel ultra high-throughput sequencing method. RNA editing is a post-transcriptional modification of pre-mRNA that results in increased diversity in transcriptomes and proteomes. It occurs in a wide variety of eukaryotic organisms and in some viruses. One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation. This phenomenon has been observed in numerous transcripts, including the mammalian 5-HT(2C) receptor, which can be edited at five distinct sites. Methods used to date to quantify 5-HT(2C) receptor editing are labor-intensive, expensive and provide limited information regarding the relative abundance of 5-HT(2C) receptor editing variants. Here, we present a novel, ultra high-throughput method to quantify 5-HT(2C) receptor editing, compare it to a more conventional method, and use it to assess the effect of a range of genetic and pharmacologic manipulations on 5-HT(2C) editing. We conclude that this new method is powerful and economical, and we provide evidence that alterations in 5-HT(2C) editing appear to be a result of regional changes in brain activity, rather than a mechanism to normalize 5-HT(2C) signaling.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 361,
                "text": "A-to-I"
            }
        },
        {
            "context": "Weaning age among foragers at Matjes river rock shelter, South Africa, from stable nitrogen and carbon isotope analyses. Matjes River Rock Shelter is a large shell midden on the southern coast of South Africa. Stable nitrogen (delta(15)N) and carbon (delta(13)C) isotope ratios were measured in bone collagen and dentine from human skeletons excavated from this site in order to establish a weaning curve in mid-Holocene hunter-gatherers. delta(15)N results show a progressive increase in individuals from birth to 1.5 years old. delta(13)C results are more tightly clustered and mirror the steady progressive change seen for delta(15)N. We deduce that children at Matjes River Rock Shelter were breastfed for at least the first 1.5 years after birth, and were weaned sometime between 2-4 years of age. A similar pattern was documented for historic-era Kalahari foraging people, where the interbirth spacing was approximately 3 years. This study provides the first direct evidence for an extended period of breastfeeding, and thus long interbirth intervals, among prehistoric foragers, even when those foragers lived in an environment with abundant food resources.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 300,
                "text": "collagen"
            }
        },
        {
            "context": "Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 554,
                "text": "tyr"
            }
        },
        {
            "context": "Imetelstat (a telomerase antagonist) exerts off - target effects on the cytoskeleton. Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non - small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 459,
                "text": "telomerase"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 366,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies. BACKGROUND: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson's disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies. RESULTS: In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition. CONCLUSIONS: Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 951,
                "text": "α-synuclein"
            }
        },
        {
            "context": "The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 1651,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor suppressors. However, how they function as tumor suppressors remains elusive. Here, I propose a number of tumor suppressor pathways that illustrate how the TA-p73 and p63 could function as negative regulators of invasion, metastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide molecular insights into how TA-p73 and p63 could function as tumor suppressors. Remarkably, the guardians--p53, p73, and p63--of the genome are in control of most of the known tumor suppressor miRNAs, tumor suppressor genes, and metastasis suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear to upregulate the expression of (1) tumor suppressor miRNAs, such as let-7, miR-34, miR-15/16a, miR-145, miR-29, miR-26, miR-30, and miR-146a; (2) tumor suppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) metastasis suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, and thereby they enlarge their tumor suppressor network to inhibit tumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs proliferation.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 29,
                "text": "p53"
            }
        },
        {
            "context": "Crystal structure of the receptor binding domain of the botulinum C-D mosaic neurotoxin reveals potential roles of lysines 1118 and 1136 in membrane interactions. The botulinum neurotoxins (BoNTs) produced by different strains of the bacterium Clostridium botulinum are responsible for the disease botulism and include a group of immunologically distinct serotypes (A, B, E, and F) that are considered to be the most lethal natural proteins known for humans. Two BoNT serotypes, C and D, while rarely associated with human infection, are responsible for deadly botulism outbreaks afflicting animals. Also associated with animal infections is the BoNT C-D mosaic protein (BoNT/CD), a BoNT subtype that is essentially a hybrid of the BoNT/C (∼two-third) and BoNT/D (∼one-third) serotypes. While the amino acid sequence of the heavy chain receptor binding (HCR) domain of BoNT/CD (BoNT/CD-HCR) is very similar to the corresponding amino acid sequence of BoNT/D, BoNT/CD-HCR binds synaptosome membranes better than BoNT/D-HCR. To obtain structural insights for the different membrane binding properties, the crystal structure of BoNT/CD-HCR (S867-E1280) was determined at 1.56 Å resolution and compared to previously reported structures for BoNT/D-HCR. Overall, the BoNT/CD-HCR structure is similar to the two sub-domain organization observed for other BoNT HCRs: an N-terminal jellyroll barrel motif and a C-terminal β-trefoil fold. Comparison of the structure of BoNT/CD-HCR with BoNT/D-HCR indicates that K1118 has a similar structural role as the equivalent residue, E1114, in BoNT/D-HCR, while K1136 has a structurally different role than the equivalent residue, G1132, in BoNT/D-HCR. Lysine-1118 forms a salt bridge with E1247 and may enhance membrane interactions by stabilizing the putative membrane binding loop (K1240-N1248). Lysine-1136 is observed on the surface of the protein. A sulfate ion bound to K1136 may mimic a natural interaction with the negatively changed phospholipid membrane surface. Liposome-binding experiments demonstrate that BoNT/CD-HCR binds phosphatidylethanolamine liposomes more tightly than BoNT/D-HCR.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 244,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. RESULTS: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. CONCLUSIONS: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. ©2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 193,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "PHYLUCE is a software package for the analysis of conserved genomic loci. UNLABELLED: Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales (<5 Ma to > 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. AVAILABILITY AND IMPLEMENTATION: PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth-lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. CONTACT: brant@faircloth-lab.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which software package is available for the analysis of conserved genomic loci?",
            "answers": {
                "answer_start": 645,
                "text": "PHYLUCE"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 958,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 815,
                "text": "factor Xa"
            }
        },
        {
            "context": "Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchange. The histone variant H2AZ is incorporated preferentially at specific locations in chromatin to modulate chromosome functions. In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by the multiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Here, we define interactions between SWR1 components and H2AZ, revealing a link between the ATPase domain of Swr1 and three subunits required for the binding of H2AZ. We discovered that Swc2 binds directly to and is essential for transfer of H2AZ. Swc6 and Arp6 are necessary for the association of Swc2 and for nucleosome binding, whereas other subunits, Swc5 and Yaf9, are required for H2AZ transfer but neither H2AZ nor nucleosome binding. Finally, the C-terminal alpha-helix of H2AZ is crucial for its recognition by SWR1. These findings provide insight on the initial events of histone exchange.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 306,
                "text": "SWR1"
            }
        },
        {
            "context": "Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients. Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes. Compared to other methods, the protein truncation test (PTT) provides improved efficiency in detecting NF1 mutations which are dispersed throughout the gene which spans 350 kilobases of genomic DNA. We have applied the PTT and subsequent sequence analysis of cloned cDNA to identify mutations in NF1 patients. We report here the identification of two novel (W336X and Q315X), and one recurrent (R304X) mutation located in exon 7 and show that all three premature termination codons lead to skipping of exon 7 in a proportion of the transcripts derived from the mutated allele. Possible mutation-induced alterations of the RNA secondary structure and their impact on skipping of exon 7 of the NF1 gene are explored and discussed.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 129,
                "text": "NF1"
            }
        },
        {
            "context": "Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs). Selective estrogen receptor modulators (SERMs), known previously as \"antiestrogens\", are a new category of therapeutic agents used for the prevention and treatment of diseases such as osteoporosis and breast cancer. SERMs act as ER-agonist in some tissues while acting as ER-antagonist in others based on conformational change of the receptors, particularly at the helix 12. Currently, there are two classes of clinically approved SERMs; triphenylethylene derivatives (e.g., tamoxifen) and benzothiophene derivatives (e.g., raloxifene). Tamoxifen, raloxifene and toremifene are the most widely used SERMs. Tamoxifen, an antagonist of the breast tissue, is the first clinically identified compound with noticeable SERM activity. Although tamoxifen has been very successful in breast cancer treatment, its agonistic effect on the uterus is said to be associated with increase risk of developing endometrial cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagonist in the breast and uterus. Therefore, the therapeutic goal of SERMs is the prevention of estrogen deficiency diseases without promoting estrogen-associated tumor growth. Therefore, the objective of this review is to summarize various effects that have been applied in improving the tissue-selectivity of SERMs, highlighting the emerging understanding of their mechanism of actions in selected target tissues and the development of the SERMs. The significance in recent discovery of selective estrogen receptor alpha modulators, SERAMs will also be reviewed.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 122,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "[Molecular pathogenesis of chronic myeloid leukemia]. Chronic myeloid leukemia (CML) is a paradigm for neoplasias that are defined by a unique genetic aberration, the BCR-ABL1 fusion gene. CML is also the best example for molecular target therapy. The development of protein tyrosine kinase inhibitor, imatinib, has entirely changed the strategy of therapy for CML. Nonetheless, many fields of pathogenesis for CML have not been elucidated, such as the mechanisms of blastic crisis, the causes of genetic instability including the inactivation of tumor suppressor genes, and oncogenic signaling pathways downstreams of the BCR-ABL1 fusion gene product. Herein, we review current knowledge on the molecular pathogenesis of CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 167,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "A phase 1 multiple-dose study of orteronel in Japanese patients with castration-resistant prostate cancer. PURPOSE: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy. RESULTS: Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30%) were hyperlipasemia (47%), hyperamylasemia (40%), and constipation (33%). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50% reduction from baseline in prostate-specific antigen. CONCLUSIONS: Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 69,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome: Classical imaging findings. A 15-year-old female presented with seizures, right-sided hemiparesis, hemiatrophy of the right side of the body and mental retardation. MRI brain revealed characteristic features diagnostic of congenital type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 272,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 493,
                "text": "AD"
            }
        },
        {
            "context": "Association between levels of IgA antibodies to tissue transglutaminase and gliadin-related nonapeptides in dermatitis herpetiformis. Dermatitis herpetiformis (DH) is an autoimmunity-driven inflammatory blistering dermatosis associated with a gluten-dependent enteropathy. Tissue transglutaminase (tTG) and nonapeptides of gliadin (npG) are considered in its pathomechanism/diagnostics. Here, the diagnostic accuracy of anti-tTG/anti-npG IgA ELISAs in Slavic DH patients with active skin rash was assessed through creating receiver operating characteristic (ROC) curves, determining cutoff values, and calculating correlations between levels of anti-tTG/anti-npG IgA in DH, IgA/neutrophil-mediated non-DH patients and healthy persons. Altogether, sera from 80 Slavic individuals were examined. There were negligible differences between cutoff points obtained by the ELISAs manufacturer and those in this study. There were statistically significant correlations between levels of anti-tTG/anti-npG IgA in both DH group and the group of IgA/neutrophil-mediated non-DH dermatoses. There was no such correlation in healthy controls. It seems that IgA autoantibodies to tTG and npG in the IgA/neutrophil-mediated DH are produced in the coordinated way implying their causal relationship.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 134,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 704,
                "text": "CD38"
            }
        },
        {
            "context": "Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys. Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses > 3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 282,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Endoplasmic reticulum aminopeptidases: biochemistry, physiology and pathology. The human endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 proteins were initially identified as homologues of human placental leucine aminopeptidase/insulin-regulated aminopeptidase. They are categorized as a unique class of proteases based on their subcellular localization on the luminal side of the endoplasmic reticulum. ERAPs play an important role in the N-terminal processing of the antigenic precursors that are presented on the major histocompatibility complex (MHC) class I molecules. ERAPs are also implicated in the regulation of a wide variety of physiological phenomena and pathogenic conditions. In this review, the current knowledge on ERAPs is summarized.",
            "question": "Which is the  subcellular localization of ERAP2?",
            "answers": {
                "answer_start": 365,
                "text": "luminal side of the endoplasmic reticulum"
            }
        },
        {
            "context": "Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 946,
                "text": "p16Ink4"
            }
        },
        {
            "context": "The atxA gene product activates transcription of the anthrax toxin genes and is essential for virulence. Bacillus anthracis plasmid pXO1 carries the structural genes for the three anthrax toxin proteins, cya (edema factor), lef (lethal factor), and pag (protective antigen). Expression of the toxin genes by B. anthracis is enhanced during growth under elevated levels of CO2. This CO2 effect is observed only in the presence of another pXO1 gene, atxA, which encodes a transactivator of anthrax toxin synthesis. Here we show that transcription of atxA does not appear to differ in cells grown in 5% CO2 compared with cells grown in air. Using a new efficient method for gene replacement in B. anthracis, we constructed an atxA-null mutant in which the atxA-coding sequence on pXO1 is replaced with an omega km-2 cassette. Transcription of all three toxin genes is decreased in the absence of atxA. The pag gene possesses two apparent transcription start sites, P1 and P2; only transcripts with 5' ends mapping to P1 are decreased in the atxA-null mutant. Deletion analysis of the pag promoter region indicates that the 111 bp region upstream of the P1 site is sufficient for atxA-mediated activation of this transcript. The cya and lef genes each have one apparent start site for transcription. Transcripts with 5' ends mapping to these sites are not detected in the atxA-null mutant. The atxA-null mutant is avirulent in mice. Moreover, the antibody response to all three toxin proteins is decreased significantly in atxA-null mutant-infected mice. These data suggest that the atxA gene product also regulates toxin gene expression during infection.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 382,
                "text": "CO2"
            }
        },
        {
            "context": "Variability in minimal genomes: analysis of tandem repeats in the microsporidia Encephalitozoon intestinalis. Microsporidia are ubiquitous fungi with genomes that have undergone a strong reduction to the extreme cases of Encephalitozoon cuniculi and Encephalitozoon intestinalis. Genetic variability within species of the Encephalitozoon genus has been reported, with most of the studies based on the internal transcribed spacer (ITS) of the rDNA. However, in contrast to the picture of E. cuniculi and Encephalitozoon hellem, where different strains have been identified, no genetic variability has yet been observed in E. intestinalis. We have analysed tandem repeats included in putative coding sequences which could be used as polymorphic markers in E. intestinalis. Eight candidate loci (M2, M2A, M3, M5, M7, M7A, M8 and PTP1) were established and 9 E. intestinalis cultured strains from North America, South America and Europe were analysed. M2, M7 and PTP1 nucleotide sequences were identical among the different strains and the GenBank sequence. In contrast, we observed variants in 4 markers (M2A, M3, M7A and M8) which did not correspond to their respective reference sequences. The most noticeable finding was that with the M5 marker two genotypes were defined among the different strains studied, demonstrating genotypic variability of E. intestinalis. Although the diversity described is certainly not high, which can be explained by a lower chance of genetic variability in its minimal genome, we have demonstrated that polymorphisms actually exist in E. intestinalis. Epidemiological studies using this genetic marker should now be conducted to elucidate the genetic variability in E. intestinalis and improve our knowledge of the epidemiology of this microsporidia.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 139,
                "text": "fungi"
            }
        },
        {
            "context": "A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome. OBJECTIVE: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome. PATIENT & METHODS: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed. RESULTS: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation. CONCLUSIONS: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 397,
                "text": "Xq28"
            }
        },
        {
            "context": "A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade > 3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 252,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 247,
                "text": "MC1R"
            }
        },
        {
            "context": "Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations. Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1483,
                "text": "xa"
            }
        },
        {
            "context": "A novel insight into the mechanism of mammalian selenoprotein synthesis. The amino acid selenocysteine is encoded by UGA, usually a stop codon, thus requiring a specialized machinery to enable its incorporation into selenoproteins. The machinery comprises the tRNA(Sec), a 3'-UTR mRNA stem-loop termed SElenoCysteine Insertion Sequence (SECIS), which is mandatory for recoding UGA as a Sec codon, the SECIS Binding Protein 2 (SBP2), and other proteins. Little is known about the molecular mechanism and, in particular, when, where, and how the SECIS and SBP2 contact the ribosome. Previous work by others used the isolated SECIS RNA to address this question. Here, we developed a novel approach using instead engineered minimal selenoprotein mRNAs containing SECIS elements derivatized with photoreactive groups. By cross-linking experiments in rabbit reticulocyte lysate, new information could be gained about the SBP2 and SECIS contacts with components of the translation machinery at various translation steps. In particular, we found that SBP2 was bound only to the SECIS in 48S pre-initiation and 80S pretranslocation complexes. In the complex where the Sec-tRNA(Sec) was accommodated to the A site but transpeptidation was blocked, SBP2 bound the ribosome and possibly the SECIS element as well, and the SECIS had flexible contacts with the 60S ribosomal subunit involving several ribosomal proteins. Altogether, our findings led to broadening our understanding about the unique mechanism of selenocysteine incorporation in mammals.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 337,
                "text": "SECIS"
            }
        },
        {
            "context": "Complications of microsurgery of vestibular schwannoma. BACKGROUND: The aim of this study was to analyze complications of vestibular schwannoma (VS) microsurgery. MATERIAL AND METHODS: A retrospective study was performed in 333 patients with unilateral vestibular schwannoma indicated for surgical treatment between January 1997 and December 2012. Postoperative complications were assessed immediately after VS surgery as well as during outpatient followup. RESULTS: In all 333 patients microsurgical vestibular schwannoma (Koos grade 1: 12, grade 2: 34, grade 3: 62, and grade 4: 225) removal was performed. The main neurological complication was facial nerve dysfunction. The intermediate and poor function (HB III-VI) was observed in 124 cases (45%) immediately after surgery and in 104 cases (33%) on the last followup. We encountered disordered vestibular compensation in 13%, permanent trigeminal nerve dysfunction in 1%, and transient lower cranial nerves (IX-XI) deficit in 6%. Nonneurological complications included CSF leakage in 63% (lateral/medial variant: 99/1%), headache in 9%, and intracerebral hemorrhage in 5%. We did not encounter any case of meningitis. CONCLUSIONS: Our study demonstrates that despite the benefits of advanced high-tech equipment, refined microsurgical instruments, and highly developed neuroimaging technologies, there are still various and significant complications associated with vestibular schwannomas microsurgery.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 501,
                "text": "vestibular schwannoma"
            }
        },
        {
            "context": "Effects of cerebrolysin administration on oxidative stress-induced apoptosis in lymphocytes from CADASIL patients. Cerebrolysin (Cere) is a peptidergic nootropic drug with neurotrophic properties which has been used to treat dementia and sequelae of stroke. Use of Cere prevents nuclear structural changes typical of apoptosis and significantly reduces the number of apoptotic cells after several apoptotic stimuli. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by mutations of the Notch3 gene encoding the Notch3 protein. Notch3 is involved in the regulation of apoptosis, modulating Fas-Ligand (Fas-L)- induced apoptosis. The aim of this study was to evaluate the in vitro protective effects of Cere against oxidative stress-induced apoptosis in cells from CADASIL patients. We used peripheral blood lymphocytes (PBLs) from 15 CADASIL patients (age range 34-70 years); 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analyzed by flow cytometry and fluorescence microscopy. Administration of Cere to PBLs from CADASIL patients cultured under standard conditions had no effect on the percentage of apoptotic cells. Administration of Cere to PBLs cultured with dRib caused a significant decrease in apoptosis after 48 h of culture in only 5 patients, whereas in the other 10 patients, Cere treatment was not associated with any significant difference in the percentage of apoptosis. This result showed a protective effect of Cere against oxidative stress-induced apoptosis only in 30 % of the CADASIL patients, suggesting that the Notch3 gene probably does not influence the anti-apoptotic properties of Cere in vitro.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 568,
                "text": "Notch3 gene"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 32,
                "text": "xa"
            }
        },
        {
            "context": "Heme-dependent up-regulation of the alpha-globin gene expression by transcriptional repressor Bach1 in erythroid cells. The transcriptional factor Bach1 forms a heterodimer with small Maf family, and functions as a repressor of the Maf recognition element (MARE) in vivo. To investigate the involvement of Bach1 in the heme-dependent regulation of the expression of the alpha-globin gene, human erythroleukemia K562 cells were cultured with succinylacetone (SA), a heme biosynthetic inhibitor, and the level of alpha-globin mRNA was examined. A decrease of alpha-globin mRNA was observed in SA-treated cells, which was restored by the addition of hemin. The heme-dependent expression of alpha-globin occurred at the transcriptional level since the expression of human alpha-globin gene promoter-reporter gene containing hypersensitive site-40 (HS-40) was decreased when K562 cells were cultured with SA. Hemin treatment restored the decrease of the promoter activity by SA. The regulation of the HS-40 activity by heme was dependent on the NF-E2/AP-1 (NA) site, which is similar to MARE. The NA site-binding activity of Bach1 in K562 increased upon SA-treatment, and the increase was diminished by the addition of hemin. The transient expression of Bach1 and mutated Bach1 lacking CP motifs suppressed the HS-40 activity, and cancellation of the repressor activity by hemin was observed when wild-type Bach1 was expressed. The expression of NF-E2 strengthened the restoration of the Bach1-effect by hemin. Interestingly, nuclear localization of Bach1 increased when cells were treated with SA, while hemin induced the nuclear export of Bach1. These results indicated that heme plays an important role in the induction of alpha-globin gene expression through disrupting the interaction of Bach1 and the NA site in HS-40 enhancer in erythroid cells.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 215,
                "text": "repressor"
            }
        },
        {
            "context": "Restless legs syndrome. Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterised by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. The pathophysiology is only partially known and a genetic component together with dopaminergic and brain iron dysregulation plays an important role. Secondary causes for RLS need to be excluded. Treatment depends on the severity and frequency of RLS symptoms, comprises non-pharmacological (eg lifestyle changes) and pharmacological interventions (eg dopaminergic medication, alpha-2-delta calcium channel ligands, opioids) and relieves symptoms only. Augmentation is the main complication of long-term dopaminergic treatment of RLS. This article will provide a clinically useful overview of RLS with provision of diagnostic criteria, differential diagnoses, possible investigations and different treatment strategies with their associated complications.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 24,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Detection of long repeat expansions from PCR-free whole-genome sequence data. Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.",
            "question": "Which algorithm is used for detection of long repeat expansions?",
            "answers": {
                "answer_start": 422,
                "text": "ExpansionHunter"
            }
        },
        {
            "context": "Clinical features of sudden unexpected death in epilepsy. People with epilepsy may die unexpectedly without a clear structural or pathologic cause. This condition is called sudden unexpected death in epilepsy (SUDEP), and it accounts for a large proportion of deaths among people with epilepsy. SUDEP incidence rates vary with the cohort studied, ranging from 0.35 per 1,000 person-years of follow-up in population-based studies to 9.3 per 1,000 person-years in patients with refractory epilepsy. Although many studies have been performed, the causes of SUDEP are not understood. However, even without precise knowledge of the underlying pathogenic mechanism(s), SUDEP prevention could start with the identification of the most prominent risk factors. SUDEP seems to occur more commonly during sleep and it preferentially affects young adults with medically intractable epilepsy (especially tonic-clonic seizures), individuals who also have neurologic comorbidity, and patients receiving antiepileptic drug polytherapy. This article reviews the clinical features associated with SUDEP and suggests preventive measures for this condition.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 173,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The status of tularemia in Europe in a one-health context: a review. The bacterium Francisella tularensis causes the vector-borne zoonotic disease tularemia, and may infect a wide range of hosts including invertebrates, mammals and birds. Transmission to humans occurs through contact with infected animals or contaminated environments, or through arthropod vectors. Tularemia has a broad geographical distribution, and there is evidence which suggests local emergence or re-emergence of this disease in Europe. This review was developed to provide an update on the geographical distribution of F. tularensis in humans, wildlife, domestic animals and vector species, to identify potential public health hazards, and to characterize the epidemiology of tularemia in Europe. Information was collated on cases in humans, domestic animals and wildlife, and on reports of detection of the bacterium in arthropod vectors, from 38 European countries for the period 1992-2012. Multiple international databases on human and animal health were consulted, as well as published reports in the literature. Tularemia is a disease of complex epidemiology that is challenging to understand and therefore to control. Many aspects of this disease remain poorly understood. Better understanding is needed of the epidemiological role of animal hosts, potential vectors, mechanisms of maintenance in the different ecosystems, and routes of transmission of the disease.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 83,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 326,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor suppressors. However, how they function as tumor suppressors remains elusive. Here, I propose a number of tumor suppressor pathways that illustrate how the TA-p73 and p63 could function as negative regulators of invasion, metastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide molecular insights into how TA-p73 and p63 could function as tumor suppressors. Remarkably, the guardians--p53, p73, and p63--of the genome are in control of most of the known tumor suppressor miRNAs, tumor suppressor genes, and metastasis suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear to upregulate the expression of (1) tumor suppressor miRNAs, such as let-7, miR-34, miR-15/16a, miR-145, miR-29, miR-26, miR-30, and miR-146a; (2) tumor suppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) metastasis suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, and thereby they enlarge their tumor suppressor network to inhibit tumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs proliferation.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 603,
                "text": "p53"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 253,
                "text": "Tyrosinase"
            }
        },
        {
            "context": "Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak-Higashi syndrome of cattle. An inheritable bleeding disorder with light coat color caused by an autosomal recessive gene has been reported in a population of Japanese black cattle. The disease has been diagnosed as Chediak-Higashi Syndrome (CHS) of cattle which correspond to a human inheritable disorder caused by mutation in LYST gene. To characterize the molecular lesion causing CHS in cattle, cDNAs encoding bovine LYST were isolated from a bovine brain cDNA library. The nucleotide and deduced amino acid sequences of bovine LYST had 89.6 and 90.2% identity with those of the human LYST gene, respectively. In order to identify the mutation within the LYST gene causing CHS in cattle, cDNA fragments of the LYST gene were amplified from an affected animal by RT-PCR and their nucleotide sequences were completely determined. Notably, a nucleotide substitution of A to G transition, resulting in an amino acid substitution of histidine to arginine (H2015R) was identified in the affected animal. The presence of the substitution was completely corresponding with the occurrence of the CHS phenotype among 105 members of pedigrees of the Japanese black cattle and no cattle of other populations had this substitution. These findings strongly suggested that H2015R is the causative mutation in CHS of Japanese black cattle.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 86,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. DESIGN: A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. SETTING: An 800-bed, teaching, university-affiliated hospital. PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant \"waking\" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1846,
                "text": "flumazenil"
            }
        },
        {
            "context": "Cross-talk between sympathetic neurons and adipocytes in coculture. White adipose tissue plays an integral role in energy metabolism and is governed by endocrine, autocrine, and neural signals. Neural control of adipose metabolism is mediated by sympathetic neurons that innervate the tissue. To investigate the effects of this innervation, an ex vivo system was developed in which 3T3-L1 adipocytes are cocultured with sympathetic neurons isolated from the superior cervical ganglia of newborn rats. In coculture, both adipocytes and neurons exhibit appropriate morphology, express cell-type-specific markers, and modulate key metabolic processes in one another. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY). Secretion of NPY by neurons is up-regulated dramatically by the presence of adipocytes in coculture and appears to be mediated by an adipocyte-derived soluble factor. Insulin, an antilipolytic agent, down-regulates NPY secretion. Our findings suggest that an adipocyte-derived factor(s) up-regulates the secretion of NPY by sympathetic neurons, which, in turn, attenuates lipolytic energy mobilization by adipocytes.",
            "question": "From which cell type is leptin secreted?",
            "answers": {
                "answer_start": 737,
                "text": "adipocytes"
            }
        },
        {
            "context": "SECISaln, a web-based tool for the creation of structure-based alignments of eukaryotic SECIS elements. SUMMARY: Selenoproteins contain the 21st amino acid selenocysteine which is encoded by an inframe UGA codon, usually read as a stop. In eukaryotes, its co-translational recoding requires the presence of an RNA stem-loop structure, the SECIS element in the 3 untranslated region of (UTR) selenoprotein mRNAs. Despite little sequence conservation, SECIS elements share the same overall secondary structure. Until recently, the lack of a significantly high number of selenoprotein mRNA sequences hampered the identification of other potential sequence conservation. In this work, the web-based tool SECISaln provides for the first time an extensive structure-based sequence alignment of SECIS elements resulting from the well-defined secondary structure of the SECIS RNA and the increased size of the eukaryotic selenoproteome. We have used SECISaln to improve our knowledge of SECIS secondary structure and to discover novel, conserved nucleotide positions and we believe it will be a useful tool for the selenoprotein and RNA scientific communities. AVAILABILITY: SECISaln is freely available as a web-based tool at http://genome.crg.es/software/secisaln/.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 339,
                "text": "SECIS"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 734,
                "text": "TYR"
            }
        },
        {
            "context": "The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31 degrees C than at 37 degrees C, and their degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 255,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Next-generation sequencing of Okazaki fragments extracted from Saccharomyces cerevisiae. Genome-wide Okazaki fragment distribution can differentiate the discontinuous from the semi-discontinuous DNA replication model. Here, we investigated the genome-wide Okazaki fragment distribution in Saccharomyces cerevisiae S288C. We improved the method based upon lambda exonuclease digestion to purify Okazaki fragments from S288C yeast cells, followed by Illumina sequencing. The distribution of Okazaki fragments around confirmed replication origins, including two highly efficient replication origins, supported the discontinuous DNA replication model. In S. cerevisiae mitochondria, Okazaki fragments were overrepresented in the transcribed regions, indicating the interplay between transcription and DNA replication.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 195,
                "text": "DNA replication"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Reliability and validity of the Korean version of the Davidson Trauma Scale. The Davidson Trauma Scale (DTS) is a validated, 17-item, brief global assessment scale for posttraumatic stress disorder (PTSD). The purposes of this study were to develop a Korean version of the DTS (DTS-K) while maintaining its basic structure and to evaluate its reliability and validity for the Korean population. Participants of this study included 93 patients with PTSD (PTSD group), 73 patients with nonpsychotic mood or other anxiety disorders (psychiatric control group), and 88 healthy controls (normal control group). Subjects completed psychometric assessments, including the DTS-K and the Korean version of the Clinician-Administered PTSD Scale and the State Trait Anxiety Inventory. The DTS-K showed good internal consistency (Cronbach alpha = .97) and test-retest reliability (r = .93). The DTS-K showed a significantly positive correlation with Clinician-Administered PTSD Scale (r = .94). The highest diagnostic efficiency of DTS-K was at a total score of 47, with sensitivity and specificity of 0.87 and 0.84, respectively. Our findings suggest that the DTS-K is composed of good psychometric properties and is a valid and reliable tool for assessing the frequency and severity of PTSD symptoms regardless of ethnicity.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 199,
                "text": "PTSD"
            }
        },
        {
            "context": "Analysis of mutations of neurofibromatosis type 1 gene and N-ras gene in acute myelogenous leukemia. Neurofibromatosis type 1 (NF1) gene is a tumor suppressor gene, and the NF1 gene product, neurofibromin, can downregulate the N-ras gene. Because the N-ras gene is often mutated in acute myelogenous leukemia (AML), we wondered if the NF1 gene might be mutated in those AML samples not having N-ras mutations. We investigated the mutational status of the N-ras gene and the FLR exon of codons 1371-1423 of the open reading frame of the full-length NF1 cDNA, which has a strong homology with the mammalian ras GTPase-activating protein (GAP), especially for a stretch of three consecutive amino acids (F, L, R), by single-strand conformation polymorphism analysis and direct sequencing in samples from patients with AML. Of 48 AML patients, 10 (21%) had point (missense) mutations of the N-ras gene involving codons 12, 13 and 61. However, mutations in the FLR exon of the NF1 gene were not detected in any of the AML samples. We also examined the difference of clinical response to induction therapy between AML patients with and without N-ras mutation. A significantly lower rate of complete remission was noted in individuals with N-ras gene mutations. These results suggest that mutation of the NF1 gene, at least in the FLR exon, is very rare in AML and the NF1 gene probably is not a functional complement of the N-ras gene mutation. The presence of N-ras gene mutation may be associated with a lower clinical response to antileukemic therapy.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 173,
                "text": "NF1"
            }
        },
        {
            "context": "Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 508,
                "text": "xa"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 253,
                "text": "Tyr"
            }
        },
        {
            "context": "Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], > 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 435,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 733,
                "text": "MethPed"
            }
        },
        {
            "context": "Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with congenital and childhood forms. Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder, caused by an expansion of a CTG triplet repeat in the DMPK gene. The aims of the present study were to classify a cohort of children with DM1, to describe their neuropsychiatric problems and cognitive level, to estimate the size of the CTG expansion, and to correlate the molecular findings with the neuropsychiatric problems. Fifty-seven children and adolescents (26 females; 31 males) with DM1 (CTG repeats > 40) were included in the study. The following instruments were used: Autism Diagnostic Interview-Revised (ADI-R), 5-15, Griffiths Mental Development Scales, and the Wechsler Scales. Based on age at onset and presenting symptoms, the children were divided into four DM1 groups; severe congenital (n = 19), mild congenital (n = 18), childhood (n = 18), and classical DM1 (n = 2). Forty-nine percent had an autism spectrum disorder (ASD) and autistic disorder was the most common diagnosis present in 35% of the subjects. Eighty-six percent of the individuals with DM1 had mental retardation (MR), most of them moderate or severe MR. ASD was significantly correlated with the DM1 form; the more severe the form of DM1, the higher the frequency of ASD. The frequency of ASD increased with increasing CTG repeat expansions. ASD and/or other neuropsychiatric disorders such as attention deficit hyperactivity disorder, and Tourette's disorder were found in 54% of the total DM1 group. In conclusion, awareness of ASD comorbidity in DM1 is essential. Further studies are warranted to elucidate the molecular etiology causing neurodevelopmental symptoms such as ASD and MR in DM1.",
            "question": "How is myotonic dystrophy inherited?",
            "answers": {
                "answer_start": 158,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Genes flanking Xist in mouse and human are separated on the X chromosome in American marsupials. X inactivation, the transcriptional silencing of one of the two X chromosomes in female mammals, achieves dosage compensation of X-linked genes relative to XY males. In eutherian mammals X inactivation is regulated by the X-inactive specific transcript (Xist), a cis-acting non-coding RNA that triggers silencing of the chromosome from which it is transcribed. Marsupial mammals also undergo X inactivation but the mechanism is relatively poorly understood. We set out to analyse the X chromosome in Monodelphis domestica and Didelphis virginiana, focusing on characterizing the interval defined by the Chic1 and Slc16a2 genes that in eutherians flank the Xist locus. The synteny of this region is retained on chicken chromosome 4 where other loci belonging to the evolutionarily ancient stratum of the human X chromosome, the so-called X conserved region (XCR), are also located. We show that in both M. domestica and D. virginiana an evolutionary breakpoint has separated the Chic1 and Slc16a2 loci. Detailed analysis of opossum genomic sequences revealed linkage of Chic1 with the Lnx3 gene, recently proposed to be the evolutionary precursor of Xist, and Fip1, the evolutionary precursor of Tsx, a gene located immediately downstream of Xist in eutherians. We discuss these findings in relation to the evolution of Xist and X inactivation in mammals.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 351,
                "text": "Xist"
            }
        },
        {
            "context": "Rett Syndrome. Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. There are several mouse models either based on conditional knocking out of the Mecp2 gene or on a truncating mutation. We discuss the clinical aspects with special emphasis on the behavioral phenotype and we review current perspectives in clinical management alongside with perspectives in altering gene expression.",
            "question": "Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2?",
            "answers": {
                "answer_start": 15,
                "text": "Rett syndrome"
            }
        },
        {
            "context": "Multimodal imaging with (18)F-FDG PET and Cerenkov luminescence imaging after MLN4924 treatment in a human lymphoma xenograft model. UNLABELLED: Cerenkov luminescence imaging (CLI) is an emerging imaging technique that combines aspects of both optical and nuclear imaging fields. The ability to fully evaluate the correlation and sensitivity of CLI to PET is critical to progress this technique further for use in high-throughput screening of pharmaceutical compounds. To achieve this milestone, it must first be established that CLI data correlate to PET data in an in vivo preclinical antitumor study. We used MLN4924, a phase 2 oncology therapeutic, which targets and inhibits the NEDD8-activating enzyme pathway involved in the ubiquitin-proteasome system. We compared the efficacious effects of MLN4924 using PET and Cerenkov luminescence image values in the same animals. METHODS: Imaging of (18)F-FDG uptake was performed at 5 time points after drug treatment in the subcutaneously implanted diffuse large B-cell lymphoma tumor line OCI-Ly10. Data were acquired with both modalities on the same day, with a 15-min delay between CLI and PET. PET data analysis was performed using percentage injected dose per cubic centimeter of tissue (%ID/cm(3)), average standardized uptake values, and total glycolytic volume. CLI measurements were radiance, radiance per injected dose (radiance/ID), and total radiant volume. RESULTS: A strong correlation was found between PET total glycolytic volume and CLI total radiant volume (r(2) = 0.99) and various PET and CLI analysis methods, with strong correlations found between PET %ID/cm(3) and CLI radiance (r(2) = 0.83) and CLI radiance/ID (r(2) = 0.82). MLN4924 demonstrated a significant reduction in tumor volume after treatment (volume ratio of treated vs. control, 0.114 at day 29). CONCLUSION: The PET and CLI data presented confirm the correlation and dynamic sensitivity of this new imaging modality. CLI provides a preclinical alternative to expensive PET instrumentation. Future high-throughput studies should provide for quicker turnaround and higher cost-to-return benefits in the drug discovery process.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 684,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 733,
                "text": "Xa"
            }
        },
        {
            "context": "Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Methylation of cytosine in DNA plays a crucial role in development through inheritable gene silencing. The DNA methyltransferase Dnmt1 is responsible for the propagation of methylation patterns to the next generation via its preferential methylation of hemimethylated CpG sites in the genome; however, how Dnmt1 maintains methylation patterns is not fully understood. Here we report the crystal structure of the large fragment (291-1620) of mouse Dnmt1 and its complexes with cofactor S-adenosyl-L-methionine and its product S-adenosyl-L-homocystein. Notably, in the absence of DNA, the N-terminal domain responsible for targeting Dnmt1 to replication foci is inserted into the DNA-binding pocket, indicating that this domain must be removed for methylation to occur. Upon binding of S-adenosyl-L-methionine, the catalytic cysteine residue undergoes a conformation transition to a catalytically competent position. For the recognition of hemimethylated DNA, Dnmt1 is expected to utilize a target recognition domain that overhangs the putative DNA-binding pocket. Taking into considerations the recent report of a shorter fragment structure of Dnmt1 that the CXXC motif positions itself in the catalytic pocket and prevents aberrant de novo methylation, we propose that maintenance methylation is a multistep process accompanied by structural changes.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 82,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 448,
                "text": "Huntington disease"
            }
        },
        {
            "context": "A selective inhibitor of Na+/Ca2+ exchanger, SEA0400, preserves cardiac function and high-energy phosphates against ischemia/reperfusion injury. The Ca2+ overload by Ca2+ influx via Na+/Ca2+ exchanger (NCX) is a critical mechanism in myocardial ischemia/reperfusion injury. We investigated protective effects of a novel selective inhibitor of NCX, SEA0400, on cardiac function and energy metabolism during ischemia and reperfusion. Langendorff-perfused rat hearts were exposed to 35 minutes global ischemia and 40 minutes reperfusion. Using 31P nuclear magnetic resonance spectroscopy, cardiac phosphocreatine (PCr), ATP, and pHi were monitored. SEA0400 did not change the basic cardiac function, but improved the recovery of left ventricular developed pressure (LVDP) after reperfusion (27.6 +/- 4.9 mm Hg in control, 101.2 +/- 19.3 mm Hg in 0.1 microM, and 115.5 +/- 13.3 mm Hg in 1 microM SEA0400, means +/- SE, n = 6, P < 0.05). SEA0400 reduced left ventricular end-diastolic pressure and increased coronary flow after reperfusion. SEA0400 improved the recoveries of cardiac phosphocreatine and ATP after reperfusion, but did not affect pHi. There were significant linear correlations between left ventricular developed pressure and cardiac phosphocreatine (r = 0.79, P < 0.05), and left ventricular developed pressure and ATP (r = 0.80, P < 0.05). However, SEA0400 increased the incidence and duration of reperfusion ventricular arrhythmias. SEA0400 added only after reperfusion also improved both the contractile function and energy metabolism. It is concluded that the selective inhibition of NCX may be effective to preserve high-energy phosphates and to improve cardiac function after reperfusion, but may not be able to prevent fatal arrhythmias.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 202,
                "text": "NCX"
            }
        },
        {
            "context": "The reduction of baseline serotonin 2A receptors in mild cognitive impairment is stable at two-year follow-up. We previously demonstrated a 20-30% reduction in cortical 5-HT2A receptor binding in patients with mild cognitive impairment (MCI) as compared to healthy subjects. Here we present a two-year follow-up of 14 patients and 12 healthy age-matched subjects. Baseline and follow-up partial volume corrected levels of 5-HT2A in four neocortical lobes and the posterior cingulate gyrus were investigated using [18F]altanserin positron emission tomography with a bolus-infusion approach. In the two-year follow-up period, 8 of 14 patients with MCI had progressed to fulfill diagnostic criteria for probable Alzheimer's disease (AD). In both patients and healthy subjects, no significant change in 5-HT2A receptor binding was found as compared to baseline values. In MCI patients, the average BPP in neocortex ranged from 1.49 to 2.45 at baseline and 1.38 to 2.29 at two-year follow-up; and in healthy subjects BPP ranged from 1.85 to 3.10 at baseline and 1.81 to 2.98 at two-year follow-up. The BPP of the patients that converted to AD during the follow-up period did not differ significantly from the patients that had not (yet) converted, neither at baseline, nor at follow-up. We conclude that the reduced levels of 5-HT2A receptor binding in MCI patients decrease only slowly and non-significantly, even in patients who convert to AD. Our finding suggests that profoundly reduced cortical 5-HT2A receptor binding is an early feature in MCI whereas the clinical progression from MCI to AD is less associated with further decrease in binding.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 422,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Mepolizumab and exacerbations of refractory eosinophilic asthma. BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 634,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Cryptococcal meningitis in Rio de Janeiro State, Brazil, 1994-2004. The objective of this article was to evaluate the epidemiology of cryptococcal meningitis in Rio de Janeiro State, Brazil, from 1994 to 2004. Six hundred and ninety-six cases of cryptococcal meningitis were reported, with a mean incidence of 0.45 per 100,000 inhabitants. Patients were predominantly male; mean age was 35.9 years; AIDS was practically the only underlying disease, reported in 61.2% of cases; case-fatality was 51.8%. No decline in incidence was observed during the study period. AIDS is the main predisposing condition for cryptococcal meningitis, and thus the profile of most patients mirrors that of HIV infection. Missing information prevented the evaluation of other underlying diseases.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 687,
                "text": "HIV"
            }
        },
        {
            "context": "Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The direct factor Xa inhibitor apixaban (Eliquis(®)) has predictable pharmacodynamics and pharmacokinetics and does not require routine anticoagulation monitoring. This article reviews the efficacy and tolerability of oral apixaban to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial in patients with AF and at least one additional risk factor for stroke, apixaban recipients were significantly less likely than warfarin recipients to experience stroke or systemic embolism, major bleeding or death; the beneficial effects of treatment with apixaban versus warfarin were generally maintained across various patient subgroups. Apixaban recipients also had a significantly lower risk of intracranial haemorrhage than warfarin recipients. In the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Therapy) trial in patients with AF and at least one additional risk factor for stroke for whom vitamin K antagonist therapy was unsuitable, apixaban was associated with a significantly lower risk of stroke or systemic embolism than aspirin, without an increase in the risk of major bleeding. In conclusion, although longer-term efficacy and safety data are needed, apixaban is an important new option for use in patients with nonvalvular AF to reduce the risk of stroke or systemic embolism.",
            "question": "What is the drug target for Eliquis (Apixaban)?",
            "answers": {
                "answer_start": 145,
                "text": "factor Xa"
            }
        },
        {
            "context": "[Clinical experience in benzodiazepine antagonist]. Flumazenil, a potent benzodiazepine antagonist, is a newly synthetic imidazo-benzodiazepine, which blocks the neurological effects of benzodiazepines. The purpose of this study was to evaluate the effects of this agent in reversal of benzodiazepine overdose and differentiation of comatous patients with drug overdose. Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration. Three cases with different drug history and variant response after flumazenil treatment were also illustrated and discussed. The dosage of flumazenil used in this study ranged from 0.25 mg to 3 mg (average 0.87 +/- 0.74 mg). We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 978,
                "text": "flumazenil"
            }
        },
        {
            "context": "Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 841,
                "text": "orbit"
            }
        },
        {
            "context": "Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. UNLABELLED: Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. PERSPECTIVE: This study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 311,
                "text": "NF1"
            }
        },
        {
            "context": "The role of LOX and LOXL2 in scar formation after glaucoma surgery. PURPOSE: The aim of this study was to elucidate the role of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) 2 in pathologic wound healing after glaucoma surgery. We therefore investigated the expression of LOX and LOXL2 and evaluated the therapeutic potential of anti-LOX (GS-639556, formerly M64) and anti-LOXL2 (GS-607601, formerly AB0023) antibodies in a rabbit model of glaucoma trabeculectomy. METHODS: Ocular expression of LOX and LOXL2 was investigated by immunohistologic staining at different time points after trabeculectomy. Treatment with GS-639556 or GS-607601 was initiated in rabbits immediately after trabeculectomy by giving both intracameral and subconjunctival injections. Thereafter, the antibodies were given twice a week subconjunctivally until day 30 after surgery (day of euthanization). Treatment outcome was studied by clinical investigation of the bleb and by immunohistochemical analysis of angiogenesis, inflammation, and collagen deposition. RESULTS: LOX and LOXL2 were both upregulated in Tenon's capsule and the conjunctiva after glaucoma surgery. Repeated administration of LOX- or LOXL2-targeting monoclonal antibodies increased bleb area and bleb survival. Analyses of immunohistologic stainings showed that both antibodies significantly decreased fibrosis, whereas the anti-LOXL2 antibody also significantly reduced blood vessel density and inflammation. CONCLUSIONS: Targeting LOXL2 with an inhibitory monoclonal antibody (GS-607601) reduced pathologic angiogenesis, inflammation, and fibrosis. These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.",
            "question": "What is the drug target for Simtuzumab?",
            "answers": {
                "answer_start": 1629,
                "text": "LOXL2"
            }
        },
        {
            "context": "FullSSR: Microsatellite Finder and Primer Designer. Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. The software was tested with 2000 sequences of Oryza sativa shotgun sequencing project from the National Center of Biotechnology Information Trace Archive and with partial genome sequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla platensis, and Zilchiopsis collastinensis. FullSSR performance was compared against other similar SSR search programs. The results of the use of this kind of approach depend on the parameters set by the user. In addition, results can be affected by the analyzed sequences because of differences among the genomes. FullSSR simplifies the detection of SSRs and primer design on a big data set. The command line interface of FullSSR was intended to be used as part of genomic analysis tools pipeline; however, it can be used as a stand-alone program because the results are easily interpreted for a nonexpert user.",
            "question": "Which tool exists for microsatellite (SSR) loci detection and primer design?",
            "answers": {
                "answer_start": 901,
                "text": "FullSSR"
            }
        },
        {
            "context": "Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene. Sotos syndrome is a well-known overgrowth syndrome caused by haploinsufficiency of NSD1 gene located at 5q35. There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). We investigated detailed craniofacial, dental, and oral findings in five patients with deletion type, and three patients with mutation type Sotos syndrome. All eight patients had a high palate, excessive tooth wear, crowding, and all but one patient had hypodontia and deep bite. Hypodontia was exclusively observed in the second premolars, and there were no differences between the deletion and mutation types in the number of missing teeth. Another feature frequently seen in common with both types was maxillary recession. Findings seen more frequently and more pronounced in deletion-type than in mutation-type included mandibular recession, scissors or posterior cross bite, and small dental arch with labioclination of the maxillary central incisors. It is noteworthy that although either scissors bite or cross bite was present in all of the deletion-type patients, neither of these was observed in mutation-type patients. Other features seen in a few patients include enamel hypoplasia (two deletion patients), and ectopic tooth eruption (one deletion and one mutation patients). Our study suggests that Sotos syndrome patients should be observed closely for possible dental and oral complications especially for malocculusion in the deletion-type patients.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 330,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "A luciferase reporter assay to investigate the differential selenium-dependent stability of selenoprotein mRNAs. The mechanisms regulating the differential selenium (Se)-dependent stability of selenoprotein mRNAs are partially characterized. To further study the Se-dependent regulation of selenoproteins, we developed a novel chemiluminescent reporter to monitor the steady-state mRNA level of an artificial selenoprotein. Our reporter is a fusion of the Renilla luciferase gene and of the β-globin gene, but contains features required for incorporation of selenocysteine (SEC), namely, a UGA-SEC codon and a 3' untranslated region RNA stem loop called a SEC incorporation sequence (SECIS). At various levels of Se, the activity of reporters containing GPX1 or GPX4 SECIS elements is proportional to the steady-state mRNA level of the reporter construct and reflects the level of the corresponding endogenous mRNA. In a reporter containing a UGA codon and a functional GPX1 SECIS, Se-dependent nonsense-mediated decay (NMD) occurred in the cytoplasm, as opposed to the more typical nuclear location. To validate the reporter system, we used genetic and pharmacologic approaches to inhibit or promote NMD. Modulation of UPF1 by siRNA, overexpression, or by inhibition of SMG1 altered NMD in this system. Our reporter is derived from a Renilla luciferase reporter gene fused to an intron containing B-globin gene and is subject to degradation by NMD when a stop codon is inserted before the second intron.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 684,
                "text": "SECIS"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 0,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Different intracellular compartmentalization of TA and DeltaNp73 in non-small cell lung cancer. The p53 homologue p73 is overexpressed in many tumors, including lung cancer. We have evaluated the differential expression and subcellular localization of the functionally distinct apoptotic (TA) and anti-apoptotic (DeltaN) isoforms of p73 in non-small cell lung cancer (NSCLC), their possible association with p53 expression and determined the methylation status of the two p73 gene promoters (P1 and P2) in this tumor type. Immunohistochemical analysis showed that both isoforms are expressed in the majority of cases. However, the oncogenic DeltaN variant, derived from the transcripts DeltaN'p73 (from P1) and/or DeltaNp73 (from P2), is localized mainly in the nucleus, while the anti-oncogenic TAp73 isoform (derived from a P1 transcript) is sequestered in the cytoplasm in almost all cases analyzed. Significant correlation was found between p53 and DeltaNp73 expression (p=0.041). Methylation analysis conducted on 41 tumor samples showed that the P1 promoter is almost invariably unmethylated (39/41 cases) whereas P2 was found completely methylated in 17 cases and partially or totally unmethylated in 24 samples. No correlation was found between the methylation status of P1 and P2 and p73 expression. Our results demonstrate that both isoforms contribute to p73 overexpression in NSCLC and suggest that their different intracellular localization may reflect an alteration of the functional p53-p73 network that might contribute to lung cancer development.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 334,
                "text": "7"
            }
        },
        {
            "context": "MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 1066,
                "text": "MC1R"
            }
        },
        {
            "context": "Evolutionary conservation of possible functional domains of the human and murine XIST genes. The human XIST gene, a candidate for a role in X chromosome inactivation, has recently been cloned and sequenced, yielding a 17 kb cDNA with no apparent significant, conserved open reading frame. In addition, the XIST transcript has been localized within the nucleus to the Barr body by RNA in situ hybridization. This subnuclear localization and lack of any significant protein-coding potential suggest that XIST may act as a functional RNA within the nucleus. In the absence of a conserved open reading frame, we have turned to evolutionary studies as a first step toward elucidating a function for XIST in the process of X inactivation. While probes for XIST detect homologues in numerous eutherians, sequence comparisons require significant gapping and reveal identity levels intermediate between those seen for coding and non-coding regions in other genes. Further, sequence comparison of the most likely candidate open reading frame among several primate species reveals sequence changes not normally associated with protein-coding regions. Other features of XIST are conserved in different species, however, including the position of a major transcription start site and active X chromosome-specific DNA methylation patterns at the gene's 5' end. Finally, a possible molecular basis for differing propensity toward X inactivation between Xce alleles in mouse is investigated by comparing the sequence of the Xist conserved 5' repeats in mouse strains carrying different Xce alleles.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 103,
                "text": "XIST"
            }
        },
        {
            "context": "SERMs and SERMs with estrogen for postmenopausal osteoporosis. Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women's Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 864,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Subviral pathogens of plants: the viroids. Research during the last 15 years has conclusively shown that viroids are not only fundamentally different from viruses at the molecular level, but that they are most likely not directly related to viruses in an evolutionary sense. Today, viroids are among the most thoroughly studied biological macromolecules. Their molecular structures have been elucidated to a large extent, but much needs to be learned regarding the correlation between molecular structure and biological function. The availability of the tools of recombinant DNA technology in viroid research promises rapid progress in these areas of inquiry.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 34,
                "text": "viroids"
            }
        },
        {
            "context": "Tolerance to oats in dermatitis herpetiformis. OBJECTIVES: Recent studies on coeliac disease have shown that oats can be included in a gluten-free diet without adverse effects on the small bowel. The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats. PATIENTS/METHODS: Eleven patients with dermatitis herpetiformis in remission on a gluten-free diet were challenged daily with 50 g oats for six months. Clinical symptoms were recorded, serum samples taken, and skin and small bowel biopsies performed before and after the oat challenge. A control group comprised of 11 patients with dermatitis herpetiformis on a conventional gluten-free diet was also studied. RESULTS: Eight patients challenged with oats remained asymptomatic, two developed a transient rash, and one withdrew because of the appearance of a more persistent but mild rash. Three of the 11 controls also developed a transient rash. IgA endomysial antibodies remained negative in all patients. The small bowel villous architecture, the densities of intraepithelial CD3 and alpha/beta and gamma/delta T cell receptor positive lymphocytes and crypt epithelial cell DR expression remained unaltered during the oat challenge. CONCLUSIONS: The results confirm the absence of oat toxicity on the gluten sensitive small bowel mucosa and suggest that the rash in patients with dermatitis herpetiformis is not activated by eating oats.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 272,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Phosphorylation of skeletal muscle calsequestrin enhances its Ca2+ binding capacity and promotes its association with junctin. Calcium signaling, intrinsic to skeletal and cardiac muscle function, is critically dependent on the amount of calcium stored within the sarcoplasmic reticulum. Calsequestrin, the main calcium buffer in the sarcoplasmic reticulum, provides a pool of calcium for release through the ryanodine receptor and acts as a luminal calcium sensor for the channel via its interactions with triadin and junctin. We examined the influence of phosphorylation of calsequestrin on its ability to store calcium, to polymerise and to regulate ryanodine receptors by binding to triadin and junctin. Our hypothesis was that these parameters might be altered by phosphorylation of threonine 353, which is located near the calcium and triadin/junctin binding sites. Although phosphorylation increased the calcium binding capacity of calsequestrin nearly 2-fold, it did not alter calsequestrin polymerisation, its binding to triadin or junctin or inhibition of ryanodine receptor activity at 1 mM luminal calcium. Phosphorylation was required for calsequestrin binding to junctin when calcium concentration was low (100 nM), and ryanodine receptors were activated by dephosphorylated calsequestrin when it bound to triadin alone. These novel data shows that phosphorylated calsequestrin is required for high capacity calcium buffering and suggest that ryanodine receptor inhibition by calsequestrin is mediated by junctin.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 288,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "Sinodielide A exerts thermosensitizing effects and induces apoptosis and G2/M cell cycle arrest in DU145 human prostate cancer cells via the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Sinodielide A (SA) is a naturally occurring guaianolide, which is isolated from the root of Sinodielsia yunnanensis. This root, commonly found in Yunnan province, is used in traditional Chinese medicine as an antipyretic, analgesic and diaphoretic agent. A number of studies have reported that agents isolated from a species of Umbelliferae (Apiaceae) have antitumor activities. We previously reported, using combined treatments with this medicinal herb and hyperthermia at various temperatures, an enhanced cytotoxicity in the human prostate cancer androgen - independent cell lines, PC3 and DU145, and analyzed the related mechanisms. In the present study, we investigated the effects of treatment with SA prior to hyperthermia on the thermosensitivity of DU145 cells, and the mechanisms related to the induction of apoptosis and G(2)/M cell cycle arrest via the activation of extracellular-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, as well as the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. Cells were exposed to hyperthermia alone (40-44˚C) or hyperthermia in combination with SA. Lethal damage to cells treated with mild hyperthermia (40 or 42˚C) for up to 6 h was slight; however, hyperthermia in combination with SA synergistically enhanced thermosensivity. Lethal damage to cells treated with acute hyperthermia (43 or 44˚C) was more severe, but these effects were also enhanced and were more significant by the combined treatment with SA. The kinetics of apoptosis induction and cell cycle distribution were analyzed by flow cytometry. In addition, the levels of ERK1/2, JNK and Akt were determined by western blot analysis. The incidence of apoptotic cells after treatment with SA (20.0 µM) at 37˚C for 4 h, hyperthermia (44˚C) alone for 30 min, and the combination in sequence were examined. The sub-G1 division (%) in the diagram obtained by flow cytometry was applied to that assay. The percentage of apoptotic cells (10.53±5.02%) was higher at 48 h as compared to 0, 12 and 24 h after treatment. The distribution of DU145 cells in the G2/M cell cycle phase was markedly increased after 24 h of heating at 44˚C and after the combined treatment with heating and SA. The phosphorylation of ERK1/2 was reduced following treatment with heating and SA, while the levels of phosphorylated JNK (p-JNK) were markedly increased immediately after heating at 44˚C and when heating was combined with SA. By contrast, the levels of phosphorylated Akt (p-Akt) were immediately increased only after heating at 44˚C. Thus, we concluded that SA exerts its thermosensitizing effects on DU145 cells by inhibiting the activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1132,
                "text": "JNK"
            }
        },
        {
            "context": "Spread of epidemic MRSA-ST5-IV clone encoding PVL as a major cause of community onset staphylococcal infections in Argentinean children. BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus-(CA-MRSA) strains have emerged in Argentina. We investigated the clinical and molecular evolution of community-onset MRSA infections (CO-MRSA) in children of Córdoba, Argentina, 2005-2008. Additionally, data from 2007 were compared with the epidemiology of these infections in other regions of the country. METHODOLOGY/PRINCIPAL FINDINGS: Two datasets were used: i) lab-based prospective surveillance of CA-MRSA isolates from 3 Córdoba pediatric hospitals-(CBAH1-H3) in 2007-2008 (compared to previously published data of 2005) and ii) a sampling of CO-MRSA from a study involving both, healthcare-associated community-onset-(HACO) infections in children with risk-factors for healthcare-associated infections-(HRFs), and CA-MRSA infections in patients without HRFs detected in multiple centers of Argentina in 2007. Molecular typing was performed on the CA-MRSA-(n: 99) isolates from the CBAH1-H3-dataset and on the HACO-MRSA-(n: 51) and CA-MRSA-(n: 213) isolates from other regions. Between 2005-2008, the annual proportion of CA-MRSA/CA-S. aureus in Córdoba hospitals increased from 25% to 49%, P<0.01. Total CA-MRSA infections increased 3.6 fold-(5.1 to 18.6 cases/100,000 annual-visits, P<0.0001), associated with an important increase of invasive CA-MRSA infections-(8.5 fold). In all regions analyzed, a single genotype prevailed in both CA-MRSA (82%) and HACO-MRSA(57%), which showed pulsed-field-gel electrophoresis-(PFGE)-type-\"I\", sequence-type-5-(ST5), SCCmec-type-IVa, spa-t311, and was positive for PVL. The second clone, pulsotype-N/ST30/CC30/SCCmecIVc/t019/PVL(+), accounted for 11.5% of total CA-MRSA infections. Importantly, the first 4 isolates of Argentina belonging to South American-USA300 clone-(USA300/ST8/CC8/SCCmecIVc/t008/PVL(+)/ACME(-)) were detected. We also demonstrated that a HA-MRSA clone-(pulsotype-C/ST100/CC5) caused 2% and 10% of CA-MRSA and HACO-MRSA infections respectively and was associated with a SCCmec type closely related to SCCmecIV(2B&5). CONCLUSIONS/SIGNIFICANCE: The dissemination of epidemic MRSA clone, ST5-IV-PVL(+) was the main cause of increasing staphylococcal community-onset infections in Argentinean children (2003-2008), conversely to other countries. The predominance of this clone, which has capacity to express the h-VISA phenotype, in healthcare-associated community-onset cases suggests that it has infiltrated into hospital-settings.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 218,
                "text": "MRSA"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 0,
                "text": "INCA"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 23,
                "text": "tyr"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 370,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 554,
                "text": "Aurora A"
            }
        },
        {
            "context": "Mosaic evolution of rodent B1 elements. We have determined sequences of PCR-amplified B1 elements from hamster and rat (Myomorpha), chipmunk (Sciuromorpha), and guinea pig (Caviomorpha). Between three and six B1 subfamilies were found in these species. In the phylogenetic analysis B1 sequences of hamster, mouse, and rat clustered separately from those of chipmunk and those of guinea pig. This is consistent with an independent evolution of B1 elements in separate rodent lineages. We exclude the possibility of convergent mutations to explain certain diagnostic characters within the modern B1 quasi-dimers and view these elements as mosaic structures assembling preexisting mutations. Furthermore, the presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element.",
            "question": "From which sequence does the Alu repeat originate from?",
            "answers": {
                "answer_start": 839,
                "text": "7SL RNA"
            }
        },
        {
            "context": "Plants contain a high number of proteins showing sequence similarity to the animal SUV39H family of histone methyltransferases. The SET domain, first identified within and named after proteins encoded by three Drosophila genes [Su(var)3-9, E(z), and Trithorax], is recognized as a signature motif for histone methyltransferases that are involved in epigenetic processes. The SUV39H family of SET domain proteins methylate specifically the residue lysine 9 of histone H3, creating a code for gene silencing. This family of proteins contain at their C termini a unique catalytic domain consisting of pre-SET, SET, and post-SET domains. Sequence homology-based searches identified 15 Arabidopsis, 14 maize, and 12 rice proteins that can be assigned to the SUV39H family. These high numbers in plants are in marked contrast to the situation in animals, in which each species appears to contain only two to three proteins of this family. Our phylogenetic analyses revealed that plant proteins can be classified into seven orthology groups. Representative members of each group can be found in single plant species, suggesting that different group members are evolutionarily conserved to perform specific functions.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 132,
                "text": "SET domain"
            }
        },
        {
            "context": "Proteomic study on X-irradiation-responsive proteins and ageing: search for responsible proteins for radiation adaptive response. We investigated high- or low-dose irradiation-responsive proteins using proteomics on two-dimensional (2D) PAGE, and the effects of ageing on cell responses to radiation in variously aged rat astrocytes. After 5 Gy irradiation, the relative abundance of peroxiredoxin 2, an antioxidant enzyme, and latexin, an inhibitor of carboxypeptidase, increased. The induction of these proteins was suppressed by ageing, suggesting that the response to high-dose radiation decreased with ageing. The relative abundance of elongation factor 2 (EF-2) fragment increased 3 h and reduced 24 h after 0.1 Gy irradiation. Temporal enhancement of the EF-2 fragment due to low-dose irradiation was suppressed by ageing. Since radiation adaptive response in cultured astrocytes was observed 3 h but not 24 h after 0.1 Gy irradiation and suppressed by ageing as previously reported, alteration of the EF-2 fragment corresponded to the radiation adaptive response. We also examined phospho-protein profiles, resulting in the relative abundance of phospho-EF-1beta and phospho-beta-actin being altered by 0.1 Gy irradiation; however, ageing did not affect the alteration of phospho-EF-1beta and phospho-beta-actin, unlike the EF-2 fragment. The results suggested that the EF-2 fragment was a possible candidate for the protein responsible for the radiation adaptive response in cultured astrocytes.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 404,
                "text": "antioxidant"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 797,
                "text": "FSHD"
            }
        },
        {
            "context": "Regulation of lamp2a levels in the lysosomal membrane. The selective degradation of cytosolic proteins in lysosomes by chaperone-mediated autophagy depends, at least in part, on the levels of a substrate receptor at the lysosomal membrane. We have previously identified this receptor as the lysosome-associated membrane protein type 2a (lamp2a) and showed that levels of lamp2a at the lysosomal membrane directly correlate with the activity of the proteolytic pathway. Here we show that levels of lamp2a at the lysosomal membrane are mainly controlled by changes in its half-life and its distribution between the lysosomal membrane and the matrix. The lysosomal degradation of lamp2a requires the combined action of at least two different proteolytic activities at the lysosomal membrane. Lamp2a is released from the membrane by the action of these proteases, and then the truncated lamp2a is rapidly degraded within the lysosomal matrix. Membrane degradation of lamp2a is a regulated process that is inhibited in the presence of substrates for chaperone-mediated autophagy and under conditions that activate that type of autophagy. Uptake of substrate proteins also results in transport of some intact lamp2a from the lysosomal membrane into the matrix. This fraction of lamp2a can be reinserted back into the lysosomal membrane. The traffic of lamp2a through the lysosomal matrix is not mediated by vesicles, and lamp2a reinsertion requires the lysosomal membrane potential and protein components of the lysosomal membrane. The distribution of lamp2a between the lysosomal membrane and matrix is a dynamic process that contributes to the regulation of lysosomal membrane levels of lamp2a and consequently to the activity of the chaperone-mediated autophagic pathway.",
            "question": "Which is the receptor for substrates of Chaperone Mediated Autophagy?",
            "answers": {
                "answer_start": 337,
                "text": "lamp2a"
            }
        },
        {
            "context": "Probe-to-bone test for diagnosing diabetic foot osteomyelitis: reliable or relic? OBJECTIVE: We sought to assess the accuracy of the probe-to-bone (PTB) test in diagnosing foot osteomyelitis in a cohort of diabetic patients with bone culture proven disease. RESEARCH DESIGN AND METHODS: In this 2-year longitudinal cohort study, we enrolled 1,666 consecutive diabetic individuals who underwent an initial standardized detailed foot assessment, followed by examinations at regular intervals. Patients were instructed to immediately come to the foot clinic if they developed a lower-extremity complication. For all patients with a lower-extremity wound, we compared the results of the PTB test with those of a culture of the affected bone. We called PTB positive if the bone or joint was palpable and defined osteomyelitis as a positive bone culture. RESULTS: Over a mean of 27.2 months of follow-up, 247 patients developed a foot wound and 151 developed 199 foot infections. Osteomyelitis was found in 30 patients: 12% of those with a foot wound and 20% in those with a foot infection. When all wounds were considered, the PTB test was highly sensitive (0.87) and specific (0.91); the positive predictive value was only 0.57, but the negative predictive value was 0.98. CONCLUSIONS: The PTB test, when used in a population of diabetic patients with a foot wound among whom the prevalence of osteomyelitis was 12%, had a relatively low positive predictive value, but a negative test may exclude the diagnosis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 34,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "Development and validation of an RP-HPLC method for the quantitation of Orteronel (TAK-700), a CYP17A1 enzyme inhibitor, in rat plasma and its application to a pharmacokinetic study. A novel, simple, specific, sensitive and reproducible high-performance liquid chromatography assay method has been developed and validated for the estimation of Orteronel in rat plasma. The bioanalytical procedure involves extraction of Orteronel and phenacetin (internal standard) from rat plasma with a simple liquid-liquid extraction process. The chromatographic analysis was performed on a Waters Alliance system using a gradient mobile phase conditions at a flow rate of 1 mL/min and a C18 column maintained at ambient room temperature. The eluate was monitored using a photodiode array detector set at 242. Orteronel and internal standard eluted at 4.8 and 6.2 min, respectively and the total run time was 9 min. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 100-3149 ng/mL (r(2) = 0.995). The intra- and inter-day precisions were in the ranges of 0.31-7.87 and 3.97-6.35, respectively, in rat plasma. The validated HPLC method was successfully applied to a pharmacokinetic study of Orteronel in rats.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 95,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Effect of IL-18 binding protein on hepatic ischemia-reperfusion injury induced by infrarenal aortic occlusion. PURPOSE: Severe local and systemic tissue damage called ischemia/reperfusion (IR) injury occurs during the period of reperfusion. Free oxygen radicals and proinflammatory cytokines are responsible for reperfusion injury. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting. The present study aimed to investigate whether IL-18BP had a protective role in remote organ hepatic IR injury. METHODS: Wistar-Albino rats were divided into three groups that contained seven rats. Group I (sham): Laparotomy and infrarenal abdominal aorta (AA) dissection were done but no clamping was done. Group II (I/R): The infrarenal AA was clamped by atraumatic microvascular clamp for 30 minutes and then was exposed to 90 minutes of reperfusion. Group III (IR + IL-18BP): 75 µg/kg of IL-18BP in 0.9% saline (1 mL) was administered 30 minutes before infrarenal AA dissection and clamping; 30 minutes of ischemia was applied and then was exposed to 90 minutes of reperfusion. RESULTS: Serum AST, ALT, and LDH levels were remarkably higher in IR group and returned to normal levels in treatment group. The proinflammatory cytokine levels had decreased in treatment group, and was statistically significant compared with the IR group. Serum levels of total oxidant status and oxidative stress index decreased and levels of total antioxidant status increased by IL-18BP. CONCLUSION: This study suggested that IL-18BP has antioxidant, anti-inflammatory and hepatoprotective effects in cases of IR with infrarenal AA induced liver oxidative damage.",
            "question": "What is the role of IL-18BP?",
            "answers": {
                "answer_start": 332,
                "text": "IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting."
            }
        },
        {
            "context": "Tumor necrosis factor alpha activates transcription of the NADPH oxidase organizer 1 (NOXO1) gene and upregulates superoxide production in colon epithelial cells. NADPH oxidase 1 (Nox1) is a multicomponent enzyme consisting of p22(phox), Nox organizer 1 (NOXO1), Nox1 activator 1, and Rac1. Interleukin-1beta, flagellin, interferon-gamma, and tumor necrosis factor alpha (TNF-alpha) similarly induced Nox1 in a colon cancer cell line (T84), whereas only TNF-alpha fully induced NOXO1 and upregulated superoxide-producing activity by ninefold. This upregulation was canceled by knockdown of NOXO1 with small interfering RNAs. TNF-alpha rapidly phosphorylated p38 mitogen-activated protein kinase and c-Jun N-terminal kinase 1/2, followed by phosphorylation of c-Jun and c-Fos and appearance of an AP-1 binding activity within 30 min. We cloned the 5' flank of the human NOXO1 gene (-3888 to +263 bp), and found that the region between -585 and -452 bp, which contains consensus elements of YY-1, AP-1, and Ets, and the GC-rich region encoding three putative binding sites for SP-1, was crucial for TNF-alpha-dependent promoter activity. Serial mutation analysis of the elements identified an AP-1 binding site (from -561 to -551 bp, agtAAGtcatg) as a crucial element for TNF-alpha-stimulated transcription of the human NOXO1 gene, which was also confirmed by the AP-1 decoy experiments. Thus, TNF-alpha acts as a potent activator of Nox1-based oxidase in colon epithelial cells, suggesting a potential role of this oxidase in inflammation of the colon.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 263,
                "text": "Nox1"
            }
        },
        {
            "context": "Properties of human red cell spectrin heterodimer (side-to-side) assembly and identification of an essential nucleation site. The antiparallel side-to-side association of spectrin alpha and beta monomers is a two-step process which occurs in seconds even at 0 degrees C and at low concentrations. Assembly involves initial contact of complementary nucleation sites on each subunit, which are located near the actin binding end of the long, flexible heterodimer rod. The minimum nucleation sites are comprised of approximately four contiguous 106-residue homologous segments or repeats. Three repeats in the nucleation site contain an 8-residue insertion and have the highest homology to the four spectrin-like repeats in alpha-actinin. The adjacent actin binding domain on the beta subunit and the adjacent EF hand motifs on the alpha subunit are not required for heterodimer assembly. The nucleation sites probably have a specific lock and key structure which defines the unique side-to-side pairing of the many homologous segments in both subunits. Assembly of spectrin heterodimers is probably most analogous to a zipper. After initial nucleation site binding, the remainder of the subunits quickly associate along their full lengths to reconstitute a normal dimer by supercoiling around each other to form a rope-like, flexible rod. Assembly is terminated if either polypeptide is interrupted by a protease cleavage. Heterozygotic mutations involving either nucleation site are predicted to affect allele incorporation into the mature membrane skeleton.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 130,
                "text": "antiparallel"
            }
        },
        {
            "context": "Neural correlates of distraction in borderline personality disorder before and after dialectical behavior therapy. Neural underpinnings of emotion dysregulation in borderline personality disorder (BPD) are characterized by limbic hyperactivity and disturbed prefrontal activity. It is unknown whether neural correlates of emotion regulation change after a psychotherapy which has the goal to improve emotion dysregulation in BPD, such as dialectical behavioral therapy (DBT). We investigated distraction as a main emotion regulation strategy before and after DBT in female patients with BPD. Thirty-one BPD patients were instructed to either passively view or memorize letters before being confronted with negative or neutral pictures in a distraction task during functional magnetic resonance imaging. This paradigm was applied before and after a 12-week residential DBT-based treatment program. We compared the DBT group to 15 BPD control patients, who continued their usual, non-DBT-based treatment or did not have any treatment, and 22 healthy participants. Behaviorally, BPD groups and healthy participants did not differ significantly with respect to alterations over time. On the neural level, BPD patients who received DBT-based treatment showed an activity decrease in the right inferior parietal lobe/supramarginal gyrus during distraction from negative rather than neutral stimuli when compared to both control groups. This decrease was correlated with improvement in self-reported borderline symptom severity. DBT responders exhibited decreased right perigenual anterior cingulate activity when viewing negative (rather than neutral) pictures. In conclusion, our findings reveal changes in neural activity associated with distraction during emotion processing after DBT in patients with BPD. These changes point to lower emotional susceptibility during distraction after BPD symptom improvement.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 36,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 857,
                "text": "early"
            }
        },
        {
            "context": "Tumor necrosis factor alpha activates transcription of the NADPH oxidase organizer 1 (NOXO1) gene and upregulates superoxide production in colon epithelial cells. NADPH oxidase 1 (Nox1) is a multicomponent enzyme consisting of p22(phox), Nox organizer 1 (NOXO1), Nox1 activator 1, and Rac1. Interleukin-1beta, flagellin, interferon-gamma, and tumor necrosis factor alpha (TNF-alpha) similarly induced Nox1 in a colon cancer cell line (T84), whereas only TNF-alpha fully induced NOXO1 and upregulated superoxide-producing activity by ninefold. This upregulation was canceled by knockdown of NOXO1 with small interfering RNAs. TNF-alpha rapidly phosphorylated p38 mitogen-activated protein kinase and c-Jun N-terminal kinase 1/2, followed by phosphorylation of c-Jun and c-Fos and appearance of an AP-1 binding activity within 30 min. We cloned the 5' flank of the human NOXO1 gene (-3888 to +263 bp), and found that the region between -585 and -452 bp, which contains consensus elements of YY-1, AP-1, and Ets, and the GC-rich region encoding three putative binding sites for SP-1, was crucial for TNF-alpha-dependent promoter activity. Serial mutation analysis of the elements identified an AP-1 binding site (from -561 to -551 bp, agtAAGtcatg) as a crucial element for TNF-alpha-stimulated transcription of the human NOXO1 gene, which was also confirmed by the AP-1 decoy experiments. Thus, TNF-alpha acts as a potent activator of Nox1-based oxidase in colon epithelial cells, suggesting a potential role of this oxidase in inflammation of the colon.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 180,
                "text": "Nox1"
            }
        },
        {
            "context": "Demographics of the UK cystic fibrosis population: implications for neonatal screening. The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.",
            "question": "Which is the most common CFTR mutation in Caucasians?",
            "answers": {
                "answer_start": 948,
                "text": "deltaF508"
            }
        },
        {
            "context": "2-Arylbenzimidazoles as antiviral and antiproliferative agents. Part 1. Being involved in an anti-Flaviviridae Project, and because of the role played by benzimidazole derivatives as promising inhibitors of the HCV helicase and RNA polymerase, as well as of the Zn finger transcription factor, we synthesized a new series of 2-arylbenzimidazoles and evaluated them for antiviral activity, as well as for antiproliferative activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). Compounds 15, 28 and 29 resulted moderately active only against Yellow Fever Virus (a Flavivirus) (range 6-27 microM), whereas none of the title benzimidazoles showed any antiviral activity at concentrations not cytotoxic for the resting cell monolayers. Compounds were also tested for antiproliferative activity against a panel of exponentially growing cell lines derived from human haematological and solid tumors. Several new benzimidazoles turned out active. Among them, compound 27 was the most potent against human haematologic and solid tumor cells and turned out to be as potent as Etoposide and more potent than 6-mercaptopurine (6-MP), used as reference antitumor agents.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 524,
                "text": "three"
            }
        },
        {
            "context": "Paediatric investigation plans for pain: painfully slow! PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.",
            "question": "How many clinical trials for off-label drugs in neonates are cited in the literature.",
            "answers": {
                "answer_start": 455,
                "text": "0"
            }
        },
        {
            "context": "Rapamycin: something old, something new, sometimes borrowed and now renewed. The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus (rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and, although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 112,
                "text": "mTOR"
            }
        },
        {
            "context": "Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 \"Janus\" genetic variation. INTRODUCTION: Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the \"Janus gene\"). AIM: The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients. METHODS: RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2. RESULTS: A cohort of 118 patients with HSCR (n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified. CONCLUSION: Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1345,
                "text": "RET"
            }
        },
        {
            "context": "Battle of the eternal rivals: restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy. Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 333,
                "text": "p53"
            }
        },
        {
            "context": "Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1(G93A) rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNFα, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These novel observations suggest that microglial regional and phenotypic heterogeneity may be an important consideration when designing new therapeutic strategies targeting microglia and neuroinflammation in ALS.",
            "question": "Which type of cells is affected in Amyotrophic Lateral Sclerosis?",
            "answers": {
                "answer_start": 314,
                "text": "motor neurons"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 1655,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "[Manifestation of glucose-6-phosphate dehydrogenase deficiency caused by primaquine in malaria therapy]. This is a report about a 9 year old turkish boy suffering from recurrent episodes of high fever caused by Plasmodium vivax-infection (Malaria tertiana), 12 months after returning from his malarious homeland. After a 3-day course of Chloroquin, we administrated Primaquin to eliminate residual extraerythrocyte forms of Plasmodium vivax. On the 7th day of treatment acute haemolysis developped. This was caused by Glucose-6-Phosphate-Dehydrogenase-Deficiency, which could be demonstrated by a red-cell-enzyme analysis. The investigation of the patient's whole family showed the typical recessive X-linked inheritance of this enzyme-defect. Frequency and clinical manifestations of this defect are discussed.",
            "question": "What is the inheritance of the glucose-6-phosphate dehydrogenase (G6PD) deficiency?",
            "answers": {
                "answer_start": 690,
                "text": "recessive X-linked inheritance"
            }
        },
        {
            "context": "Stereotactic radiosurgery for intracranial dural arteriovenous fistulas: a systematic review. OBJECT: The goal of this study was to evaluate the obliteration rate of intracranial dural arteriovenous fistulas (DAVFs) in patients treated with stereotactic radiosurgery (SRS), and to compare obliteration rates between cavernous sinus (CS) and noncavernous sinus (NCS) DAVFs, and between DAVFs with and without cortical venous drainage (CVD). METHODS: A systematic literature review was performed using PubMed. The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. The DAVFs were also categorized by location and by the presence of CVD. Statistical analyses of pooled data were conducted to assess complete obliteration rates in CS and NCS DAVFs, and in DAVFs with and without CVD. RESULTS: Nineteen studies were included, comprising 729 patients harboring 743 DAVFs treated with SRS. The mean obliteration rate was 63% (95% CI 52.4%-73.6%). Complete obliteration for CS and NCS DAVFs was achieved in 73% and 58% of patients, respectively. No significant difference in obliteration rates between CS and NCS DAVFs was found (OR 1.72, 95% CI 0.66-4.46; p=0.27). Complete obliteration in DAVFs with and without CVD was observed in 56% and 75% of patients, respectively. A significantly higher obliteration rate was observed in DAVFs without CVD compared with DAVFs with CVD (OR 2.37, 95% CI 1.07-5.28; p=0.03). CONCLUSIONS: Treatment with SRS offers favorable rates of DAVF obliteration with low complication rates. Patients harboring DAVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using SRS.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 515,
                "text": "DAVF"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1336,
                "text": "XK"
            }
        },
        {
            "context": "Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 (FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 504,
                "text": "connective tissue"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome: a clinicoradiological amalgam. Dyke-Davidoff-Masson syndrome is a relatively rare syndrome with its typical clinical and radiological features including facial asymmetry, hemiplegia, cerebral hemiatrophy, mental retardation with calvarial thickening, hypertrophy of sinuses and elevated petrous ridge on imaging. We present here a case of congenital type Dyke-Davidoff-Masson syndrome with some additional features in the form of microcephaly, hypospadias and pachygyria.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 214,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 351,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 47,
                "text": "BRG1"
            }
        },
        {
            "context": "Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 878,
                "text": "L-dopa"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "Tyrosinase"
            }
        },
        {
            "context": "S phase-dependent interaction with DNMT1 dictates the role of UHRF1 but not UHRF2 in DNA methylation maintenance. Recent studies demonstrate that UHRF1 is required for DNA methylation maintenance by targeting DNMT1 to DNA replication foci, presumably through its unique hemi-methylated DNA-binding activity and interaction with DNMT1. UHRF2, another member of the UHRF family proteins, is highly similar to UHRF1 in both sequence and structure, raising questions about its role in DNA methylation. In this study, we demonstrate that, like UHRF1, UHRF2 also binds preferentially to methylated histone H3 lysine 9 (H3K9) through its conserved tudor domain and hemi-methylated DNA through the SET and Ring associated domain. Like UHRF1, UHRF2 is enriched in pericentric heterochromatin. The heterochromatin localization depends to large extent on its methylated H3K9-binding activity and to less extent on its methylated DNA-binding activity. Coimmunoprecipitation experiments demonstrate that both UHRF1 and UHRF2 interact with DNMT1, DNMT3a, DNMT3b and G9a. Despite all these conserved functions, we find that UHRF2 is not able to rescue the DNA methylation defect in Uhrf1 null mouse embryonic stem cells. This can be attributed to the inability for UHRF2 to recruit DNMT1 to replication foci during S phase of the cell cycle. Indeed, we find that while UHRF1 interacts with DNMT1 in an S phase-dependent manner in cells, UHRF2 does not. Thus, our study demonstrates that UHRF2 and UHRF1 are not functionally redundant in DNA methylation maintenance and reveals the cell-cycle-dependent interaction between UHRF1 and DNMT1 as a key regulatory mechanism targeting DNMT1 for DNA methylation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 209,
                "text": "DNMT1"
            }
        },
        {
            "context": "Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome's epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells.",
            "question": "Do A-type lamins bind euchromatin or heterochromatin?",
            "answers": {
                "answer_start": 790,
                "text": "both euchromatin and heterochromatin"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 613,
                "text": "SERCA"
            }
        },
        {
            "context": "The natural history of myoclonic astatic epilepsy (Doose syndrome) and Lennox-Gastaut syndrome. The purpose of this article is to present a short review of the natural history of myoclonic astatic epilepsy (MAE; Doose syndrome) and the Lennox-Gastaut syndrome (LGS). In the 1989 classification of the International League Against Epilepsy (ILAE, 1989), MAE and LGS were initially included in group 2.2: \"Cryptogenic or symptomatic generalized epilepsies and syndromes.\" The subsequent classification of the Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy (see Ref. 8) placed MAE in axis 3 in the \"generalized epilepsy\" group and LGS, severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and atypical benign partial epilepsy/pseudo-Lennox syndrome (ABPE/PLS) in the \"epileptic encephalopathy\" group. The semiology of MAE and LGS and their differential diagnosis from SMEI and ABPE/PLS are described. Before the onset of SMEI, MAE, and ABPE/PLS, the development of the child is usually normal. In contrast, in LGS, development is frequently retarded at the onset, depending on the etiopathogenesis of the underlying brain disease. The course of MAE is highly variable with regard to seizure outcome (complete remission in some cases, persistent epilepsy in others) and cognitive development (normal or delayed). The course of LGS and SMEI is generally poor, both with regard to the epilepsy and to the cognitive development whereas the course and seizure outcome of ABPE/PLS is favorable; the patients will be seizure-free at puberty. However, the neuropsychological outcome is less favorable; most patients remain mentally retarded.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 179,
                "text": "myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "A Study to Determine if Addition of Palatal Petechiae to Centor Criteria Adds More Significance to Clinical Diagnosis of Acute Strep Pharyngitis in Children. Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 2142,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. Necrobiosis lipoidica (NL) is a rare chronic granulomatous disease that has historically been associated with diabetes mellitus. Debate exists regarding the etiology and pathogenesis of NL with a widely accepted theory that microangiopathy plays a significant role. NL typically presents clinically as erythematous papules on the front of the lower extremities that can coalesce to form atrophic telangiectatic plaques. NL is usually a clinical diagnosis, but if the clinical suspicion is uncertain, skin biopsy specimen can help differentiate it from sarcoidosis, necrobiotic xanthogranuloma, and granuloma annulare. NL is a difficult disease to manage despite a large armamentarium of treatment options that include topical and intralesional corticosteroids, immunomodulators, biologics, platelet inhibitors, phototherapy, and surgery. Randomized control trials are lacking to evaluate the many treatment methods and establish a standard regimen of care. Disease complications such as ulceration are common, and lesions should also be monitored for transition to squamous cell carcinoma, a less common sequelae.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 199,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 749,
                "text": "ADAR"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 456,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Apixaban: a new factor Xa inhibitor for stroke prevention in patients with nonvalvular atrial fibrillation. Atrial fibrillation (AF) is an independent risk factor for ischemic stroke occurrence, severity, recurrence, and mortality. Anticoagulation therapy for the prevention of thromboembolism is critical in patients with AF who are at risk of stroke. Warfarin has been an efficacious anticoagulant for this purpose, but its use has been limited by frequent laboratory monitoring, drug interactions, unpredictable individual response, delayed onset of action, and bleeding. Apixaban is the second oral direct selective factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with nonvalvular AF. It was significantly better than aspirin in reducing stroke (ischemic or hemorrhagic) or systemic embolism without increasing the risk of major bleeding in patients with AF who were at increased risk of stroke and for whom warfarin was unsuitable. In a randomized, double-blind trial that was originally designed to test for noninferiority, apixaban was superior to warfarin (target international normalized ratio 2-3) in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF. Apixaban has a half-life of about 12 hours, and the normal dosage is 5 mg orally twice daily. However, it may be reduced to 2.5 mg twice daily based on individual factors of the patient (age, renal function, and body weight) and the concomitant use of potent dual inhibitors of cytochrome P450 3A4 and P-glycoprotein. Similar to other novel oral anticoagulants (dabigatran and rivaroxaban), apixaban has no reversal agent for its anticoagulant effect. Overall, apixaban is a safe and efficacious alternative for stroke prophylaxis in high-risk patients who have AF and who are unable to achieve therapeutic goals with warfarin therapy.",
            "question": "What is the drug target for Eliquis (Apixaban)?",
            "answers": {
                "answer_start": 620,
                "text": "factor Xa"
            }
        },
        {
            "context": "Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use).",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 318,
                "text": "Naloxone"
            }
        },
        {
            "context": "Estrogen attenuates lipopolysaccharide-induced nitric oxide production in macrophages partially via the nongenomic pathway. Steroid hormones exert genotropic effects through members of the nuclear hormone receptor family. In the present study, we examined the effects of 17β-estradiol (E2) on nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation and investigated the mechanisms in mouse bone marrow-derived macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2 inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen, we found that the increase in NO production induced by LPS was also attenuated. In addition, the intracellular estrogen receptor blocker, ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated NO production capacity. E2 also attenuated the LPS activation of p38 mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB 203580, greatly reduced the LPS-induced NO production, and the remaining NO levels were no longer regulated by E2. Additionally, E2-BSA inhibited LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover, E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially antagonized by ICI 182780. Taken together, these results suggest that E2 has an inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects are mediated at least in part via a nongenomic pathway.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1080,
                "text": "c-Jun NH2-terminal kinase"
            }
        },
        {
            "context": "Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients. OBJECTIVE: To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients. METHODS: Twenty RA patients were treated with rituximab (cohort 1). Clinical response was defined as a decrease in the Disease Activity Score evaluated in 28 joints (DAS28) and as a response according to the European League Against Rheumatism (EULAR) criteria at week 12 and week 24. The presence of an IFN signature was analyzed in peripheral blood mononuclear cells by measuring the expression levels of 3 IFN response genes by quantitative polymerase chain reaction analysis. After comparison with the findings in healthy controls, patients were classified as having an IFN high or an IFN low signature. The data were confirmed in a second independent cohort (n = 31). Serum IFNα bioactivity was analyzed using a reporter assay. RESULTS: In cohort 1, there was a better clinical response to rituximab in the IFN low signature group. Consistent with these findings, patients with an IFN low signature had a significantly greater reduction in the DAS28 and more often achieved a EULAR response at weeks 12 and 24 as compared with the patients with an IFN high signature in cohort 2 versus cohort 1. The pooled data showed a significantly stronger decrease in the DAS28 in IFN low signature patients at weeks 12 and 24 as compared with the IFN high signature group and a more frequent EULAR response at week 12. Accordingly, serum IFNα bioactivity at baseline was inversely associated with the clinical response, although this result did not reach statistical significance. CONCLUSION: The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. This finding supports the notion that IFN signaling plays a role in the immunopathology of RA.",
            "question": "Which is the most common gene signature in Rheumatoid Arthritis patients?",
            "answers": {
                "answer_start": 32,
                "text": "interferon signature"
            }
        },
        {
            "context": "Analysis of the intracellular localization of p73 N-terminal protein isoforms TAp73 and ∆Np73 in medulloblastoma cell lines. The protein homologous to the tumor suppressor p53, p73, has essential roles in development and tumorigenesis. This protein exists in a wide range of isoforms with different, even antagonistic, functions. However, there are virtually no detailed morphological studies analyzing the endogenous expression of p73 isoforms at the cellular level in cancer cells. In this study, we investigated the expression and subcellular distribution of two N-terminal isoforms, TAp73 and ΔNp73, in medulloblastoma cells using immunofluorescence microscopy. Both proteins were observed in all cell lines examined, but differences were noted in their intracellular localization between the reference Daoy cell line and four newly established medulloblastoma cell lines (MBL-03, MBL-06, MBL-07 and MBL-10). In the new cell lines, TAp73 and ΔNp73 were located predominantly in cell nuclei. However, there was heterogeneity in TAp73 distribution in the cells of all MBL cell lines, with the protein located in the nucleus and also in a limited non-random area in the cytoplasm. In a small percentage of cells, we detected cytoplasmic localization of TAp73 only, i.e., nuclear exclusion was observed. Our results provide a basis for future studies on the causes and function of distinct intracellular localization of p73 protein isoforms with respect to different protein-protein interactions in medulloblastoma cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 600,
                "text": "7"
            }
        },
        {
            "context": "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in > 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 10,
                "text": "CD38"
            }
        },
        {
            "context": "Maintenance DNA methyltransferase (Met1) and silencing of CpG-methylated foreign DNA in Volvox carteri. DNA methylation plays an important role in the gene-silencing network of higher eukaryotes. We have analyzed the 21.5-kb maintenance methyltransferase (M-MTase) gene, met1, of the multicellular green alga Volvox carteri. The met1 transcript was detected only during the period when DNA replication and cell division are taking place. It encodes a 238 kDa protein containing eight C-terminal activity domains typical of M-MTases, plus upstream DNA-binding domains including the ProDom domain PD003757, which experimental analyses in animal systems have indicated is required for targeting the enzyme to DNA-replication foci. Several insertions of unknown function make Volvox Met1 the largest known member of the Met1/Dnmt1 family. Here we also show that several endogenous transposon families are CpG-methylated in Volvox, which we think causes them to be inactive. This view is supported by the observation that an in vitro CpG-methylated gene introduced into Volvox was maintained in the methylated and silent state over >100 generations. Thus, we believe that Met1 recognizes and perpetuates the in vitro methylation signal, and that the silencing machinery is then able to transduce such a methylation-only signal into a stable heterochromatic (and silent) state.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 271,
                "text": "met1"
            }
        },
        {
            "context": "Genomic context analysis reveals dense interaction network between vertebrate ultraconserved non-coding elements. MOTIVATION: Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic. RESULTS: In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online and at http://ccg.vital-it.ch/ucne/",
            "question": "How are ultraconserved elements called when they form clusters?",
            "answers": {
                "answer_start": 488,
                "text": "gene regulatory blocks (GRBs)"
            }
        },
        {
            "context": "[Genetics of Gaucher's disease. Genotype-phenotype correlation]. Gaucher's disease (GD) results from a deficiency of the lysosomal enzyme glucocerebrosidase and, in very rare occasions, a deficiency of its activator, the saposin C. The complexity of identification and characterization of mutations in the gene of glucocerebrosidase (GBA1) is caused by a great amount of mutated alleles, the existence of a highly homologous pseudogene and its location in a very rich zone in genes, which promotes the presence of complex alleles. Although genotype-phenotype correlations in EG are not completely established, there are a series of generalities, as the mutation c.1226A>G (N370S) is often associated with a certain degree of neuroprotection and the homozygosity for the c.1448T>C (L444P) mutation presents with neurological symptoms.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 138,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "The dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1, enhances protective cell-mediated immunity to murine malaria. Cell-mediated immunity plays a crucial role in the control of many infectious diseases, necessitating the need for adjuvants that can augment cellular immune responses elicited by vaccines. It is well established that protection against one such disease, malaria, requires strong CD8(+) T cell responses targeted against the liver stages of the causative agent, Plasmodium spp. In this report we show that the dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1 (DC-CK1), which is produced in humans and acts on naive lymphocytes, can enhance Ag-specific CD8(+) T cell responses when coadministered with either irradiated Plasmodium yoelii sporozoites or a recombinant adenovirus expressing the P. yoelii circumsporozoite protein in mice. We further show that these enhanced T cell responses result in increased protection to malaria in immunized mice challenged with live P. yoelii sporozoites, revealing an adjuvant activity for DC-CK1. DC-CK1 appears to act preferentially on naive mouse lymphocytes, and its adjuvant effect requires IL-12, but not IFN-gamma or CD40. Overall, our results show for the first time an in vivo role for DC-CK1 in the establishment of primary T cell responses and indicate the potential of this chemokine as an adjuvant for vaccines against malaria as well as other diseases in which cellular immune responses are important.",
            "question": "Which is the causative agent of malaria?",
            "answers": {
                "answer_start": 502,
                "text": "Plasmodium spp."
            }
        },
        {
            "context": "Hereditary conjugated hyperbilirubinaemia: 37 years later. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 636,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 960,
                "text": "xa"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 146,
                "text": "TYR"
            }
        },
        {
            "context": "Spinal hematoma: a literature survey with meta-analysis of 613 patients. Spinal hematoma has been described in autopsies since 1682 and as a clinical diagnosis since 1867. It is a rare and usually severe neurological disorder that, without adequate treatment, often leads to death or permanent neurological deficit. Epidural as well as subdural and subarachnoid hematomas have been investigated. Some cases of subarachnoid spinal hematoma may present with symptoms similar to those of cerebral hemorrhage. The literature offers no reliable estimates of the incidence of spinal hematoma, perhaps due to the rarity of this disorder. In the present work, 613 case studies published between 1826 and 1996 have been evaluated, which represents the largest review on this topic to date. Most cases of spinal hematoma have a multifactorial etiology whose individual components are not all understood in detail. In up to a third of cases (29.7%) of spinal hematoma, no etiological factor can be identified as the cause of the bleeding. Following idiopathic spinal hematoma, cases related to anticoagulant therapy and vascular malformations represent the second and third most common categories. Spinal and epidural anesthetic procedures in combination with anticoagulant therapy represent the fifth most common etiological group and spinal and epidural anesthetic procedures alone represent the tenth most common cause of spinal hematoma. Anticoagulant therapy alone probably does not trigger spinal hemorrhage. It is likely that there must additionally be a \"locus minoris resistentiae\" together with increased pressure in the interior vertebral venous plexus in order to cause spinal hemorrhage. The latter two factors are thought to be sufficient to cause spontaneous spinal hematoma. Physicians should require strict indications for the use of spinal anesthetic procedures in patients receiving anticoagulant therapy, even if the incidence of spinal hematoma following this combination is low. If spinal anesthetic procedures are performed before, during, or after anticoagulant treatment, close monitoring of the neurological status of the patient is warranted. Time limits regarding the use of anticoagulant therapy before or after spinal anesthetic procedures have been proposed and are thought to be safe for patients. Investigation of the coagulation status alone does not necessarily provide an accurate estimate of the risk of hemorrhage. The most important measure for recognizing patients at high risk is a thorough clinical history. Most spinal hematomas are localized dorsally to the spinal cord at the level of the cervicothoracic and thoracolumbar regions. Subarachnoid hematomas can extend along the entire length of the subarachnoid space. Epidural and subdural spinal hematoma present with intense, knife-like pain at the location of the hemorrhage (\"coup de poignard\") that may be followed in some cases by a pain-free interval of minutes to days, after which there is progressive paralysis below the affected spinal level. Subarachnoid hematoma can be associated with meningitis symptoms, disturbances of consciousness, and epileptic seizures and is often misdiagnosed as cerebral hemorrhage based on these symptoms. Most patients are between 55 and 70 years old. Of all patients with spinal hemorrhage, 63.9% are men. The examination of first choice is magnetic resonance imaging. The treatment of choice is surgical decompression. Of the patients investigated in the present work, 39.6% experienced complete recovery. The less severe the preoperative symptoms are and the more quickly surgical decompression can be performed, the better are the chances for complete recovery. It is therefore essential to recognize the relatively typical clinical presentation of spinal hematoma in a timely manner to allow correct diagnostic and therapeutic measures to be taken to maximize the patient's chance of complete recovery.",
            "question": "What drug treatment can cause a spinal epidural hematoma?",
            "answers": {
                "answer_start": 1249,
                "text": "anticoagulant therapy"
            }
        },
        {
            "context": "New patterns of methicillin-resistant Staphylococcus aureus (MRSA) clones, community-associated MRSA genotypes behave like healthcare-associated MRSA genotypes within hospitals, Argentina. Methicillin-resistant Staphylococcus aureus (MRSA) burden is increasing worldwide in hospitals [healthcare-associated (HA)-MRSA] and in communities [community-associated (CA)-MRSA]. However, the impact of CA-MRSA within hospitals remains limited, particularly in Latin America. A countrywide representative survey of S. aureus infections was performed in Argentina by analyzing 591 clinical isolates from 66 hospitals in a prospective cross-sectional, multicenter study (Nov-2009). This work involved healthcare-onset infections-(HAHO, >48 hospitalization hours) and community-onset (CO) infections [including both, infections (HACO) in patients with healthcare-associated risk-factors (HRFs) and infections (CACO) in those without HRFs]. MRSA strains were genetically typed as CA-MRSA and HA-MRSA genotypes (CA-MRSAG and HA-MRSAG) by SCCmec- and spa-typing, PFGE, MLST and virulence genes profile by PCR. Considering all isolates, 63% were from CO-infections and 55% were MRSA [39% CA-MRSAG and 16% HA-MRSAG]. A significantly higher MRSA proportion among CO- than HAHO-S. aureus infections was detected (58% vs 49%); mainly in children (62% vs 43%). The CA-MRSAG/HA-MRSAG have accounted for 16%/33% of HAHO-, 39%/13% of HACO- and 60.5%/0% of CACO-infections. Regarding the epidemiological associations identified in multivariate models for patients with healthcare-onset CA-MRSAG infections, CA-MRSAG behave like HA-MRSAG within hospitals but children were the highest risk group for healthcare-onset CA-MRSAG infections. Most CA-MRSAG belonged to two major clones: PFGE-type N-ST30-SCCmecIVc-t019-PVL(+) and PFGE-type I-ST5-IV-SCCmecIVa-t311-PVL(+) (45% each). The ST5-IV-PVL(+)/ST30-IV-PVL(+) clones have caused 31%/33% of all infections, 20%/4% of HAHO-, 43%/23% of HACO- and 35%/60% of CACO- infections, with significant differences by age groups (children/adults) and geographical regions. Importantly, an isolate belonging to USA300-0114-(ST8-SCCmecIVa-spat008-PVL(+)-ACME(+)) was detected for the first time in Argentina. Most of HA-MRSAG (66%) were related to the Cordobes/Chilean clone-(PFGE-type A-ST5-SCCmecI-t149) causing 18% of all infections (47% of HAHO- and 13% of HACO-infections). Results strongly suggest that the CA-MRSA clone ST5-IV-PVL(+) has begun to spread within hospitals, replacing the traditional Cordobes/Chilean-HA-MRSA clone ST5-I-PVL(-), mainly in children. Importantly, a growing MRSA reservoir in the community was associated with spreading of two CA-MRSA clones: ST5-IV-PVL(+), mainly in children with HRFs, and ST30-IV-PVL(+) in adults without HRFs. This is the first nationwide study in Argentina providing information about the molecular and clinical epidemiology of CA-MRSA, particularly within hospitals, which is essential for designing effective control measures in this country and worldwide.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 61,
                "text": "MRSA"
            }
        },
        {
            "context": "Role of terminal nonhomologous domains in initiation of human red cell spectrin dimerization. Human erythrocyte spectrin is an antiparallel heterodimer comprised of a 280 kDa alpha subunit and a 246 kDa beta subunit which further associates into tetramers in the red cell membrane cytoskeleton. Lateral association of the flexible rodlike monomers involves a multiple-step process that is initiated by a high affinity association near the actin-binding end of the molecule (dimer nucleation site). In this study, recombinant alpha and beta proteins comprising two or four \"spectrin type\" motifs with and without adjacent, terminal nonhomologous domains were evaluated for their relative contributions to dimer initiation, and the thermodynamic properties of these heterodimer complexes were measured. Sedimentation equilibrium studies showed that in the absence of the heterologous subunit, individual recombinant proteins formed weak homodimers (K(d) > 0.3 mM). When 2-motif (alpha20-21 and beta1-2) and 4-motif (alpha18-21 and beta1-4) recombinants lacking the terminal nonhomologous domains were paired with the complementary protein, high affinity heterodimers were formed in sedimentation equilibrium analysis. Both the alpha20-21/beta1-2 complex and the alpha20-21EF/betaABD1-2 complex showed stoichiometric binding with similar binding affinities (K(d) approximately 10 nM) using isothermal titration calorimetry. The alpha20-21/beta1-2 complex showed an enthalpy of -10 kcal/mol, while the alpha20-21EF/betaABD1-2 complex showed an enthalpy of -13 kcal/mol. Pull-down assays using alpha spectrin GST fusion proteins showed strong associations between all heterodimer complexes in physiological buffer, but all heterodimer complexes were destabilized by the presence of Triton X-100 and other detergents. Complexes lacking the nonhomologous domains were destabilized to a greater extent than complexes that included the nonhomologous domains. The detergent effect appears to be responsible for the apparent essential role of the nonhomologous domains in prior reports. Taken together, our results indicate that the terminal nonhomologous domains do not contribute to dimer initiation nor are they required for formation of high affinity spectrin heterodimers in physiological buffers.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 127,
                "text": "antiparallel"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L.) 11. Molecular cloning and expression of alfalfa isoflavone reductase, a key enzyme of isoflavonoid phytoalexin biosynthesis. The major phytoalexin in alfalfa is the isoflavonoid (-)-medicarpin (or 6aR, 11aR)-medicarpin. Isoflavone reductase (IFR), the penultimate enzyme in medicarpin biosynthesis, is responsible for introducing one of two chiral centers in (-)-medicarpin. We have isolated a 1.18 kb alfalfa cDNA (pIFRalf1) which, when expressed in Escherichia coli, converts 2'-hydroxyformononetin stereospecifically to (3R)-vestitone, as would be predicted for IFR from alfalfa. The calculated molecular weight of the polypeptide (35,400) derived from the 954 bp open reading frame compares favorably to estimated Mrs determined for IFR proteins purified from other legumes. The transcript (1.4 kb) is highly induced in elicited alfalfa cell cultures. The kinetics of induction are consistent with the appearance of IFR activity, the accumulation of medicarpin, and the observed induction of other enzymes in the pathway. Low levels of IFR transcripts were found in healthy plant parts (roots and nodules) which accumulate low levels of a medicarpin glucoside. IFR appears to be encoded by a single gene in alfalfa. The cloning of IFR opens up the possibility of genetic manipulation of phytoalexin biosynthesis in alfalfa by altering isoflavonoid stereochemistry.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 231,
                "text": "medicarpin"
            }
        },
        {
            "context": "Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family? AIM: to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. METHODS: this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. RESULTS: during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. CONCLUSION: the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 133,
                "text": "MRSA"
            }
        },
        {
            "context": "2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine. Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is involved in the regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which include several subtypes (4). There are three receptor subtypes within the G-protein–coupled 5-HT2 receptor family: 5-HT2A, 5-HT2B, and 5-HT2C. 5-HT2A receptors are abundantly present in the cerebral cortex, basal forebrain, hippocampus, amygdala, dorsal thalamus, hypothalamus, superior colliculus, substantia nigra, pedunculopontine nucleus, legmental area, and myelencephalon (5). 5-HT2A receptors are involved in mediation of normal and psychotic states, working memory, regulation of GABAergic and cholinergic neuronal cells, sleep, peripheral pain, and cardiovascular functions. 5-HT2B receptors are found mainly in several peripheral tissues, such as the stomach, intestine, pulmonary smooth muscle, and myocardium. In the brain, 5-HT2B receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT2C receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT2A receptors are implicated in several psychiatric disorders, such as schizophrenia, depression, and obsessive-compulsive disorder. Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT2A receptors. There have been several studies to develop specific 5-HT2A radioligands, such as [11C]ketanserin (6), [18F]spiperone (7), [11C]methylspiperone ([11C]NMSP), and [18F]setoperone [PubMed], for positron emission tomography (8) imaging. However, none of these ligands has proven to be specific for 5-HT2A receptors because these compounds also bind to other receptors, such as dopamine receptors and the 5-HT1 receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent antagonist of 5-HT2A receptors with >100-fold selectivity over D2/3 receptors, 5-HT1A, 5-HT6, and 5-HT7 (9, 10). This led to the development of 3-{2-[4-(4-[18F]fluorobenzoyl)-1-piperidyl]ethyl}-2-sulfanyl-3H-quinazolin-4-one ([18F]altanserin) as a useful tool for 5-HT2A receptor PET imaging in vivo (11). 5-HT2A antagonists bind to the total pool of receptors, whereas 5-HT2A agonists bind only to the high-affinity functional state of the receptor but may be more important in disease states because the high affinity sites are the ones that transmit the intracellular signals. Furthermore, 2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine ([11C]CIMBI-5), a potent and selective 5-HT2A agonist, has been shown to have similar cortical binding potentials as compared with [18F]altanserin in the pigs using the simplified reference tissue model (12). 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine ([11C]CIMBI-36), a bromo analog of [11C]CIMBI-5, has also been developed as a tool for studying 5-HT2A agonist binding in the brain (13).",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2424,
                "text": "5-HT2A"
            }
        },
        {
            "context": "A yeast functional screen predicts new candidate ALS disease genes. Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.",
            "question": "Which domain allowing self-association do exist in TDP-43 and FUS proteins?",
            "answers": {
                "answer_start": 245,
                "text": "prion-like domain"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 579,
                "text": "malaria"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 805,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat. Using a rat model of L-DOPA-induced dyskinesia (LID), the contributions of dopamine D1 and D2 receptors to axial, limb, and orolingual (ALO) abnormal involuntary movements (AIMs) elicited by L-DOPA were examined. Chronic L-DOPA-treated rats received the D1 receptor antagonist SCH23390 (0.01, 0.1, and 1.0 mg/kg; i.p.), the D2 receptor antagonist Eticlopride (0.01, 0.1, and 1.0 mg/kg; i.p.), a mixture of both antagonists (0.01, 0.1, 1.0 mg/kg each; i.p.), or vehicle 30 min prior to L-DOPA (6 mg/kg; i.p.)+Benserazide (15 mg/kg; i.p.). SCH23390 (0.1 and 1.0 mg/kg) significantly reduced axial and limb AIMs, while the same doses of Eticlopride significantly decreased axial, limb, and orolingual AIMs. Co-administration of SCH23390+Eticlopride significantly reduced axial (0.01, 0.1 and 1.0 mg/kg), limb (0.1 and 1.0 mg/kg), and orolingual (0.1 and 1.0 mg/kg) AIMs. These results indicate the importance of D1 and D2 receptors to LID and further validate the rat AIMs model.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 586,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Massively parallel sequencing reveals an accumulation of de novo mutations and an activating mutation of LPAR1 in a patient with metastatic neuroblastoma. Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations.",
            "question": "Are most driver gene mutations synonymous or non-synonymous?",
            "answers": {
                "answer_start": 926,
                "text": "non-synonymous"
            }
        },
        {
            "context": "The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation. Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here, we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2, and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 55,
                "text": "FOXP2"
            }
        },
        {
            "context": "Multiple Myeloma Gets Three New Drugs. In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 146,
                "text": "proteasome"
            }
        },
        {
            "context": "Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 47,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Stress Responses in Alfalfa (Medicago sativa L.): I. Induction of Phenylpropanoid Biosynthesis and Hydrolytic Enzymes in Elicitor-Treated Cell Suspension Cultures. Alfalfa (Medicago sativa L.) cell suspension cultures accumulated high concentrations of the pterocarpan phytoalexin medicarpin, reaching a maximum within 24 hours after exposure to an elicitor preparation from cell walls of the phytopathogenic fungus Colletotrichum lindemuthianum. This was preceded by increases in the extractable activities of the isoflavonoid biosynthetic enzymes l-phenylalanine ammonia-lyase, cinnamic acid 4-hydroxylase, 4-coumarate coenzyme A-ligase, chalcone synthase, chalcone isomerase, and isoflavone O-methyltransferase. Pectic polysaccharides were weak elicitors of phenylalanine ammonia-lyase activity but did not induce medicarpin accumulation, whereas reduced glutathione was totally inactive as an elicitor in this system. The fungal cell wall extract was a weak elicitor of the lignin biosynthetic enzymes, caffeic acid O-methyltransferase and coniferyl alcohol dehydrogenase, but did not induce appreciable increases in the activities of the hydrolytic enzymes chitinase and 1,3-beta-d-glucanase. The results are discussed in relation to the activation of isoflavonoid biosynthesis in other legumes and the development of the alfalfa cell culture system as a model for studying the enzymology and molecular biology of plant defense expression.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 281,
                "text": "medicarpin"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 1010,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the \"vicious cycle\" of bone destruction induced by these cells.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1507,
                "text": "RANKL"
            }
        },
        {
            "context": "The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 302,
                "text": "EGFR"
            }
        },
        {
            "context": "Expression characteristics of the SUMOylation genes SUMO-1 and Ubc9 in the developing testis and ovary of Chinese mitten crab, Eriocheir sinensis. The small ubiquitin-like modifier (SUMO) pathway in eukaryotes is an essential post-translational modification required for a variety of cellular processes, development and organelle biogenesis. SUMO-conjugating enzyme (Ubc9) is an important conjunction enzyme in the SUMO pathway. SUMO-1 and Ubc9 have been found in vertebrates; however, their expression in crustaceans was poorly characterized. In this study, the SUMO-1 and Ubc9 genes were identified in the developing testis and ovary of Chinese mitten crab, Eriocheir sinensis, and designated EsSUMO-1 and EsUbc9, respectively. Quantitative real-time PCR demonstrated the expression level of both mRNAs varied significantly during testis and ovary development. In the testis, EsSUMO-1 and EsUbc9 were expressed at moderate levels in stage II-1, increased at stage II-2, and then gradually declined in stage IV. In the ovary, EsSUMO-1 and EsUbc9 expression were low in the early stage, reach the highest level at stage III-2, and then gradually decreased in stage IV. Transcripts from both genes were detected using in situ hybridization throughout the testis and ovary, in the spermatids and oocytes. The pattern of EsSUMO-1 and EsUbc9 expression in the testis and ovary suggests that SUMOylation may play an important role in spermatogenesis and oogenesis in E. sinensis.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 342,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "Rare causes of dystonia parkinsonism. The list of genetic causes of syndromes of dystonia parkinsonism grows constantly. As a consequence, the diagnosis becomes more and more challenging for the clinician. Here, we summarize the important causes of dystonia parkinsonism including autosomal-dominant, recessive, and x-linked forms. We cover dopa-responsive dystonia, Wilson's disease, Parkin-, PINK1-, and DJ-1-associated parkinsonism (PARK2, 6, and 7), x-linked dystonia-parkinsonism/Lubag (DYT3), rapid-onset dystonia-parkinsonism (DYT12) and DYT16 dystonia, the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) including pantothenate kinase (PANK2)- and PLA2G6 (PARK14)-associated neurodegeneration, neuroferritinopathy, Kufor-Rakeb disease (PARK9) and the recently described SENDA syndrome; FBXO7-associated neurodegeneration (PARK15), autosomal-recessive spastic paraplegia with a thin corpus callosum (SPG11), and dystonia parkinsonism due to mutations in the SLC6A3 gene encoding the dopamine transporter. They have in common that in all these syndromes there may be a combination of dystonic and parkinsonian features, which may be complicated by pyramidal tract involvement. The aim of this review is to familiarize the clinician with the phenotypes of these disorders.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 454,
                "text": "x-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 155,
                "text": "orbit"
            }
        },
        {
            "context": "A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia. Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 119,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "[Early detection of color blindness from the viewpoint of occupational medicine with various references to internistic and human genetic symptom complexes]. Vision screening tests within the limits of industrial medicine examinations, together with physical examinations, were done on human individuals by means of pseudo-isochromatic charts in order to detect \"red-green blindness\". The tests were carried out on 1589 individuals (males and females) from 10 medium-scale plants of the Saarbrücken area (Federal Republic of Germany). The results obtained from male individuals by 919 Ishihara-tests were only considered, categorized and graphically represented according to their age groups. The data have been collected from the cases examined mostly between the years 1976 to 1977. About 1500 cases were examined per year. Because the samples were not selected at random, one has to be cautious with regard to the statistical interpretations of the results. However, due to the large number of cases included in the study, it can be statistically represented. The histogram illustrating the distribution of colour-vision deficiency, according to each age group, shows the highest peak at an age range of 30 to 35 years. This indicates that a considerable number of cases with colour-vision deficiency was discovered late. The individuals have to be early examined by school physicians, house physicians, occupational physicians, internists or ophthalmologists with this colour-vision screening test, before they enter professional life. Some symptomatical complexes of internal diseases and human genetics, i.e. related to \"colour-vision blindness\" are also emphasized hemophilia and hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 584,
                "text": "Ishihara"
            }
        },
        {
            "context": "Detecting low frequent loss-of-function alleles in genome wide association studies with red hair color as example. Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r²>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10⁻¹⁴² vs. P for rs258322 = 1.33×10⁻⁶⁶). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 1525,
                "text": "MC1R"
            }
        },
        {
            "context": "Using Mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes. Plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. To understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. Since extensive data support the proposal that foreign DNA acquires the host's nucleotide composition during long-term residence, comparison of nucleotide composition of plasmids and chromosomes could shed light on a plasmid's evolutionary history. The average absolute dinucleotide relative abundance difference, termed delta-distance, has been commonly used to measure differences in dinucleotide composition, or 'genomic signature', between bacterial chromosomes and plasmids. Here, we introduce the Mahalanobis distance, which takes into account the variance-covariance structure of the chromosome signatures. We demonstrate that the Mahalanobis distance is better than the delta-distance at measuring genomic signature differences between plasmids and chromosomes of potential hosts. We illustrate the usefulness of this metric for proposing candidate long-term hosts for plasmids, focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from Escherichia coli O157:H7, as well as the broad host range multi-drug resistance plasmid pB10 from an unknown host.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 767,
                "text": "delta-distance"
            }
        },
        {
            "context": "emMAW: computing minimal absent words in external memory. Motivation: The biological significance of minimal absent words has been investigated in genomes of organisms from all domains of life. For instance, three minimal absent words of the human genome were found in Ebola virus genomes. There exists an O(n) -time and O(n) -space algorithm for computing all minimal absent words of a sequence of length n on a fixed-sized alphabet based on suffix arrays. A standard implementation of this algorithm, when applied to a large sequence of length n , requires more than 20 n  bytes of RAM. Such memory requirements are a significant hurdle to the computation of minimal absent words in large datasets. Results: We present emMAW, the first external-memory algorithm for computing minimal absent words. A free open-source implementation of our algorithm is made available. This allows for computation of minimal absent words on far bigger data sets than was previously possible. Our implementation requires less than 3 h on a standard workstation to process the full human genome when as little as 1 GB of RAM is made available. We stress that our implementation, despite making use of external memory, is fast; indeed, even on relatively smaller datasets when enough RAM is available to hold all necessary data structures, it is less than two times slower than state-of-the-art internal-memory implementations. Availability and implementation: https://github.com/solonas13/maw (free software under the terms of the GNU GPL). Contact: alice.heliou@lix.polytechnique.fr or solon.pissis@kcl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm is available for computing minimal absent words using external memory?",
            "answers": {
                "answer_start": 721,
                "text": "emMAW"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 973,
                "text": "xa"
            }
        },
        {
            "context": "Discovery of replicating circular RNAs by RNA-seq and computational algorithms. Replicating circular RNAs are independent plant pathogens known as viroids, or act to modulate the pathogenesis of plant and animal viruses as their satellite RNAs. The rate of discovery of these subviral pathogens was low over the past 40 years because the classical approaches are technical demanding and time-consuming. We previously described an approach for homology-independent discovery of replicating circular RNAs by analysing the total small RNA populations from samples of diseased tissues with a computational program known as progressive filtering of overlapping small RNAs (PFOR). However, PFOR written in PERL language is extremely slow and is unable to discover those subviral pathogens that do not trigger in vivo accumulation of extensively overlapping small RNAs. Moreover, PFOR is yet to identify a new viroid capable of initiating independent infection. Here we report the development of PFOR2 that adopted parallel programming in the C++ language and was 3 to 8 times faster than PFOR. A new computational program was further developed and incorporated into PFOR2 to allow the identification of circular RNAs by deep sequencing of long RNAs instead of small RNAs. PFOR2 analysis of the small RNA libraries from grapevine and apple plants led to the discovery of Grapevine latent viroid (GLVd) and Apple hammerhead viroid-like RNA (AHVd-like RNA), respectively. GLVd was proposed as a new species in the genus Apscaviroid, because it contained the typical structural elements found in this group of viroids and initiated independent infection in grapevine seedlings. AHVd-like RNA encoded a biologically active hammerhead ribozyme in both polarities, and was not specifically associated with any of the viruses found in apple plants. We propose that these computational algorithms have the potential to discover novel circular RNAs in plants, invertebrates and vertebrates regardless of whether they replicate and/or induce the in vivo accumulation of small RNAs.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 147,
                "text": "viroids"
            }
        },
        {
            "context": "Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. INTRODUCTION: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid , a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB. AREA COVERED: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug's safety and tolerability profiles are also considered. EXPERT OPINION: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 802,
                "text": "tuberculosis"
            }
        },
        {
            "context": "NRG Oncology/National Surgical Adjuvant Breast and Bowel Project Decision-Making Project-1 Results: Decision Making in Breast Cancer Risk Reduction. Selective estrogen receptor modulators (SERMs) reduce breast cancer risk. Adoption of SERMs as prevention medication remains low. This is the first study to quantify social, cultural, and psychologic factors driving decision making regarding SERM use in women counseled on breast cancer prevention options. A survey study was conducted with women counseled by a health care provider (HCP) about SERMs. A statistical comparison of responses was performed between those who decided to use and those who decided not to use SERMs. Independent factors associated with the decision were determined using logistic regression. Of 1,023 participants, 726 made a decision: 324 (44.6%) decided to take a SERM and 402 (55.4%) decided not to. The most important factor for deciding on SERM use was the HCP recommendation. Other characteristics associated with the decision included attitudes and perceptions regarding medication intake, breast cancer worry, trust in HCP, family members with blood clots, and others' experiences with SERMs. The odds of SERM intake when HCP recommended were higher for participants with a positive attitude toward taking medications than for those with a negative attitude (P = 0.01). This study highlights the importance of social and cultural aspects for SERM decision making, most importantly personal beliefs and experiences. HCPs' recommendations play a statistically significant role in decision making and are more likely to be followed if in line with patients' attitudes. Results indicate the need for developing interventions for HCPs that not only focus on the presentation of medical information but, equally as important, on addressing patients' beliefs and experiences. Cancer Prev Res; 10(11); 625-34. ©2017 AACRSee related editorial by Crew, p. 609.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 149,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Familial Mediterranean fever. Familial Mediterranean fever (FMF) is the most frequent hereditary inflammatory disease characterized by self-limited recurrent attacks of fever and serositis. It is transmitted in an autosomal recessive pattern and affects certain ethnic groups mainly Jews, Turks, Arabs, and Armenians. FMF is caused by mutations in MEFV gene, which encodes pyrin. This protein is expressed mainly in myeloid/monocytic cells and modulates IL-1beta processing, NF-kappaB activation, and apoptosis. A mutated pyrin probably results in uncontrolled inflammation. The most devastating complication of FMF is amyloidosis, leading to chronic renal failure. M694V homozygocity, male gender and the alpha/alpha genotype of serum amyloid A1 gene are the currently established risk factors for development of amyloidosis. Daily colchicine is the mainstay of the therapy for the disease, resulting in complete remission or marked reduction in the frequency and duration of attacks in most patients. It is also effective in preventing and arresting renal amyloidosis.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 348,
                "text": "MEFV gene"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1047,
                "text": "bicarbonate"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2096,
                "text": "stroke"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 371,
                "text": "CD38"
            }
        },
        {
            "context": "Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations. METHODS AND RESULTS: We resequenced ANGPTL3 in 4 members of 3 kindreds originally identified for very low levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, respectively) in whom no mutations of known candidate genes for monogenic hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of triglyceride-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-β-high-density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI-, and ABCG1-mediated efflux); however, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol (2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol. CONCLUSIONS: Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.",
            "question": "What is the results of inactivated ANGPLT3?",
            "answers": {
                "answer_start": 1923,
                "text": "recessive hypolipidemia"
            }
        },
        {
            "context": "Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 755,
                "text": "S-Adenosyl methionine"
            }
        },
        {
            "context": "Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Although most eukaryotic genomes lack operons, they contain some physical clusters of genes that are related in function despite being unrelated in sequence. How these clusters are formed during evolution is unknown. The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. We show here that the DAL cluster was assembled, quite recently in evolutionary terms, through a set of genomic rearrangements that happened almost simultaneously. Six of the eight genes involved in allantoin degradation, which were previously scattered around the genome, became relocated to a single subtelomeric site in an ancestor of S. cerevisiae and Saccharomyces castellii. These genomic rearrangements coincided with a biochemical reorganization of the purine degradation pathway, which switched to importing allantoin instead of urate. This change eliminated urate oxidase, one of several oxygen-consuming enzymes that were lost by yeasts that can grow vigorously in anaerobic conditions. The DAL cluster is located in a domain of modified chromatin involving both H2A.Z histone exchange and Hst1-Sum1-mediated histone deacetylation, and it may be a coadapted gene complex formed by epistatic selection.",
            "question": "Which is the largest metabolic gene cluster in yeast?",
            "answers": {
                "answer_start": 289,
                "text": "The DAL cluster"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 105,
                "text": "xa"
            }
        },
        {
            "context": "Essential role of cytoplasmic cdk5 and Prx2 in multiple ischemic injury models, in vivo. Recent evidence suggests that abnormal activation of cyclin-dependent kinase 5 (cdk5) is a critical prodeath signal in stroke. However, the mechanism(s) by which cdk5 promotes death is unclear. Complicating the role of cdk5 are the observations that cdk5 can exist in multiple cellular regions and possess both prosurvival and prodeath characteristics. In particular, the critical role of cytoplasmic or nuclear cdk5 in neuronal jury, in vivo, is unclear. Therefore, we determined where cdk5 was activated in models of ischemia and how manipulation of cdk5 in differing compartments may affect neuronal death. Here, we show a critical function for cytoplasmic cdk5 in both focal and global models of stroke, in vivo. Cdk5 is activated in the cytoplasm and expression of DNcdk5 localized to the cytoplasm is protective. Importantly, we also demonstrate the antioxidant enzyme Prx2 (peroxiredoxin 2) as a critical cytoplasmic target of cdk5. In contrast, the role of cdk5 in the nucleus is context-dependent. Following focal ischemia, nuclear cdk5 is activated and functionally relevant while there is no evidence for such activation following global ischemia. Importantly, myocyte enhancer factor 2D (MEF2D), a previously described nuclear target of cdk5 in vitro, is also phosphorylated by cdk5 following focal ischemia. In addition, MEF2D expression in this paradigm ameliorates death. Together, our results address the critical issue of cdk5 activity compartmentalization, as well as define critical substrates for both cytoplasmic and nuclear cdk5 activity in adult models of stroke.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 945,
                "text": "antioxidant"
            }
        },
        {
            "context": "Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3 -adrenoceptor activation and α1 -adrenoceptor blockade. LINKED ARTICLE: This article is commented on by Michel, M. C., pp. 429-430 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.13379. BACKGROUND AND PURPOSE: Mirabegron is the first β3 -adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of β3 -adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts α1 -adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting α1A - (vas deferens and prostate), α1D - (aorta) and α1B -adrenoceptors (spleen). EXPERIMENTAL APPROACH: Functional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of [(3) H]prazosin to membrane preparations of HEK-293 cells expressing each of the human α1 -adrenoceptors, as well as β-adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed. KEY RESULTS: Mirabegron produced concentration-dependent urethral relaxations that were shifted to the right by the selective β3 -adrenoceptor antagonist L-748,337 but unaffected by β1 - and β2 -adrenoceptor antagonists (atenolol and ICI-118,551 respectively). Mirabegron-induced relaxations were enhanced by the PDE4 inhibitor rolipram, and the agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the α1 -adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α1 -adrenoceptors in urethra, vas deferens and prostate (α1A -adrenoceptor, pA2  ≅ 5.6) and aorta (α1D -adrenoceptor, pA2  ≅ 5.4) but not in spleen (α1B -adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α1A - and α1D -adrenoceptors (pKi  ≅ 6.0). CONCLUSION AND IMPLICATIONS: The effects of mirabegron in urethral smooth muscle are the result of β3 -adrenoceptor agonism together with α1A and α1D -adrenoceptor antagonism.",
            "question": "What is the indication for Mirabegron?",
            "answers": {
                "answer_start": 387,
                "text": "overactive bladder syndrome"
            }
        },
        {
            "context": "Molecularly targeted treatment of chronic myeloid leukemia: beyond the imatinib era. Chronic myeloid leukemia cells contain a BCR-ABL oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal 'cause' of the leukemia. Though the precise mechanisms underlying the leukemogenesis remains enigmatic, the use of imatinib to inhibit the dysregulated kinase activity has proved remarkably successful in clinical practice. Imatinib was the first small molecule developed to inhibit BCR-ABL tyrosine kinase activity and its success introduced the current era of molecularly targeted therapies for a number of other malignancies. In patients with chronic myeloid leukaemia who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-established. This has led to the emergence of a number of alternative treatment strategies designed to target the leukemic cell which are resistant to imatinib.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 126,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "The p73 tumor suppressor is targeted by Pirh2 RING finger E3 ubiquitin ligase for the proteasome-dependent degradation. The p73 gene, a homologue of the p53 tumor suppressor, is expressed as TA and ΔN isoforms. TAp73 has similar activity as p53 and functions as a tumor suppressor whereas ΔNp73 has both pro- and anti-survival functions. While p73 is rarely mutated in spontaneous tumors, the expression status of p73 is linked to the sensitivity of tumor cells to chemotherapy and prognosis for many types of human cancer. Thus, uncovering its regulators in tumors is of great interest. Here, we found that Pirh2, a RING finger E3 ubiquitin ligase, promotes the proteasome-dependent degradation of p73. Specifically, we showed that knockdown of Pirh2 up-regulates, whereas ectopic expression of Pirh2 down-regulates, expression of endogenous and exogenous p73. In addition, Pirh2 physically associates with and promotes TAp73 polyubiquitination both in vivo and in vitro. Moreover, we found that p73 can be degraded by both 20 S and 26 S proteasomes. Finally, we showed that Pirh2 knockdown leads to growth suppression in a TAp73-dependent manner. Taken together, our findings indicate that Pirh2 promotes the proteasomal turnover of TAp73, and thus targeting Pirh2 to restore TAp73-mediated growth suppression in p53-deficient tumors may be developed as a novel anti-cancer strategy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 125,
                "text": "7"
            }
        },
        {
            "context": "Doege-potter syndrome: a report of a histologically benign but clinically malignant case. BACKGROUND: Solitary fibrous tumors of the pleura (SFTPs) are relatively rare tumors that originate from mesenchymal cells of submesothelial tissue of the pleura. Most patients with SFTPs are asymptomatic; however, pleuritic chest pain, cough, and dyspnea can develop. If hypoglycemia is associated with a solitary fibrous tumor, it is referred to as the Doege-Potter syndrome. CASE PRESENTATION: A 70-year-old man had visited our hospital with a chief complaint of dyspnea, and he was diagnosed as having a solitary fibrous tumor. A few years later, he developed hypoglycemia, and he underwent excision of the mass. CONCLUSION: Occasionally, SFTPs induce several paraneoplastic events, such as hypertrophic osteoarthropathy. We described here a patient with an SFTP with Doege-Potter syndrome who was successfully treated with complete resection. Although lesions can be histologically benign, they can clinically present with malignant features.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 362,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "[Clinical results of selective estrogen receptor modulators (SERM)]. The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 80,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 270,
                "text": "dabigatran"
            }
        },
        {
            "context": "Onyx 18 embolisation of dural arteriovenous fistula via arterial and venous pathways: preliminary experience and evaluation of the short-term outcomes. OBJECTIVE: This paper mainly focuses on our preliminary experience and short-term outcome evaluation of embolisation of non-cavernous dural arteriovenous fistulas (ncsDAVFs) and cavernous sinus dural arteriovenous fistulas (csDAVFs) using Onyx 18 (ev3, Plymouth, MN), and in combination with coils, via arterial and venous approaches, respectively. METHODS: Between August 2008 and March 2010, 21 DAVFs (11 ncsDAVFs and 10 csDAVFs; age range: 28-68 years; 12 females and 9 males) were undertaken. Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs. Onyx 18 was used in 11 ncsDAVFs (10 via single feeder and 1 via 2 feeders). Onyx 18 or in combination with coils was used in 10 csDAVFs (9 via the inferior petrosal sinus and 1 via the superior ophthalmic vein). RESULTS: Total occlusion in immediate angiography was achieved in 18 cases (85.7%; 10 ncsDAVFs and 8 csDAVFs), and near-total occlusion in 1 ncsDAVF and 2 csDAVFs. Onyx 18 was migrated into normal vasculature in two ncsDAVFs without any sequelae. One csDAVF had VI cranial nerve palsy post-operatively, which completely recovered 2 weeks post-embolisation. Follow-up angiography at 3-12 months showed complete occlusion in 20 cases (95.2%; 10 ncsDAVFs and 10 csDAVFs). One ncsDAVF (4.8%) recurred after 3 months and was successfully re-embolised. CONCLUSION: Preliminary results achieved after embolising 11 ncsDAVFs and 10 csDAVFs using Onyx 18 and in combination with coils via arterial and venous pathways, respectively, appeared to be safe, feasible and effective, as 95.2% of cases were totally occluded without any clinical sequelae.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 755,
                "text": "DAVF"
            }
        },
        {
            "context": "The future of the new selective estrogen receptor modulators. Selective estrogen receptor modulators (SERMs) are compounds that display mixed estrogen agonist/antagonist activity. Currently, four SERMs are licensed for clinical use: tamoxifen, toremifene, clomifene and raloxifene. The STAR and RUTH trials have provided useful data about the potential role of SERMs in the primary prevention of breast cancer and cardiovascular disease in postmenopausal women. New-generation SERMs, such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene, are currently being evaluated. The aim is to find a SERM that conserves the skeleton and prevents breast cancer without increasing the risk of endometrial cancer and venous thromboembolism, and without inducing hot flushes. Technological advances in the study of estrogen receptor activation will provide key information for drug development.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 62,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 125,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Marfan's syndrome with aortic valve endocarditis. Marfans syndrome is an Autosomal dominant disorder of the connective tissues resulting in abnormalities of the musculoskeletal system, cardiovascular system and eyes. It has a prevalence of 1 in 100,000 population1 and occurs in all ethnic groups. It may be familial or due to new mutation (30%), in the fibrillin gene on arm of chromosome 15. It is estimated that one person in every 3000-5000 has Marfans syndrome may have cardiovascular abnormalities and may be complicated by infective endocartditis. About 90% of Marfan patients will develop cardiac complications2. The patient under discussion has musculoskeletal (Tall stature, reduced upper-lower segment ratio, arm-span to height ratio > 1.05, high arched palate) and Cardiovascular features (Severe aortic regurgitation complicated with infective endocarditis).",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 108,
                "text": "connective tissue"
            }
        },
        {
            "context": "Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis. The pathogenesis of RA is a complex and ever-changing landscape but amid the chaos of the disease process we have found effective treatment regimes. However, our current therapeutics, although targeting various components of both the innate and adaptive immune response, do not result in disease remission. Protein kinase inhibitors are attractive targets due to their ability to influence downstream signalling and their oral bioavailability. Fostamatinib (R788) inhibits spleen tyrosine kinase (Syk) and has been in clinical trials involving both MTX inadequate responders (MTX-IRs) and biologic inadequate responders. Studies on the MTX-IR population revealed ACR20 responses of 67-72% at higher doses (150 mg bd and 100 mg bd), ACR50 responses of 43-57% and ACR70 responses of 28-40%. The trial in the biologic non-responder population showed no efficacy, however, post hoc analyses of the data suggested that a further trial in this population is warranted. The most common adverse events included gastrointestinal effects, hypertension, neutropenia and transaminitis. Many adverse effects were dose responsive and hypertension was amenable to treatment. Upper respiratory tract infections were more likely at higher doses, but no serious infections with tuberculosis, fungi or opportunistic infections were reported. The oral availability of these agents makes them attractive treatment options for our patients, although the literature from the oncology field suggests that patients will only choose the oral route if efficacy is equivalent. Long-term follow-up studies are ongoing and will be critical for rare side effects. The role of these agents in our current arsenal is unclear and economic analyses are awaited.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 552,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Skin layer-specific transcriptional profiles in normal and recessive yellow (Mc1re/Mc1re) mice. The melanocortin 1 receptor (Mc1r) plays a central role in cutaneous biology, but is expressed at very low levels by a small fraction of cells in the skin. In humans, loss-of-function MC1R mutations cause fair skin, freckling, red hair, and increased predisposition to melanoma; in mice, Mc1r loss-of-function is responsible for the recessive yellow mutation, associated with pheomelanic hair and a decreased number of epidermal melanocytes. To better understand how Mc1r signaling affects different cutaneous phenotypes, we examined large-scale patterns of gene expression in different skin components (whole epidermal sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and recessive yellow mice, starting with a 26K mouse cDNA microarray. From c. 17 000 genes whose levels could be accurately measured in neonatal skin, we identified 883, 2097 and 552 genes that were uniquely expressed in the suprabasal epidermis, basal epidermis and dermis, respectively; specific biologic roles could be assigned for each class. Comparison of normal and recessive yellow mice revealed 69 differentially expressed genes, of which the majority had not been previously implicated in Mc1r signaling. Surprisingly, many of the Mc1r-dependent genes are expressed in cells other than melanocytes, even though Mc1r expression in the skin is confined almost exclusively to epidermal melanocytes. These results reveal new targets for Mc1r signaling, and point to a previously unappreciated role for a Mc1r-dependent paracrine effect of melanocytes on other components of the skin.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 280,
                "text": "MC1R"
            }
        },
        {
            "context": "The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression. Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 433,
                "text": "Ecm22"
            }
        },
        {
            "context": "Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. The Philadelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein kinases were thought to be poor therapeutic targets because of their ubiquitous nature and crucial role in many normal physiologic processes. However, the advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer kinase inhibitors could be specific. This agent has shown striking activity in chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell factor receptor) and platelet-derived growth factor receptor. In addition, it has shown similar impressive responses, with little host toxicity, in gastrointestinal stromal tumors, which harbor activating Kit mutations, and in tumors with activated platelet-derived growth factor receptor. The studies of imatinib mesylate provide proof-of-principle for using aberrant kinases as a therapeutic target and are a model for the promise of molecular therapeutics. This paper reviews the current knowledge on the function of Bcr-Abl and its normal counterparts (Bcr and Abl), as well as the impact of this knowledge on the development of a remarkably successful targeted therapy approach.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 262,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Multiple replication origins of the archaeon Halobacterium species NRC-1. The genomic sequence of the halophilic archaeon Halobacterium NRC-1 has been analyzed by the Z curve method. The Z curve is a three-dimensional curve that uniquely represents a given DNA sequence. Based on the known behaviors of the Z curves for the archaea whose replication origins have been identified, the analysis of the Z curve for the genome of Halobacterium NRC-1 strongly suggests that the large genome has two replication origins, oriC1 (921,863-922,014) and oriC2 (1,806,444-1,807,229), which are located at two sharp peaks of the Z curve. These two regions are next to the cdc6 genes and contain multiple copies of stretches of G and C, i.e., ggggtgggg and ccccacccc, which may also be regarded as direct and inverted repeats. Based on the above analysis, a model of replication of Halobacterium NRC-1 with two replication origins and two termini has been proposed. The experimental confirmation of this model would constitute the first example of multiple replication origins of archaea, which will finally provide much insight into the understanding of replication mechanisms of eukaryotic organisms, including human. In addition, the potential multiple replication origins of the archaeon Sulfolobus solfataricus are suggested by the analysis based on the Z curve method.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 1233,
                "text": "multiple"
            }
        },
        {
            "context": "Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study. BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.",
            "question": "Neurostimulation of which nucleus is used for treatment of dystonia?",
            "answers": {
                "answer_start": 366,
                "text": "globus pallidus internus"
            }
        },
        {
            "context": "Gene looping is conferred by activator-dependent interaction of transcription initiation and termination machineries. Gene looping juxtaposes the promoter and terminator regions of RNA polymerase II-transcribed genes in yeast and mammalian cells. Here we report an activator-dependent interaction of transcription initiation and termination factors during gene looping in budding yeast. Chromatin analysis revealed that MET16, INO1, and GAL1p-BUD3 are in a stable looped configuration during activated transcription. Looping was nearly abolished in the absence of transcription activators Met28, Ino2, and Gal4 of MET16, INO1, and GAL1p-BUD3 genes, respectively. The activator-independent increase in transcription was not accompanied by loop formation, thereby suggesting an essential role for activators in gene looping. The activators did not facilitate loop formation directly because they did not exhibit an interaction with the 3' end of the genes. Instead, activators physically interacted with the general transcription factor TFIIB when the genes were activated and in a looped configuration. TFIIB cross-linked to both the promoter and the terminator regions during the transcriptionally activated state of a gene. The presence of TFIIB on the terminator was dependent on the Rna15 component of CF1 3' end processing complex. Coimmunoprecipitation revealed a physical interaction of Rna15 with TFIIB. We propose that the activators facilitate gene looping through their interaction with TFIIB during transcriptional activation of genes.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1102,
                "text": "TFIIB"
            }
        },
        {
            "context": "Molecular mechanisms of inherited ventricular arrhythmias. BACKGROUND: Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. PRESENT KNOWLEDGE: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified (\"channelopathy\"), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. FUTURE PERSPECTIVES: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. CONCLUSION: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias.",
            "question": "Which gene is mutated in a subtype of arrhythmogenic right ventricular cardiomyopathy known as Naxos disease?",
            "answers": {
                "answer_start": 1651,
                "text": "the plakoglobin gene"
            }
        },
        {
            "context": "The evolutionary basis for the feeding behavior of domestic dogs (Canis familiaris) and cats (Felis catus). The dentition, sense of taste and meal patterning of domestic dogs and cats can be interpreted in terms of their descent from members of the order Carnivora. The dog is typical of its genus, Canis, in its relatively unspecialized dentition, and a taste system that is rather insensitive to salt. The preference of many dogs for large infrequent meals reflects the competitive feeding behavior of its pack-hunting ancestor, the wolf Canis lupus. However, its long history of domestication, possibly 100,000 years, has resulted in great intraspecific diversity of conformation and behavior, including feeding. Morphologically and physiologically domestic cats are highly specialized carnivores, as indicated by their dentition, nutritional requirements, and sense of taste, which is insensitive to both salt and sugars. Their preference for several small meals each day reflects a daily pattern of multiple kills of small prey items in their ancestor, the solitary territorial predator Felis silvestris. Although in the wild much of their food selection behavior must focus on what to hunt, rather than what to eat, cats do modify their food preferences based on experience. For example, the \"monotony effect\" reduces the perceived palatability of foods that have recently formed a large proportion of the diet, in favor of foods with contrasting sensory characteristics, thereby tending to compensate for any incipient nutritional deficiencies. Food preferences in kittens during weaning are strongly influenced by those of their mother, but can change considerably during at least the first year of life.",
            "question": "The common house cat, Felis silvestris catus and the domestic dog, Canis familiaris both belong to what taxonomic order?",
            "answers": {
                "answer_start": 255,
                "text": "Carnivora"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 105,
                "text": "bicarbonate"
            }
        },
        {
            "context": "SEF, a new protein required for flowering repression in Arabidopsis, interacts with PIE1 and ARP6. The SWR1/SRCAP complex is a chromatin-remodeling complex that has been shown to be involved in substitution of histone H2A by the histone variant H2A.Z in yeast (Saccharomyces cerevisiae) and animals. Here, we identify and characterize SERRATED LEAVES AND EARLY FLOWERING (SEF), an Arabidopsis (Arabidopsis thaliana) homolog of the yeast SWC6 protein, a conserved subunit of the SWR1/SRCAP complex. SEF loss-of-function mutants present a pleiotropic phenotype characterized by serrated leaves, frequent absence of inflorescence internodes, bushy aspect, and flowers with altered number and size of organs. sef plants flower earlier than wild-type plants both under inductive and noninductive photoperiods. This correlates with strong reduction of FLOWERING LOCUS C and MADS-AFFECTING FLOWERING4 transcript levels and up-regulation of FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 gene expression. The sef phenotype is similar to that of the photoperiod-independent early flowering1 (pie1) and the actin-related protein 6 (arp6) mutants. PIE1 and ARP6 proteins are also homologs of SWR1/SRCAP complex subunits. Analysis of sef pie1 double mutants demonstrates genetic interaction between these two genes. We also show physical interactions between SEF, ARP6, and PIE1 proteins. Taken together, our data indicate that SEF, ARP6, and PIE1 might form a molecular complex in Arabidopsis related to the SWR1/SRCAP complex identified in other eukaryotes.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 103,
                "text": "SWR1"
            }
        },
        {
            "context": "A polymorphism study of the human Agouti gene and its association with MC1R. To determine whether the Agouti Signalling Protein (ASP) gene is associated with skin and hair coloration in humans, the complete coding region of ASP was screened for polymorphisms. Analysis of ASP in Caucasian, African-American, Spanish Basque, Hispanic, Apache and Australian Aboriginal populations revealed no amino acid substitutions. A single polymorphism in the 3' untranslated region occurred at a frequency of 0.2 in African-Americans. Variants of the Melanocortin 1 Receptor (MC1R) gene have been found to be associated with red hair and fair skin in humans. Red hair individuals are usually compound heterozygotes or homozygous for one of a number of MC1R polymorphisms associated with red hair. Some individuals however are heterozygous for only one of these polymorphisms and dizygotic twins can be concordant for MC1R variants but discordant for hair colour. A recent study has also identified rare redheads carrying no MC1R variants indicating that polymorphisms of the human MC1R gene are required but not sufficient for the red hair phenotype. To address the question of whether ASP also contributes to the red hair phenotype, individuals previously identified as having unexpected MC1R genotypes were screened for polymorphisms at the ASP locus. No polymorphisms were found in any of these individuals. Results indicate that the human ASP gene is unlikely to function in normal human pigmentation in the same way as MC1R.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 563,
                "text": "MC1R"
            }
        },
        {
            "context": "Alternative polyadenylation sites reveal distinct chromatin accessibility and histone modification in human cell lines. MOTIVATION: In addition to alternative splicing, alternative polyadenylation has also been identified as a critical and prevalent regulatory mechanism in human gene expression. However, the mechanism of alternative polyadenylation selection and the involved factors is still largely unknown. RESULTS: We use the ENCODE data to scan DNA functional elements, including chromatin accessibility and histone modification, around transcript cleavage sites. Our results demonstrate that polyadenylation sites tend to be less sensitive to DNase I. However, these polyadenylation sites have preference in nucleosome-depleted regions, indicating the involvement of chromatin higher-order structure rather than nucleosomes in the resultant lower chromatin accessibility. More interestingly, for genes using two polyadenylation sites, the distal sites show even lower chromatin accessibility compared with the proximal sites or the unique sites of genes using only one polyadenylation site. We also observe that the histone modification mark, histone H3 lysine 36 tri-methylation (H3K36Me3), exhibits different patterns around the cleavage sites of genes using multiple polyadenylation sites from those of genes using a single polyadenylation site. Surprisingly, the H3K36Me3 levels are comparable among the alternative polyadenylation sites themselves. In summary, polyadenylation and alternative polyadenylation are closely related to functional elements on the DNA level. CONTACT: liang.chen@usc.edu.",
            "question": "What histone trimethylation has been associated to RNA splicing?",
            "answers": {
                "answer_start": 1189,
                "text": "H3K36Me3"
            }
        },
        {
            "context": "Essential roles of Da transactivation domains in neurogenesis and in E(spl)-mediated repression. E proteins are a special class of basic helix-loop-helix (bHLH) proteins that heterodimerize with many bHLH activators to regulate developmental decisions, such as myogenesis and neurogenesis. Daughterless (Da) is the sole E protein in Drosophila and is ubiquitously expressed. We have characterized two transcription activation domains (TADs) in Da, called activation domain 1 (AD1) and loop-helix (LH), and have evaluated their roles in promoting peripheral neurogenesis. In this context, Da heterodimerizes with proneural proteins, such as Scute (Sc), which is dynamically expressed and also contributes a TAD. We found that either one of the Da TADs in the Da/Sc complex is sufficient to promote neurogenesis, whereas the Sc TAD is incapable of doing so. Besides its transcriptional activation role, the Da AD1 domain serves as an interaction platform for E(spl) proteins, bHLH-Orange family repressors which antagonize Da/Sc function. We show that the E(spl) Orange domain is needed for this interaction and strongly contributes to the antiproneural activity of E(spl) proteins. We present a mechanistic model on the interplay of these bHLH factors in the context of neural fate assignment.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 401,
                "text": "transcription activation domain"
            }
        },
        {
            "context": "Behavioral testing strategies in a localized animal model of multiple sclerosis. To assess neurological impairments quantitatively in an animal model of multiple sclerosis (MS), we have used a targeted model of experimental autoimmune encephalomyelitis (EAE), which leads to the formation of anatomically defined lesions in the spinal cord. Deficits in the hindlimb locomotion are therefore well defined and highly reproducible, in contrast to the situation in generalized EAE with disseminated lesions. Behavioral tests for hindlimb sensorimotor functions, originally established for traumatic spinal cord injury, revealed temporary or persistent deficits in open field locomotion, the grid walk, the narrow beam and the measurement of the foot exorotation angle. Such refined behavioral testing in EAE will be crucial for the analysis of new therapeutic approaches for MS that seek to improve or prevent neurological impairment.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 211,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Absence of toxicity of oats in patients with dermatitis herpetiformis. BACKGROUND: People with gluten sensitivity should avoid foods containing wheat, rye, and barley, but there has been debate about whether they should avoid oats. Although patients with celiac disease have recently been shown to tolerate oats, less is known about the effects of oats on patients with dermatitis herpetiformis. METHODS: We studied seven men and three women (mean age, 58 years) with biopsy-confirmed dermatitis herpetiformis. They had followed a strict gluten-free diet for a mean of 15.8 years, which controlled their rash and enteropathy. The patients added oats that were not contaminated with gluten to their diets for 12 weeks (mean [+/-SD] daily intake, 62.5+/-10.8 g). RESULTS: None of the patients had any adverse effects. Serologic tests for antigliadin, antireticulin, and antiendomysial antibodies were negative before oats were introduced into the diet and after they were discontinued. Villous architecture remained normal: the mean (+/-SE) ratio of the height of villi to the depth of crypts was 3.59+/-0.11 before the diet and 3.71+/-0.09 afterward (normal, 3 to 5), and the mean enterocyte heights were 31.36+/-0.58 microm and 31.75+/-44 microm, respectively (normal range, 29 to 34). Duodenal intraepithelial lymphocyte counts all remained within normal limits (mean, 13.8+/-1.03 per 100 enterocytes before the diet and 14.2+/-1.2 per 100 enterocytes afterward; normal range, 10 to 30). Dermal IgA showed no significant changes. CONCLUSIONS: Patients with dermatitis herpetiformis can include moderate amounts of oats in their gluten-free diets without deleterious effects to the skin or intestine.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 1558,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Flumazenil reversal of psychomotor impairment due to midazolam or diazepam for conscious sedation for upper endoscopy. BACKGROUND: Flumazenil is a competitive benzodiazepine antagonist that acts to reverse their sedative and hypnotic effects. It is indicated in the management of benzodiazepine overdose, but its role in the routine reversal of endoscopic conscious sedation has not been defined. METHODS: Patients undergoing diagnostic upper endoscopy who received sedation with either diazepam or midazolam alone were given flumazenil 0.2 mg incrementally immediately following the procedure until awake. They were then asked to repeat three psychomotor tests measuring cognitive and motor skills, with their baseline scores compared with postprocedure scores over a 3-hour period. RESULTS: Full psychomotor function was restored to baseline values within 30 minutes after flumazenil in 79% of patients, with no differences in the reversal of psychomotor skill impairment observed between diazepam and midazolam sedation. There was no evidence of rebound sedation seen for up to 3 hours. No significant anterograde amnesia was evident in 78% of individuals. CONCLUSIONS: These results demonstrate that flumazenil's effects on reversing psychomotor impairment are similar when midazolam or diazepam are used for conscious sedation. However, the potential usefulness of routine flumazenil reversal of conscious sedation will require further evaluation of specific psychomotor performance skills (such as driving a car) before we lift the admonition against leaving the endoscopic suite unattended, driving a vehicle, or operating complicated machinery for several hours.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 131,
                "text": "Flumazenil"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 508,
                "text": "MethPed"
            }
        },
        {
            "context": "Interaction between DNMT1 and DNA replication reactions in the SV40 in vitro replication system. In contrast to normal cells, cancer cells exhibit both genetic and epigenetic instability. These unique properties give rise to genetic and epigenetic heterogeneity in a given population of cancer cells and provide a means for the population to undergo phenotypic progression by clonal selection. DNA methylation at CpG dinucleotides is one of the epigenetic marks that are frequently disturbed in cancer cells. To understand how the CpG methylation pattern is changeable in cancer cells, it is necessary to know how it is faithfully maintained in normal cell proliferation. Toward this goal, we have developed a novel in vitro system that is based on the well-established SV40 in vitro replication system and functions to reconstitute concurrent DNA replication and DNA maintenance methylation reactions. We found that DNA methylation was maintained only when exogenous DNA methyltransferase 1 (DNMT1) and S-adenosyl methionine (SAM) were added to the reaction. We demonstrated that DNMT1 associates with replicating and/or replicated chromatin irrespective of the DNA methylation status of template DNA. Moreover, the PCNA-binding domain (PBD) of DNMT1 is not required for the association. Taken together, we suggest that DNMT1 is recruited to replicating and/or replicated chromatin in a constitutive manner independent of the DNA methylation reaction. The in vitro system described in this report is very useful for analyzing the molecular mechanism underlying the DNA maintenance methylation reaction.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 993,
                "text": "DNMT1"
            }
        },
        {
            "context": "Molecularly targeted treatment of chronic myeloid leukemia: beyond the imatinib era. Chronic myeloid leukemia cells contain a BCR-ABL oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal 'cause' of the leukemia. Though the precise mechanisms underlying the leukemogenesis remains enigmatic, the use of imatinib to inhibit the dysregulated kinase activity has proved remarkably successful in clinical practice. Imatinib was the first small molecule developed to inhibit BCR-ABL tyrosine kinase activity and its success introduced the current era of molecularly targeted therapies for a number of other malignancies. In patients with chronic myeloid leukaemia who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-established. This has led to the emergence of a number of alternative treatment strategies designed to target the leukemic cell which are resistant to imatinib.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 511,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Identification of different clonal complexes and diverse amino acid substitutions in penicillin-binding protein 2 (PBP2) associated with borderline oxacillin resistance in Canadian Staphylococcus aureus isolates. Borderline oxacillin-resistant Staphylococcus aureus (BORSA) exhibit oxacillin MIC values of 1-8 microg ml(-1), but lack mecA, which encodes the low-affinity penicillin-binding protein (PBP)2a. The relationship of the BORSA phenotype with specific genetic backgrounds was assessed, as well as amino acid sequence variation in the normal PBP2. Among 38 BORSA, 26 had a common PFGE profile of genomic DNA, and were multilocus sequence type (ST)25. The other isolates were genetically diverse. Complete pbp2 sequences were determined for three BORSA, corresponding to ST25, ST1 and ST47, which were selected on the basis of lacking blaZ-encoded beta-lactamase. The essential transpeptidase-domain-encoding segment of pbp2 was also sequenced from seven additional ST25 isolates. Amino acid substitutions occurred in the transpeptidase domain of all BORSA, irrespective of clonal type. A Gln(629)-->Pro substitution was common to all ST25 BORSA, but most could be distinguished from one another by additional unique substitutions in the transpeptidase domain. The ST1 and ST47 isolates also possessed unique substitutions in the transpeptidase domain. Plasmid-mediated expression of pbp2 from an ST25 or ST1 isolate in S. aureus RN6390 increased its oxacillin MIC from 0.25 to 4 microg ml(-1), while pbp2 from a susceptible strain, ATCC 25923, had no effect. Therefore, different amino acid substitutions in PBP2 of diverse BORSA lineages contribute to borderline resistance. The predominant ST25 lineage was not related to any of the five clonal complexes that contain meticillin-resistant S. aureus (MRSA), suggesting that ST25 cannot readily acquire mecA-mediated resistance.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 213,
                "text": "Borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Leu628 of the KIX domain of CBP is a key residue for the interaction with the MLL transactivation domain. Physical interaction between the transactivation domain (TAD) of the mixed-lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL-mediated transcriptional activation. We show by alanine-scanning mutagenesis that hydrophobic surface residues of KIX, especially L628, are energetically important for binding the MLL TAD. NMR studies of the KIX-L628A mutant suggest that L628 plays a crucial role in conformational transitions at the MLL binding site, necessary for high affinity interactions with MLL. Unexpectedly, MLL also binds to the c-Myb/phosphorylated kinase-inducible domain of CREB (pKID) site of KIX, highlighting the complex nature of interactions involving intrinsically disordered transcriptional activators.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 139,
                "text": "transactivation domain"
            }
        },
        {
            "context": "p73 plays a role in erythroid differentiation through GATA1 induction. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. Although TAp73alpha and -beta proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, DeltaNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or DeltaN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73alpha. Furthermore, TAp73alpha induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and DeltaNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 139,
                "text": "7"
            }
        },
        {
            "context": "Somatic cell genetic analysis of the galactocerebrosidase gene: lack of complementation in human Krabbe disease/twitcher mouse cell hybrids. The inherited deficiency of galactosylceramide beta-galactosidase (E.C. 3.2.1.46: galactocerebrosidase) activity results in globoid cell leukodystrophy in humans (Krabbe disease) and in mice (twitcher mutant). To determine whether Krabbe patients' cells complement twitcher cells to produce, in hybrid combination, greater than deficient levels of galactocerebrosidase activity, five separate crosses were made between an established twitcher mouse cell line and five cell strains from unrelated Krabbe disease patients. A total of 57 twitcher mouse/Krabbe somatic cell hybrid lines developed from all of these crosses were deficient in galactocerebrosidase activity despite the presence of human chromosomes 14 or 17, which have been previously implicated as bearing the galactocerebrosidase gene. A control cross between twitcher mouse/positive control human fibroblasts resulted in 14 of 21 independent hybrid lines that expressed higher than deficient levels of galactocerebrosidase activity. The lack of complementation between Krabbe disease patient and twitcher mutant mouse cells provides further evidence that the twitcher mouse is an authentic murine model for Krabbe disease and supports the hypothesis that the mutations in both species are within the structural gene for the galactocerebrosidase enzyme.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 1429,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. BACKGROUND: IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. METHODS: We performed an open-label trial of anti-IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. RESULTS: Anti-IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti-IL-5. In addition, anti-IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti-IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. CONCLUSIONS: These results suggest that anti-IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti-IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 5,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Ecm22 and Upc2 regulate yeast mating through control of expression of the mating genes PRM1 and PRM4. Budding yeast mating is an excellent model for receptor-activated cell differentiation. Here we identify the related transcription factors Ecm22 and Upc2 as novel regulators of mating. Cells lacking both ECM22 and UPC2 display strong mating defects whereas deletion of either gene has no effect. Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4. These genes are strongly induced in response to mating pheromone, which is also largely dependent on ECM22 and UPC2. We further show that deletion of PRM4 like PRM1 results in markedly reduced mating efficiency. Expression of PRM1 but not of PRM4 is also regulated by Ste12, a key transcription factor for mating. STE12 deletion lowers basal PRM1 expression, whereas STE12 overexpression strongly increases PRM1 levels. This regulation of PRM1 transcription is mediated through three Ste12-binding sites in the PRM1 promoter. Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways. In summary, we propose a novel mechanism for budding yeast mating. We suggest that Ecm22 and Upc2 regulate mating through the induction of the mating genes PRM1 and PRM4.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 1019,
                "text": "ECM22"
            }
        },
        {
            "context": "Activation of peroxisome proliferator-activated receptor α induces lysosomal biogenesis in brain cells: implications for lysosomal storage disorders. Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic interior and are central to the autophagic, endocytic, or phagocytic pathway. In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core. However, mechanisms by which TFEB is regulated are poorly understood. This study demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated receptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPARα, but not PPARβ and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB caused an increase in lysosomal protein and the lysosomal abundance in cell. Collectively, this study reinforces the link between lysosomal biogenesis and lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of therapeutic value in the treatment of lysosomal storage disorders in which autophagy-lysosome pathway plays an important role.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 593,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 227,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 75,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "[Analysis of mutations of ribosomal protein genes in 21 cases of Diamond-Blackfan anemia]. This study was aimed to explore the mutations of ribosomal protein (RP) genes in patients with Diamond Blackfan anemia (DBA). Twenty-one cases of DBA admitted in our hospital from Dec 2008 to Aug 2012 were screened by PCR for mutations in the nine known genes associated with DBA: RPS19, RPS24, RPS17, RPL5, RPL11, RPS7, RPL35a, RPS10 and RPS26. The results found that 8 patients (38.1%) with DBA had mutations in the genes coding for ribosomal protein, in which RPS19 mutation was identified in 3 patients, RPS24, RPS7, RPL5, RPL11 and RPL35A mutations were identified respectively in 1 of the patient. No mutations were detected in RPS17, RPS10 or RPS26 genes. Thumb anomalies were found in 2 patients with RPL11 or RPL5 mutation, and hypospadias was found in 1 patient with RPS19 mutation. It is concluded that the mutation frequency of the genes coding for ribosomal protein in the patients with DBA here is lower than that in western countries. The hypospadias can be observed in some patients with RPS19 mutation and some dactyl anomalies are associated with RPL11 and RPL5 mutations.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 237,
                "text": "DBA"
            }
        },
        {
            "context": "Selenocysteine biosynthesis and insertion machinery in Naegleria gruberi. Selenium (Se) is an essential trace element primarily found in selenoproteins as the 21st amino acid (selenocysteine, Sec, or U). Selenoproteins play an important role in growth and proliferation and are typically involved in cellular redox balance. Selenocysteine is encoded by an in-frame UGA codon specified by a stem-loop structure, the Sec insertion sequence element (SECIS), which, in eukaryotes, is located in the 3'-untranslated region (UTR). The availability of the Naegleria gruberi (ATCC 30224) genome sequence and the use of this organism as a model system for the pathogenic amoeba N. fowleri allowed us to investigate the Sec incorporation pathway in this primitive eukaryote. Using bioinformatics tools, we identified gene sequences encoding PSTK (O-phosphoseryl-tRNA(Sec) kinase), SepSecS (O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase), SelD/SPS2 (selenophosphate synthetase), EFSec (selenocysteine-specific elongation factor) and SBP (SECIS binding protein). These findings were confirmed by RT-PCR and by sequencing. A potential tRNA(Ser)Sec (SelC) gene and a putative selenoprotein with sequence similarity to a mitochondrial thioredoxin reductase (TR3) were also identified. Our results show that the selenocysteine incorporation machinery is indeed present in N. gruberi. Interestingly, the SelD/SPS2 gene is 2214 bp in length and contains two distinct domains. The N-terminal region shows sequence similarity to predicted methyltransferase proteins, and the C-terminal region is homologous to prokaryotic SelD/SPS2. Our results suggest the possibility of novel selenoproteins.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 447,
                "text": "SECIS"
            }
        },
        {
            "context": "SMARCB1/INI1 Involvement in Pediatric Chordoma: A Mutational and Immunohistochemical Analysis. Chordomas arise in the skull base and spine and usually occur in adults and are rare in the pediatric population. Cases of chordoma in pediatric age are often poorly differentiated, showing cytologic atypia, increased cellularity, and mitosis, and their aggressive behavior is associated with a high incidence of metastatic spread and a short patient survival. Recent studies have described loss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not with point mutations but with SMARCB1/INI1 gene deletions instead. In this study, we considered immunohistochemistry and SMARCB1/INI1 mutational status to examine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 poorly differentiated). We performed immunohistochemical tests for INI1, brachyury, S100, and cytokeratins and conducted a genetic analysis on the SMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex ligation-dependent probe amplification to detect abnormal copy numbers of the gene locus. All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma. Genetic analysis identified a missense mutation in 2 cases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and features of poorly differentiated tumor in 1. These mutations were novel variants occurring in heterozygosity, and they were judged to be pathogenic by 3 different bioinformatic tools. In 7 of 8 cases we performed multiplex ligation-dependent probe amplification, and 3 cases showed deletions at the SMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in childhood chordoma. We also describe 3 novel pathogenic mutations.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 768,
                "text": "chordomas"
            }
        },
        {
            "context": "The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs that are found in plants and animals (for recent reviews, see ). miRNAs are expressed in a developmentally and tissue-specific manner and regulate the translational efficiency and stability of partial or fully sequence-complementary mRNAs. miRNAs are excised in a stepwise process from double-stranded RNA precursors that are embedded in long RNA polymerase II primary transcripts (pri-miRNA). Drosha RNase III catalyzes the first excision event, the release in the nucleus of a hairpin RNA (pre-miRNA), which is followed by export of the pre-miRNA to the cytoplasm and further processing by Dicer to mature miRNAs. Here, we characterize the human DGCR8, the DiGeorge syndrome critical region gene 8, and its Drosophila melanogaster homolog. We provide biochemical and cell-based readouts to demonstrate the requirement of DGCR8 for the maturation of miRNA primary transcripts. RNAi knockdown experiments of fly and human DGCR8 resulted in accumulation of pri-miRNAs and reduction of pre-miRNAs and mature miRNAs. Our results suggest that DGCR8 and Drosha interact in human cells and reside in a functional pri-miRNA processing complex.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 523,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "The RTS,S vaccine candidate for malaria. Malaria continues to be a worldwide leading cause of morbidity and mortality, and the development of an effective malaria vaccine remains a research imperative. Of the multiple approaches that have been pursued, the RTS,S/AS01 vaccine candidate represents the most developed and clinically validated malaria vaccine formulation. Throughout its development, increasingly more effective adjuvants have been key in improving the potency of the vaccine. RTS,S-based vaccine formulations have been demonstrated to be safe, well tolerated, immunogenic, and to confer partial efficacy in both malaria-naive and -experienced adults as well as children. Further research to optimize and improve vaccine efficacy is ongoing.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 341,
                "text": "malaria"
            }
        },
        {
            "context": "Measuring selective estrogen receptor modulator (SERM)-membrane interactions with second harmonic generation. The interaction of selective estrogen receptor modulators (SERMs) with lipid membranes has been measured at clinically relevant serum concentrations using the label-free technique of second harmonic generation (SHG). The SERMs investigated in this study include raloxifene, tamoxifen, and the tamoxifen metabolites 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. Equilibrium association constants (Ka) were measured for SERMs using varying lipid compositions to examine how lipid phase, packing density, and cholesterol content impact SERM-membrane interactions. Membrane-binding properties of tamoxifen and its metabolites were compared on the basis of hydroxyl group substitution and amine ionization to elucidate how the degree of drug ionization impacts membrane partitioning. SERM-membrane interactions were probed under multiple pH conditions, and drug adsorption was observed to vary with the concentration of soluble neutral species. The agreement between Ka values derived from SHG measurements of the interactions between SERMs and artificial cell membranes and independent observations of the SERMs efficacy from clinical studies suggests that quantifying membrane adsorption properties may be important for understanding SERM action in vivo.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 129,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Difficulties in diagnosing Marfan syndrome using current FBN1 databases. PURPOSE: The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and more accessible, the expected increase in the number of genetic tests will become evident, resulting in numerous genetic variants that need to be evaluated for disease-causing effects based on database information. The aim of this study was to evaluate genetic variants in four databases and review the relevant literature. METHODS: We assessed background data on 23 common variants registered in ESP6500 and classified as causing MFS in the Human Gene Mutation Database (HGMD). We evaluated data in four variant databases (HGMD, UMD-FBN1, ClinVar, and UniProt) according to the diagnostic criteria for MFS and compared the results with the classification of each variant in the four databases. RESULTS: None of the 23 variants was clearly associated with MFS, even though all classifications in the databases stated otherwise. CONCLUSION: A genetic diagnosis of MFS cannot reliably be based on current variant databases because they contain incorrectly interpreted conclusions on variants. Variants must be evaluated by time-consuming review of the background material in the databases and by combining these data with expert knowledge on MFS. This is a major problem because we expect even more genetic test results in the near future as a result of the reduced cost and process time for next-generation sequencing.Genet Med 18 1, 98-102.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 161,
                "text": "FBN1"
            }
        },
        {
            "context": "Primary cutaneous pre-B lymphoblastic lymphoma immunohistologically mimics Ewing's sarcoma/primitive neuroectodermal tumor. Precursor B-cell lymphoblastic lymphomas (B-LBLs) are rare and most often involve the skin in the head and neck region. Histologically, cutaneous B-LBLs may be confused with other small round-cell neoplasms. Moreover, half of B-LBL patients are negative for CD45 (leucocyte common antigen, LCA), a widely used marker for the diagnosis of lymphoma, and a significant portion express CD99, a marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET). Therefore, an extranodal B-LBL may be misinterpreted as PNET or ES. Here, we report on 2 boys, aged 10 and 5 years, with primary cutaneous B-LBL of the scalp. PNET was initially misdiagnosed because the tumor cells were negative for CD45 but strongly positive for CD99. Advanced stage of acute lymphoblastic leukemia (ALL) developed later and both patients died during the course of treatment for ALL. In retrospective analyses, tumor cells in the initial biopsy specimens of both patients were found to be reactive to terminal deoxynucleotidyl transferase (TdT), CD43 and CD10. Thus, the diagnosis of B-LBL was confirmed. These cases illustrate the possibility that primary cutaneous B-LBL may mimic ES or PNET immunophenotypically, and that correct diagnosis in doubtful cases may be facilitated by analysis using a complete panel of antibodies, particularly including TdT and CD43.",
            "question": "Which biomarker is widely used in the diagnosis of Ewing sarcoma?",
            "answers": {
                "answer_start": 506,
                "text": "CD99"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 858,
                "text": "ADAR"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 204,
                "text": "thyroid"
            }
        },
        {
            "context": "ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. BACKGROUND & AIMS: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC. RESULTS: ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β inhibits apoptosis emanating from mitochondria. CONCLUSIONS: Thus, ΔNp73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the ΔNp73ß target gene signature can predict the prognosis of patients suffering from HCC.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 453,
                "text": "7"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 187,
                "text": "MRSA"
            }
        },
        {
            "context": "Failure of cloxacillin in treatment of a patient with borderline oxacillin-resistant Staphylococcus aureus endocarditis. Clinical evidence for failure with beta-lactam therapy has been lacking for patients with borderline oxacillin-resistant Staphylococcus aureus (BORSA) infections. We describe a failure of cloxacillin for a patient with endocarditis due to BORSA. The isolate also had false-negative thermonuclease and coagulase test results.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 54,
                "text": "borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Necrobiosis lipoidica and diabetic control revisited. Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 241,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "An alternative to killing? Treatment of reservoir hosts to control a vector and pathogen in a susceptible species. Parasite-mediated apparent competition occurs when one species affects another through the action of a shared parasite. One way of controlling the parasite in the more susceptible host is to manage the reservoir host. Culling can cause issues in terms of ethics and biodiversity impacts, therefore we ask: can treating, as compared to culling, a wildlife host protect a target species from the shared parasite? We used Susceptible Infected Recovered (SIR) models parameterized for the tick-borne louping ill virus (LIV) system. Deer are the key hosts of the vector (Ixodes ricinus) that transmits LIV to red grouse Lagopus lagopus scoticus, causing high mortality. The model was run under scenarios of varying acaricide efficacy and deer densities. The model predicted that treating deer can increase grouse density through controlling ticks and LIV, if acaricide efficacies are high and deer densities low. Comparing deer treated with 70% acaricide efficacy with a 70% cull rate suggested that treatment may be more effective than culling if initial deer densities are high. Our results will help inform tick control policies, optimize the targeting of control methods and identify conditions where host management is most likely to succeed. Our approach is applicable to other host-vector-pathogen systems.",
            "question": "Which is the vector of Louping ill virus?",
            "answers": {
                "answer_start": 681,
                "text": "Ixodes ricinus"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 668,
                "text": "three"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 623,
                "text": "xa"
            }
        },
        {
            "context": "The SWR1 histone replacement complex causes genetic instability and genome-wide transcription misregulation in the absence of H2A.Z. The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions. This dynamic alteration in nucleosome structure provides a molecular mechanism to regulate transcription, gene silencing, chromosome segregation and DNA repair. Here we show that genetic instability, sensitivity to drugs impairing different cellular processes and genome-wide transcriptional misregulation in htz1Delta can be partially or totally suppressed if SWR1 is not formed (swr1Delta), if it forms but cannot bind to chromatin (swc2Delta) or if it binds to chromatin but lacks histone replacement activity (swc5Delta and the ATPase-dead swr1-K727G). These results suggest that in htz1Delta the nucleosome remodelling activity of SWR1 affects chromatin integrity because of an attempt to replace H2A with Htz1 in the absence of the latter. This would impair transcription and, either directly or indirectly, other cellular processes. Specifically, we show that in htz1Delta, the SWR1 complex causes an accumulation of recombinogenic DNA damage by a mechanism dependent on phosphorylation of H2A at Ser129, a modification that occurs in response to DNA damage, suggesting that the SWR1 complex impairs the repair of spontaneous DNA damage in htz1Delta. In addition, SWR1 causes DSBs sensitivity in htz1Delta; consistently, in the absence of Htz1 the SWR1 complex bound near an endonuclease HO-induced DSB at the mating-type (MAT) locus impairs DSB-induced checkpoint activation. Our results support a stepwise mechanism for the replacement of H2A with Htz1 and demonstrate that a tight control of this mechanism is essential to regulate chromatin dynamics but also to prevent the deleterious consequences of an incomplete nucleosome remodelling.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 137,
                "text": "SWR1"
            }
        },
        {
            "context": "Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 98,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on human non-small cell lung cancer cells. The antitumor effect of CGP41251 (4'-N-benzoyl staurosporine), a selective protein kinase C (PKC) inhibitor, was examined on two kinds of human non-small cell lung cancer (NSCLC) cell lines (adenocarcinoma: A549 and squamous cell carcinoma: NCI-H520). CGP41251 at 0.5 or 1.0 microM inhibited the proliferation of these tumor cell lines significantly; However, at 0.1 microM, it did not show any significant inhibition. Cell cycle analysis indicated that CGP41251 at 0.5 or 1.0 microM arrested the cell cycle progression at the G2/M phase up to 24 hr, but 0.1 microM did not. It seems that the antiproliferative action of CGP41251 against human NSCLC is related to G2/M accumulation. In NCI-H520, CGP41251 caused DNA re-replication without mitosis. In a nude mice xenograft, CGP41251 at a dose of 200 mg/kg showed antitumor activity against these cell lines. Histopathologically, expansion of central necrosis was observed, although no destruction of tumor nests was seen by CGP41251 administration. In both tumor tissues, the PKC activity of the particulate fraction was significantly decreased by CGP41251 treatment. From these results, it is thought that the antitumor activity of CGP41251 against human NSCLS is accompanied by the decrease of PKC activity in the particulate fraction. Moreover, the G2/M arrest of the cell cycle induced by CGP41251 might be important for the growth inhibitory action of this compound.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 276,
                "text": "lung"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8"
            }
        },
        {
            "context": "Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay. We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 307,
                "text": "HEXA"
            }
        },
        {
            "context": "Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL) Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most common progressive encephalopathy of childhood, is caused by mutations in a novel lysosomal membrane protein (CLN3) with unknown function. In this study, we have confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by co-localizing it with soluble and membrane-associated lysosomal proteins. We have analysed the intracellular processing and localization of two mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the classical JNCL, and E295K [corrected], which is a rare missense mutation associated with an atypical form of JNCL. Pulse-chase labelling and immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461-677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 polypeptide. Transient expression of the two mutants in BHK cells showed that 461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected] was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wild-type CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutant was arrested in the cell soma. Interestingly, co-localization of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle marker indicates that the CLN3 protein might participate in synaptic vesicle transport/transmission. The data presented here provide clear evidence for a cellular distinction between classical and atypical forms of Batten disease both in neural and non-neural cells.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 153,
                "text": "JNCL"
            }
        },
        {
            "context": "A mammalian herpesvirus uses noncanonical expression and processing mechanisms to generate viral MicroRNAs. Canonical primary microRNA (pri-miRNA) precursors are transcribed by RNA polymerase II and then processed by the Drosha endonuclease to generate approximately 60 nt pre-miRNA hairpins. Pre-miRNAs in turn are cleaved by Dicer to generate mature miRNAs. Previously, some short introns, called miRtrons, were reported to fold into pre-miRNA hairpins after splicing and debranching, and miRNAs can also be excised by Dicer cleavage of rare endogenous short hairpin RNAs. Here we report that the miRNAs encoded by murine gamma-herpesvirus 68 (MHV68) are also generated via atypical mechanisms. Specifically, MHV68 miRNAs are transcribed from RNA polymerase III promoters located within adjacent viral tRNA-like sequences. The resultant pri-miRNAs, which bear a 5' tRNA moiety, are not processed by Drosha but instead by cellular tRNase Z, which cleaves 3' to the tRNA to liberate pre-miRNA hairpins that are then processed by Dicer to yield the mature viral miRNAs.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 745,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study. OBJECTIVE: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects. MATERIALS AND METHODS: This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 x 200 μg tablets (reference: A) or 1 x 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated. RESULTS: 80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 μg b.i.d. TREATMENTS: The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCτ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679. CONCLUSIONS: Bioequivalence was demonstrated between 8 x 200 μg and 1 x 1,600 μg selexipag at steady state.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 277,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Hereditary conjugated hyperbilirubinaemia: 37 years later. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 636,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), the predominating Ser/Thr phosphatase in the heart. Non-phosphorylated I-1 is inactive, whereas I-1 phosphorylated by protein kinase A (PKA) at Thr35 is a potent PP1 inhibitor. The phosphatases that dephosphorylate I-1Thr35 and thus deactivate I-1 in the heart are not established. Here we overexpressed I-1 in neonatal rat cardiac myocytes with recombinant adenovirus and determined phosphorylation of I-1, and one of the major target proteins of PKA/PP1 in the heart, phospholamban (PLB), by Western blot with phospho-specific antibodies. Incubation with the calcineurin inhibitor cyclosporine A or okadaic acid, used at a concentration preferentially inhibiting phosphatase 2A (PP2A), increased significantly I-1Thr35 (approximately 2- to 6-fold) and PLB Ser16 phosphorylation (approximately 2-fold). The results indicate that calcineurin and PP2A act to maintain a low basal level of phosphorylated (active) I-1 in living cardiac myocytes. Calcineurin may constitute a cross-talk between calcium- and cAMP-dependent pathways.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 113,
                "text": "Inhibitor 1"
            }
        },
        {
            "context": "Stereotactic radiosurgery for intracranial dural arteriovenous fistulas: a systematic review. OBJECT: The goal of this study was to evaluate the obliteration rate of intracranial dural arteriovenous fistulas (DAVFs) in patients treated with stereotactic radiosurgery (SRS), and to compare obliteration rates between cavernous sinus (CS) and noncavernous sinus (NCS) DAVFs, and between DAVFs with and without cortical venous drainage (CVD). METHODS: A systematic literature review was performed using PubMed. The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. The DAVFs were also categorized by location and by the presence of CVD. Statistical analyses of pooled data were conducted to assess complete obliteration rates in CS and NCS DAVFs, and in DAVFs with and without CVD. RESULTS: Nineteen studies were included, comprising 729 patients harboring 743 DAVFs treated with SRS. The mean obliteration rate was 63% (95% CI 52.4%-73.6%). Complete obliteration for CS and NCS DAVFs was achieved in 73% and 58% of patients, respectively. No significant difference in obliteration rates between CS and NCS DAVFs was found (OR 1.72, 95% CI 0.66-4.46; p=0.27). Complete obliteration in DAVFs with and without CVD was observed in 56% and 75% of patients, respectively. A significantly higher obliteration rate was observed in DAVFs without CVD compared with DAVFs with CVD (OR 2.37, 95% CI 1.07-5.28; p=0.03). CONCLUSIONS: Treatment with SRS offers favorable rates of DAVF obliteration with low complication rates. Patients harboring DAVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using SRS.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 515,
                "text": "DAVF"
            }
        },
        {
            "context": "Links between granuloma annulare, necrobiosis lipoidica diabeticorum and childhood diabetes: a matter of time? Diabetes mellitus is associated with a range of dermatologic presentations, including granuloma annulare and necrobiosis lipoidica diabeticorum. Granuloma annulare occurs earlier than necrobiosis lipoidica diabeticorum and the association with diabetes mellitus is much weaker. We describe two children with diabetes who both developed granuloma annulare and later, necrobiosis lipoidica diabeticorum. We postulate that the early onset and transient nature of granuloma annulare, compared with the later onset and persistence of necrobiosis lipoidica diabeticorum, might account for the different apparent rates of association with diabetes mellitus.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 111,
                "text": "Diabetes mellitus"
            }
        },
        {
            "context": "Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 721,
                "text": "thyroid"
            }
        },
        {
            "context": "Unique properties of lamp2a compared to other lamp2 isoforms. Lamp2a acts as a receptor in the lysosomal membrane for substrate proteins of chaperone-mediated autophagy. Using antibodies specific for the cytosolic tail of lamp2a and others recognizing all lamp2 isoforms, we found that in rat liver lamp2a represents 25% of lamp2s in the lysosome. We show that lamp2a levels in the lysosomal membrane in rat liver and fibroblasts in culture directly correlate with rates of chaperone-mediated autophagy in a variety of physiological and pathological conditions. The concentration of other lamp2s in the lysosomal membrane show no correlation under the same conditions. Furthermore, substrate proteins bind to lamp2a but not to other lamp2s. Four positively-charged amino acids uniquely present in the cytosolic tail of lamp2a are required for the binding of substrate proteins. Lamp2a also distributes to an unique subpopulation of perinuclear lysosomes in cultured fibroblasts in response to serum withdrawal, and lamp2a, more than other lamp2s, tends to multimerize. These characteristics may be important for lamp2a to act as a receptor for chaperone-mediated autophagy.",
            "question": "Which is the receptor for substrates of Chaperone Mediated Autophagy?",
            "answers": {
                "answer_start": 1112,
                "text": "lamp2a"
            }
        },
        {
            "context": "Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Glioblastoma multiforme (GBM) is the most common and deadly of the human brain cancers. The EGF receptor is often amplified in GBM and provides a potential therapeutic target. However, targeting the normal receptor is complicated by its nearly ubiquitous and high level of expression in certain tissues. A naturally occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively active variant originally identified in a high percentage of brain cancer cases, and more importantly is rarely found in normal tissue. A peptide vaccine, rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon 1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy in preclinical models. Recent Phase II clinical trials in patients with newly diagnosed GBM have shown EGFRvIII-specific immune responses and significantly increased time to progression and overall survival in those receiving vaccine therapy, as compared with published results for standard of care. Rindopepimut therefore represents a very promising therapy for patients with GBM.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 752,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 719,
                "text": "webSDA"
            }
        },
        {
            "context": "Restless leg syndrome manifested by iron deficiency from chronic hemoptysis in cystic fibrosis. Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be a continuum of a neurological sleep disorder associated with abnormal iron metabolism or deficiency. I describe a case of RLS and PLMD in a cystic fibrosis patient with iron deficiency from chronic hemoptysis. This is the first case that reports RLS and PLMD manifesting from iron deficiency caused by chronic hemoptysis in advanced cystic fibrosis lung disease.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 357,
                "text": "iron"
            }
        },
        {
            "context": "Inter-observer reproducibility of diagnosis of diabetic foot osteomyelitis based on a combination of probe-to-bone test and simple radiography. Probe-to-bone test and simple X-rays are both standard tests for the diagnosis of diabetic foot osteomyelitis. This study demonstrates the importance of considering jointly clinical information (probe-to-bone test) and diagnostic tests (simple radiography) to increase agreement among clinicians on diagnosis of diabetic foot osteomyelitis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 226,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1387,
                "text": "53BP1"
            }
        },
        {
            "context": "A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family. Giant axonal neuropathy is a severe autosomal recessive neurodegenerative disorder of childhood that affects both the peripheral and central nervous systems. It is caused by mutations in the GAN gene linked to chromosome 16q24.1 At least 45 distinct disease-causing mutations have been identified throughout the gene in families of various ethnic origins, with different symptomatologies and different clinical courses. To date, no characteristic mutation or phenotype-genotype correlation has been established. We describe a novel missense mutation in four siblings born to consanguineous parents of Arab original with clinical and molecular features compatible with giant axonal neuropathy. The phenotype was characterized by a predominant motor and sensory peripheral neuropathies and severe skeletal deformities.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 24,
                "text": "GAN gene"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 909,
                "text": "MethPed"
            }
        },
        {
            "context": "Inhibition of sPLA2 and endothelial function: a substudy of the SPIDER-PCI trial. BACKGROUND: Inflammation plays an important role in the pathophysiology of atherosclerosis and endothelial dysfunction, and occurs after percutaneous coronary intervention (PCI). We evaluated whether endothelial function is attenuated after PCI and if inhibition of secretory phospholipase A2 (sPLA2) activity augments endothelial function and coronary flow reserve (CFR) in these patients. METHODS: In the sPLA2 Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (SPIDER-PCI) study, patients undergoing elective PCI were randomized to receive Varespladib (Anthera Pharmaceuticals Inc, San Mateo, CA), an inhibitor of sPLA2, or placebo 3-5 days prior to PCI and for 5 days after PCI. In this substudy, endothelial function was assessed in 31 patients by flow-mediated dilation (FMD) before treatment and on the day after PCI, while taking study medication. During the PCI procedure, CFR was assessed using a Doppler guide wire. RESULTS: Baseline and procedural characteristics were comparable in both groups and sPLA2 activity was similar at baseline. After PCI, sPLA2 activity decreased only in the Varespladib group (2.9 ± 0.9 to 0.5 ± 0.4 ng/mL), and high-sensitivity C-reactive protein (hsCRP) increased by more than 100% in both groups. FMD at baseline was 3.66 ± 2.45% (Varespladib) and 3.37 ± 1.73% (placebo) with nonsignificant increase in both groups after PCI. The effect of Varespladib on FMD, adjusted for pre-PCI FMD by linear regression, was -1.16 ± 1.68%; P = 0.5. CFR was 2.45 ± 0.66 and 2.77 ± 0.85 in the Varespladib and placebo groups, respectively (P = 0.36). CONCLUSIONS: Systemic endothelial function is not reduced after elective PCI despite eliciting acute inflammatory response. Acute inhibition of sPLA2 activity with Varespladib does not affect endothelial or microvascular function after PCI.",
            "question": "Which enzyme is inhibited by Varespladib?",
            "answers": {
                "answer_start": 348,
                "text": "secretory phospholipase A2"
            }
        },
        {
            "context": "The bone-anchor sub-urethral sling for the treatment of iatrogenic male incontinence: subjective and objective assessment after 41 months of mean follow-up. OBJECTIVES: To evaluate retrospectively the objective and subjective parameters in 42 male patients who underwent bone anchored sub-urethral sling positioning (BAUS) for SUI (stress urinary incontinence) due to ISD (intrinsic sphincter deficiency). METHODS: Patients with SUI due to radical retropubic prostatectomy (36 patients), transurethral resection of prostate (5 patients) and open simple prostatectomy (1 patient) underwent BAUS positioning between July 1999 and September 2005 (mean FU = 41 months). Before and after surgery, the patients were evaluated by physical examination, urethrocystoscopy, urodynamics, 1 h pad test and QoL questionnaire. Surgical technique involved perineal implantation to the pubic rami using four anchors of a sub-urethral sling made of synthetic (26 patients), biological (4 patients) or mixed (12 patients) material. Patients were stratified into three groups: (1) Cured: dry patients at stress test, pad weight 0-1 g. (2) Improved: patients with mild-moderate incontinence, pad weight 2-50 g. (3) Failed: unchanged patients, pad weight > 50 g. RESULTS: At the final follow-up visit cured, improved and failed patients were 26 (62%), 4 (8%) and 12 (30%), respectively. Mean pad weight significantly decreased from 104.6 to 47.3 g (55%) and mean total questionnaire score significantly increased to 50.7 (66%). Mean ALPP significantly increased to 50.4 cmH2O (44.8%). Better results were seen with synthetic slings. Main complications were perineal pain (76%), detrusor overactivity (12%) and sling infection (4.8%). CONCLUSIONS: BAUS implantation is a safe, effective, minimally invasive option for iatrogenic male incontinence due to ISD. It compares favourably with AUS.",
            "question": "What is the gold standard treatment for Iatrogenic male incontinence?",
            "answers": {
                "answer_start": 1727,
                "text": "AUS"
            }
        },
        {
            "context": "Diagnosis of Krabbe disease by use of a natural substrate. This chapter describes in detail a practical procedure for the preparation of radiolabeled galactocerebroside and its use in the assay of galactocerebrosidase (GalCase), the enzyme deficient in globoid cell leukodystrophy (Krabbe disease). The reference range for leukocytes and fibroblasts is 0.9-4.4 and 8-36 nmoles substrate hydrolyzed per hour per milligram of protein, respectively. Because of its low abundance this enzyme is difficult to assay in certain situations, such as prenatal diagnosis by chorionic villus sampling. To obviate this a modified assay is used where only the radiolabeled substrate is included in the incubation. This provides a clear separation between affected samples and unaffected controls. The methods detailed here should be reproducible in any laboratory.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 197,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Daratumumab granted breakthrough drug status. Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 586,
                "text": "CD38"
            }
        },
        {
            "context": "Integrated nonclinical and clinical risk assessment of the investigational proteasome inhibitor ixazomib on the QTc interval in cancer patients. BACKGROUND: Ixazomib is the first oral, proteasome inhibitor to reach phase III trials. Here, we present an integrated nonclinical and clinical assessment of ixazomib's effect on QTc intervals. METHODS: Nonclinical studies assessed (1) the in vitro binding of ixazomib to the hERG channel and (2) its effect on QT/QTc in dogs (N = 4) via telemetry. Pharmacokinetic-matched triplicate electrocardiograms were collected in four clinical phase I studies of intravenous (0.125-3.11 mg/m(2), N = 125, solid tumors/lymphoma) or oral (0.24-3.95 mg/m(2), N = 120, multiple myeloma) ixazomib. The relationship between ixazomib plasma concentration and heart rate (HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was analyzed using linear mixed-effects models with fixed effects for day and time. RESULTS: In vitro binding potency for ixazomib to the hERG channel was weak (K i 24.9 μM; IC50 59.6 μM), and nonclinical telemetry studies showed no QT/QTc prolongation at doses up to 4.2 mg/m(2). In cancer patients, ixazomib, when evaluated at doses yielding various plasma concentrations (with 26 % of data greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was no relationship between ixazomib concentration and RR, suggesting no effect on HR. CONCLUSIONS: Ixazomib has no clinically meaningful effects on QTc or HR. Integrating preclinical data and concentration-QTc modeling of phase 1 data may obviate the need for a dedicated QTc study in oncology. A framework for QT assessment in oncology drug development is proposed.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 185,
                "text": "proteasome"
            }
        },
        {
            "context": "The new calcium antagonist isradipine. Effect on blood pressure and the left ventricle in black hypertensive patients. Treatment with the new calcium antagonist isradipine significantly reduced diastolic blood pressure to less than 90 mm Hg in 64% of fourteen blacks with mild or moderately severe essential hypertension. There was a significant reduction in the echocardiographic measures of left ventricular wall thickness and mass in these patients. There was also an increase in fractional left ventricular mass index, shortening and ejection fraction per 100 g left ventricular mass and no indication in mean circumferential shortening. There was another indication of improved left ventricular performance. With the reduced left ventricular mass and diastolic blood pressure, there was a reduction in the ratio of peak systolic wall stress to fractional shortening per 100 g left ventricular mass. There was a significant relationship between peak systolic wall stress and fractional shortening per 100 g left ventricular mass index. The directional change after left ventricular mass reduction with isradipine indicated improved left ventricular function. There was an increase in left ventricular wall thickness and mass both in those patients not controlled on isradipine combined with those treated with placebo (n = 10), and in those treated with placebo (n = 5) there was an increase in wall thickness. These changes occurred in five weeks. There was no regression to a lower mean of left ventricular mass or wall thickness during placebo. There was reduction in electrocardiogram (ECG) ST-T changes of ischemia in those patients with diastolic blood pressure reduced to less than 90 mm Hg. Isradipine monotherapy was an effective antihypertensive drug in blacks with essential hypertension, resulting in regression of left ventricular wall thickness and mass and augmentation of fractional shortening per 100 g left ventricular mass.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 1790,
                "text": "hypertension"
            }
        },
        {
            "context": "Anomalous Radial Artery as an Incidental Finding During a Routine Carpal Tunnel Release. BACKGROUND: Compression of the median nerve at the wrist, or carpal tunnel syndrome, is the most commonly recognized nerve entrapment syndrome. Carpal tunnel syndrome is usually caused by compression of the median nerve due to synovial swelling, tumor, or anomalous anatomical structure within the carpal tunnel. METHODS: During a routine carpal tunnel decompression, a large vessel was identified within the carpal tunnel. RESULTS: The large vessel was the radial artery. It ran along the radial aspect of the carpal tunnel just adjacent to the median nerve. CONCLUSIONS: The unusual presence of the radial artery within the carpal tunnel could be a contributing factor to the development of carpal tunnel syndrome. In this case, after surgical carpal tunnel release, all symptoms of carpal tunnel syndrome resolved.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 120,
                "text": "median"
            }
        },
        {
            "context": "The neurofibromatoses: when less is more. The study of cancer predisposition syndromes presents unique opportunities to gain insights into the genetic events associated with tumor pathogenesis. Individuals with two inherited cancer syndromes, neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), develop both benign and malignant tumors. The corresponding genes mutated in these two disorders encode tumor suppressor proteins, termed neurofibromin (NF1) and merlin (NF2), which function in novel ways to regulate cell growth and differentiation. Neurofibromin inhibits cell proliferation, at least in part, by modulating mitogenic pathway signaling through inactivation of p21-ras. In contrast, merlin may act as a membrane-associated molecular switch that regulates cell-cell and cell-matrix signals transduced by cell surface receptors. Significant progress in our understanding of the genetics and biology of NF1 and NF2 has elucidated the roles of these genes in tumor initiation and progression.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 453,
                "text": "NF1"
            }
        },
        {
            "context": "Restless leg syndrome: is it a real problem? Restless legs syndrome (RLS) is a common condition that is frequently unrecognized, misdiagnosed and poorly managed. It is characterized by uncomfortable sensations deep in the legs developing at rest that compel the person to move; symptoms are worst at night and sleep disturbance is common. RLS occurs in 7%-11% of the population in Western countries, and many such people experience troublesome symptoms. Primary RLS is familial in up to two thirds of patients. RLS may also be secondary to a number of conditions including iron deficiency, pregnancy and end-stage renal failure and, perhaps, neuropathy. Secondary RLS is most common in those presenting for the first time in later life. The pathogenesis of RLS probably involves the interplay of systemic or brain iron deficiency and impaired dopaminergic neurotransmission in the subcortex of the brain. RLS is very responsive to dopaminergic therapies. Rebound of RLS symptoms during the early morning and development of severe symptoms earlier in the day (augmentation) are problematic in those treated for a prolonged period with levodopa. Consequently, dopamine agonists have become first line treatment. Anti-convulsant medications and opioids are helpful in some patients. Correction of underlying problem wherever possible is important in the management of secondary RLS.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 573,
                "text": "iron"
            }
        },
        {
            "context": "The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. The classical view of the molecular clock is based on interlocked transcriptional-translational feedback loops. Because a substantial fraction of the mammalian genome is expressed in a circadian manner, chromatin remodeling has been proposed to be crucial in clock function. Here we show that Lys4 (K4) trimethylation of histone H3 is rhythmic and follows the same profile as previously described H3 acetylation on circadian promoters. MLL1, a mammalian homolog of Drosophila trithorax, is an H3K4-specific methyltransferase implicated in transcriptional control. We demonstrate that MLL1 is essential for circadian transcription and cyclic H3K4 trimethylation. MLL1 is in a complex with CLOCK-BMAL1 and contributes to its rhythmic recruitment to circadian promoters and to H3 acetylation. Yet MLL1 fails to interact with CLOCKΔ19, providing an explanation for this mutation's dominant negative phenotype. Our results favor a scenario in which H3K4 trimethylation by MLL1 is required to establish a permissive chromatin state for circadian transcription.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 582,
                "text": "H3K4"
            }
        },
        {
            "context": "Update of the FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation. The international Functional Annotation Of the Mammalian Genomes 4 (FANTOM4) research collaboration set out to better understand the transcriptional network that regulates macrophage differentiation and to uncover novel components of the transcriptome employing a series of high-throughput experiments. The primary and unique technique is cap analysis of gene expression (CAGE), sequencing mRNA 5'-ends with a second-generation sequencer to quantify promoter activities even in the absence of gene annotation. Additional genome-wide experiments complement the setup including short RNA sequencing, microarray gene expression profiling on large-scale perturbation experiments and ChIP-chip for epigenetic marks and transcription factors. All the experiments are performed in a differentiation time course of the THP-1 human leukemic cell line. Furthermore, we performed a large-scale mammalian two-hybrid (M2H) assay between transcription factors and monitored their expression profile across human and mouse tissues with qRT-PCR to address combinatorial effects of regulation by transcription factors. These interdependent data have been analyzed individually and in combination with each other and are published in related but distinct papers. We provide all data together with systematic annotation in an integrated view as resource for the scientific community (http://fantom.gsc.riken.jp/4/). Additionally, we assembled a rich set of derived analysis results including published predicted and validated regulatory interactions. Here we introduce the resource and its update after the initial release.",
            "question": "What was the purpose of the FANTOM4 project?",
            "answers": {
                "answer_start": 214,
                "text": "better understand the transcriptional network that regulates macrophage differentiation"
            }
        },
        {
            "context": "Stereotactic radiosurgery for intracranial dural arteriovenous fistulas: a systematic review. OBJECT: The goal of this study was to evaluate the obliteration rate of intracranial dural arteriovenous fistulas (DAVFs) in patients treated with stereotactic radiosurgery (SRS), and to compare obliteration rates between cavernous sinus (CS) and noncavernous sinus (NCS) DAVFs, and between DAVFs with and without cortical venous drainage (CVD). METHODS: A systematic literature review was performed using PubMed. The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. The DAVFs were also categorized by location and by the presence of CVD. Statistical analyses of pooled data were conducted to assess complete obliteration rates in CS and NCS DAVFs, and in DAVFs with and without CVD. RESULTS: Nineteen studies were included, comprising 729 patients harboring 743 DAVFs treated with SRS. The mean obliteration rate was 63% (95% CI 52.4%-73.6%). Complete obliteration for CS and NCS DAVFs was achieved in 73% and 58% of patients, respectively. No significant difference in obliteration rates between CS and NCS DAVFs was found (OR 1.72, 95% CI 0.66-4.46; p=0.27). Complete obliteration in DAVFs with and without CVD was observed in 56% and 75% of patients, respectively. A significantly higher obliteration rate was observed in DAVFs without CVD compared with DAVFs with CVD (OR 2.37, 95% CI 1.07-5.28; p=0.03). CONCLUSIONS: Treatment with SRS offers favorable rates of DAVF obliteration with low complication rates. Patients harboring DAVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using SRS.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 533,
                "text": "DAVF"
            }
        },
        {
            "context": "Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up. Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 564,
                "text": "IgG4"
            }
        },
        {
            "context": "Management of patients with newly diagnosed chronic myeloid leukemia: opportunities and challenges. Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm characterized by the presence of the Philadelphia chromosome. This arises from a balanced translocation between chromosomes 9 and 22, creating the bcr-abl fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation, which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy. After imatinib treatment, > 90% of patients had a complete hematologic response, and 70%-80% had a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging and exhibit a major change in the natural history of the disease. The understanding of some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that might overcome this resistance. The outlook today for patients with CML is much brighter than that of a few years ago.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 518,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "An update on the rotenone models of Parkinson's disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by two major neuropathological hallmarks: the degeneration of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies in the surviving SN neurons, as well as other regions of the central and peripheral nervous system. Animal models have been invaluable tools for investigating the underlying mechanisms of the pathogenesis of PD and testing new potential symptomatic, neuroprotective and neurorestorative therapies. However, the usefulness of these models is dependent on how precisely they replicate the features of clinical PD with some studies now employing combined gene-environment models to replicate more of the affected pathways. The rotenone model of PD has become of great interest following the seminal paper by the Greenamyre group in 2000 (Betarbet et al., 2000). This paper reported for the first time that systemic rotenone was able to reproduce the two pathological hallmarks of PD as well as certain parkinsonian motor deficits. Since 2000, many research groups have actively used the rotenone model worldwide. This paper will review rotenone models, focusing upon their ability to reproduce the two pathological hallmarks of PD, motor deficits, extranigral pathology and non-motor symptoms. We will also summarize the recent advances in neuroprotective therapies, focusing on those that investigated non-motor symptoms and review rotenone models used in combination with PD genetic models to investigate gene-environment interactions.",
            "question": "Which disease of the central nervous system is characterized by the presence of Lewy bodies?",
            "answers": {
                "answer_start": 158,
                "text": "Parkinson's disease (PD)"
            }
        },
        {
            "context": "Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 1055,
                "text": "obesity"
            }
        },
        {
            "context": "SUMO-conjugating enzyme E2 UBC9 mediates viral immediate-early protein SUMOylation in crayfish to facilitate reproduction of white spot syndrome virus. Successful viruses have evolved superior strategies to escape host defenses or exploit host biological pathways. Most of the viral immediate-early (ie) genes are essential for viral infection and depend solely on host proteins; however, the molecular mechanisms are poorly understood. In this study, we focused on the modification of viral IE proteins by the crayfish small ubiquitin-related modifier (SUMO) and investigated the role of SUMOylation during the viral life cycle. SUMO and SUMO ubiquitin-conjugating enzyme 9 (UBC9) involved in SUMOylation were identified in red swamp crayfish (Procambarus clarkii). Both SUMO and UBC9 were upregulated in crayfish challenged with white spot syndrome virus (WSSV). Replication of WSSV genes increased in crayfish injected with recombinant SUMO or UBC9, but injection of mutant SUMO or UBC9 protein had no effect. Subsequently, we analyzed the mechanism by which crayfish SUMOylation facilitates WSSV replication. Crayfish UBC9 bound to all three WSSV IE proteins tested, and one of these IE proteins (WSV051) was covalently modified by SUMO in vitro. The expression of viral ie genes was affected and that of late genes was significantly inhibited in UBC9-silenced or SUMO-silenced crayfish, and the inhibition effect was rescued by injection of recombinant SUMO or UBC9. The results of this study demonstrate that viral IE proteins can be modified by crayfish SUMOylation, prompt the expression of viral genes, and ultimately benefit WSSV replication. Understanding of the mechanisms by which viruses exploit host components will greatly improve our knowledge of the virus-host \"arms race\" and contribute to the development of novel methods against virulent viruses.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 0,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The pathogenic events in multiple sclerosis (MS) that result in immune cell infiltration, multifocal demyelination and axonal loss have been focused by the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) towards the hypothesis that MS is an entirely T cell-mediated disease. Although conspicuous humoral immune responses have been known since Kabal's seminal finding of elevated immunoglobulins (Igs) in the cerebrospinal fluid (CSF), only in the past few years evidence derived from recent studies of the MS lesion of anti-myelin antibodies (Abs) in patients with early MS and of MS animal models has led to a renewed interest in the role for B cells, plasma cells and their products in the pathogenesis of MS. This review surveys the actual data concerning the role of the humoral immune system in MS and EAE and explains potential modes of action and long-time persistence in the inflamed brain tissue as a B cell-supportive microenvironment in MS. These mechanisms include the modulation of antigen presentation and costimulation to T cells, increased myelin opsonisation und recruitment of inflammatory cells to the CNS, but also immunoregulatory influences on the remyelination by anti-myelin B cells and Abs. So, affecting the humoral immune system in MS would be a reasonable therapeutic option.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 331,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma. p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic DeltaNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. DeltaNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate DeltaNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73beta and its target genes. COX inhibitors also downregulate the alternative-spliced DeltaNp73(AS) isoforms, Deltaexon2 and Deltaexon2/3. Furthermore, forced expression of DeltaNp73(AS) results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of DeltaNp73(AS) is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 422,
                "text": "7"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 226,
                "text": "NCX"
            }
        },
        {
            "context": "Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues. Attempts to prevent HIV infection through pre-exposure prophylaxis (PrEP) include topical application of anti-HIV drugs to the mucosal sites of infection; however, a potential role for local drug metabolizing enzymes in modulating the exposure of the mucosal tissues to these drugs has yet to be explored. Here we present the first report that enzymes belonging to the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) families of drug metabolizing enzymes are expressed and active in vaginal and colorectal tissue using biopsies collected from healthy volunteers. In doing so, we discovered that dapivirine and maraviroc, a non-nucleoside reverse transcriptase inhibitor and an entry inhibitor currently in development as microbicides for HIV PrEP, are differentially metabolized in colorectal tissue and vaginal tissue. Taken together, these data should help to guide the optimization of small molecules being developed for HIV PrEP.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 874,
                "text": "HIV"
            }
        },
        {
            "context": "Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate. Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreER and GFP from ten different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium, including sources for specific subtypes of amygdala neurons. We then focused on deciphering transcriptional mechanisms that control enhancer activity. Using machine-learning computations, in vivo chromosomal occupancy of 13 transcription factors that regulate subpallial patterning and differentiation and analysis of enhancer activity in Dlx1/2 and Lhx6 mutants, we elucidated novel molecular mechanisms that regulate region-specific enhancer activity in the developing brain. Thus, these subpallial enhancer transgenic lines are data and tool resources to study transcriptional regulation of GABAergic cell fate.",
            "question": "Which resource has been developed in order to study the transcriptional regulation of GABAergic cell fate?",
            "answers": {
                "answer_start": 0,
                "text": "Subpallial Enhancer Transgenic Lines"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 132,
                "text": "OikoBase"
            }
        },
        {
            "context": "Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 124,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Right cerebral hemiatrophy: neurocognitive and electroclinical features. The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS]). Cognitive assessments with a particular emphasis on visuospatial functions, electroclinical features, and neuroimaging characteristics were analyzed for five patients with a clinically and neuroradiologically confirmed diagnosis of right-sided DDMS. Intelligence tests revealed mental retardation in all but one. Neuropsychological assessments demonstrated consistent impairments in tasks that have a spatial component (spatial processing and orientation discrimination), whereas attention, executive functions and verbal memory domains were variably impaired. Electroclinically, the main seizure types were simple partial motor, complex partial, and secondarily generalized seizures. Interictal EEG delineated lower amplitudes and slow background activity in the affected hemisphere. Overall, the cognitive performance of patients with DDMS encompasses a broad spectrum of impairments affecting multiple domains. Our findings support the concept that dorsal visual pathways responsible for spatial processing may be lateralized to the right hemisphere.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 190,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells. Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNγ promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNγ drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcγRI, which mediates effector responses to therapeutic antibodies. Importantly, IFNγ was able to up-regulate CD38, the target of the therapeutic antibody daratumumab. Because the antigen (CD38) and effector receptor (FcγRI) were both simultaneously up-regulated on the AML blasts, we tested whether IFNγ treatment of the AML cell lines THP-1 and MV4-11 could stimulate them to target one another after the addition of daratumumab. Results showed that IFNγ significantly increased daratumumab-mediated cytotoxicity, as measured both by Cr release and lactate dehydrogenase release assays. We also found that the combination of IFNγ and activation of FcγR led to the release of granzyme B by AML cells. Finally, using a murine NSG model of subcutaneous AML, we found that treatment with IFNγ plus daratumumab significantly attenuated tumor growth. Taken together, these studies show a novel mechanism of daratumumab-mediated killing and a possible new therapeutic strategy for AML.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 708,
                "text": "CD38"
            }
        },
        {
            "context": "Gaucher disease: N370S glucocerebrosidase gene frequency in the Portuguese population. In the Portuguese population the most frequent form of Gaucher disease is type 1. The N370S glucocerebrosidase gene mutation accounts for 63% of mutated alleles. The frequency of this mutation was accurately determined in the Portuguese population, which does not present an Ashkenazi Jewish genetic background. A gene frequency of 0.0043, with 95% confidence limits between 0.0023 and 0.0063, was obtained studying the genomic DNA of 2000 blood cards randomly sampled from the national neonatal screening program. On the basis of this frequency a significantly high number of homozygotes for the N370S mutation should be expected in the Portuguese population. This finding supports the idea that the majority of homozygotes for this mutation present a very mild clinical phenotype and remain undiagnosed.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 179,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 566,
                "text": "telomerase"
            }
        },
        {
            "context": "Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation. BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 39,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 25,
                "text": "TFIIS"
            }
        },
        {
            "context": "The tyrosinase gene and oculocutaneous albinism type 1 (OCA1): A model for understanding the molecular biology of melanin formation. Through the last century there has been a steady progression in our understanding of the biology of melanin biosynthesis. Much of this work includes the analysis of coat color mutations of the mouse and albinism in man. Our understanding has been greatly enhanced in the last 10 years, as the molecular pathogenesis of albinism has been better understood. Different mutations of the tyrosinase gene (TYR) , and their association with oculocutaneous albinism type 1 (OCA1) has provided insight into the biology of tyrosinase, including protein trafficking and structure/function analysis. Several questions still remain, including cryptic mutations that affect tyrosinase activity and the minimum amount of pigment required for normal optic development. The next 10 years should prove just as exciting as the last.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 4,
                "text": "tyrosinase"
            }
        },
        {
            "context": "LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.",
            "question": "Which R / bioconductor package is used for enrichment analysis of genomic regions?",
            "answers": {
                "answer_start": 402,
                "text": "LOLA"
            }
        },
        {
            "context": "Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. BACKGROUND: Cryptococcal disease is an opportunistic infection that causes significant morbidity and mortality in adults with HIV. Primary prophylaxis with antifungal interventions may decrease cryptococcal disease incidence and associated mortality. OBJECTIVES: To assess the efficacy of antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. SEARCH STRATEGY: We searched the following databases: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), Latin American and Caribbean Literature on the Health Sciences (LILACS), and the Cochrane Controlled Trials Register (CCTR). We reviewed abstracts from the following relevant conferences: International AIDS Conference, International AIDS Society Conference on HIV Pathogenesis and Treatment, and Conference on Retroviruses and Opportunistic Infections. We searched reference lists for all primary and other pertinent articles identified. We attempted to contact experts in the field, particularly primary authors of included studies, to better ensure completeness of included studies. We also approached pharmaceutical companies for any available and relevant unpublished data. The time period searched was from 1980 to August 2004. We placed no language restrictions on the search. Key words used include: meningitis, cryptococcal, cryptococcus, cryptococcosis, acquired immunodeficiency syndrome, human immunodeficiency virus, prophylaxis, chemoprevention, antifungal agents, and the Cochrane screen for randomized controlled trials. SELECTION CRITERIA: Randomized controlled trials using antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. Trial authors, experts, and pharmaceutical companies were contacted for additional and/or missing information. Data were abstracted by two reviewers. Data were pooled, where appropriate, to yield summary estimates. MAIN RESULTS: Five studies (N=1316) were identified. All study patients had CD4 cell counts <300 cells/microl, and the majority of patients had CD4 cell counts <150 cells/microl. When all five studies are analyzed as a single group (N=1316), the incidence of cryptococcal disease was decreased in those taking primary prophylaxis (RR 0.21, 95% CI 0.09, 0.46) compared to those taking placebo. However, there was no significant difference in overall mortality observed (RR 1.01, 95% CI 0.71, 1.44). When the three studies using itraconazole as the intervention were analyzed together (N=798), the incidence of cryptococcal disease was decreased in those taking itraconazole for primary prophylaxis (RR 0.12, 95% CI 0.03, 0.51) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 1.12, 95% CI 0.70, 1.80). When the two studies using fluconazole as the intervention were analyzed together (N=518), the incidence of cryptococcal disease was decreased in those taking fluconazole for primary prophylaxis (RR 0.25, 95% CI 0.07, 0.87) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 0.59, 95% CI 0.14, 2.62). AUTHORS' CONCLUSIONS: Antifungal primary prophylaxis with either itraconazole or fluconazole is effective in reducing the incidence of cryptococcal disease in adults with advanced HIV disease. However, neither of these interventions has a clear effect on overall mortality. Further research is needed to better understand these interventions and the populations in which they may be most effective.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 957,
                "text": "HIV"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 4,
                "text": "p53-binding protein 1"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1242,
                "text": "factor Xa"
            }
        },
        {
            "context": "2-Arylbenzimidazoles as antiviral and antiproliferative agents--Part 2. In prosecution of an anti-Flaviviridae project a new series of variously substituted 2-diphenyl-benzimidazoles were synthesized and tested in vitro for antiviral and antiproliferative activities. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). The 5-Acetyl-2-(4'-nitrobiphenyl-4-yl)-1H-benzimidazole (24) emerged as potent active lead compound against Yellow Fever Virus (a Flavivirus) (EC(50) = 0.5 microM) and CVB-2 at 1 microM and was not cytotoxic, whereas the other title benzimidazoles showed no antiviral activity at concentrations not cytotoxic for the resting cell monolayers. Among the examined series, the most cytotoxic derivatives (11,12,14,16,18,19,20,21,23,25-30) against mock-infected MT-4 cells (CC50 < 8.0 microM) were evaluated against a panel of human cell lines derived from haematological and solid tumours,using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, compounds 26 and 28 showed a similar potency of 6-MP and etoposide.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 360,
                "text": "three"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 215,
                "text": "MITF"
            }
        },
        {
            "context": "Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 81,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Genetic analysis of oculocutaneous albinism type 1 (OCA1) in Indian families: two novel frameshift mutations in the TYR Gene. PURPOSE: Oculocutaneous albinism type 1 (OCA1) patients demonstrate a partial or total lack of melanin in the skin, hair and eye. OCA1 is an autosomal recessive genetic disorder caused by mutations in the TYR gene located at chromosome band 11q14-q25. The purpose of this study was to carry out genetic analysis of OCA1 in Indian families. METHODS: Genomic DNA was isolated from blood leukocytes of all the individuals in this study. Haplotype analysis was performed at the TYR locus using informative microsatellite markers. Eight sets of primers were used to amplify the entire coding region of the TYR gene for bidirectional direct sequencing mutation analysis. RESULTS: Two novel deletions (c.937del8, c.1379del2) and a previously known nonsense mutation (R278X) in the TYR gene were identified from a total of 8 oculocutaneous albinism patients in India. CONCLUSIONS: Our study reports the distribution of two novel frameshift and a previously reported nonsense mutations in four OCA1 families from the Indian population. These findings will contribute to the development of a diagnostic method for OCA1 carrier status and genetic counseling for OCA1 affected families.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 116,
                "text": "TYR"
            }
        },
        {
            "context": "[Paraneoplastic hypoglycemia: The hopes of pathophysiological documentation]. Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. These tumors are rare and usually asymptomatic. The syndrome of hypoglycemia is seen in less than 5% of the cases, and the associated tumors are large with a high mitotic rate. The cause of hypoglycemia is related to insulin-like growth factors produced by these tumors called \"big\" IGF-2. Several biological tests can demonstrate the increase of \"big\" IGF-2 plasma levels confirming the diagnosis of non-islet cell tumor induced hypoglycemia. The diagnosis is suggested by imaging but diagnostic confirmation is provided by the surgery, which remains the treatment of choice. Resection in many cases is the cure leading to hypoglycemia resolution. Recurrences and malignant transformations are possible which imposes a long-term monitoring. We report a case with relapsed malignant pleural fibrous tumor for which the pathophysiological mechanism of hypoglycemia could be documented as a paraneoplastic syndrome.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 167,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Specific isoforms of p73 control the induction of cell death induced by the viral proteins, E1A or apoptin. A member of the p53 family, p73, has several isoforms and differentially regulates transcription of genes involved in the control of the cell cycle and apoptosis. We have previously shown efficient and p53-independent, tumor-specific cell death induced by the viral proteins E1A and Apoptin. Here, we demonstrate that the induction of apoptosis by these viral proteins involves activation of TAp73. Both E1A and Apoptin induced expression of endogenous TAp73 and the p53/p73 BH3-only pro-apoptotic target, PUMA, independently of the p53 function. Furthermore, exogenous expression of TAp73 isoforms, particularly TAp73beta, sensitized cells to killing by both E1A and Apoptin, while expression of DeltaNp73alpha blocked this activity. Besides, knockout of the p73 regulator, c-Abl, attenuated E1A-induced apoptosis. In accordance with the role of p73 in apoptosis induced by these viral proteins, overexpression of TAp73beta strongly induced apoptosis in p53-deficient cancer cells in vitro and in HNSCC xenografts. Using a doxycycline-inducible system, we provide evidence for target selectivity and significant differences in protein stability for specific p73 isoforms, suggesting a diverse and pivotal role for p73 in response to various genotoxic agents. Collectively, our data show that in the absence of the p53 function, viral proteins E1A and Apoptin utilize the p73 pathway to induce efficient tumor cell death.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 137,
                "text": "7"
            }
        },
        {
            "context": "diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data?",
            "answers": {
                "answer_start": 476,
                "text": "diffloop"
            }
        },
        {
            "context": "Sushi.R: flexible, quantitative and integrative genomic visualizations for publication-quality multi-panel figures. Interpretation and communication of genomic data require flexible and quantitative tools to analyze and visualize diverse data types, and yet, a comprehensive tool to display all common genomic data types in publication quality figures does not exist to date. To address this shortcoming, we present Sushi.R, an R/Bioconductor package that allows flexible integration of genomic visualizations into highly customizable, publication-ready, multi-panel figures from common genomic data formats including Browser Extensible Data (BED), bedGraph and Browser Extensible Data Paired-End (BEDPE). Sushi.R is open source and made publicly available through GitHub (https://github.com/dphansti/Sushi) and Bioconductor (http://bioconductor.org/packages/release/bioc/html/Sushi.html).",
            "question": "Which R/bioconductor package is used for integrative genomics visualizations?",
            "answers": {
                "answer_start": 416,
                "text": "Sushi.R"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 0,
                "text": "GBshape"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 42,
                "text": "Xa"
            }
        },
        {
            "context": "Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations. Gaucher disease (GD) is a disorder of glycosphinglipid metabolism caused by deficiency of lysosomal acid beta-glucosidase (GC), resulting in progressive deposition of glucosylceramide in macrophages. The glucose analogue, N-butyl-deoxynojirimycin (NB-DNJ, Miglustat), is an inhibitor of the ceramide-specific glucosyltransferase (CSG) which catalyzes the first step of glycosphingolipids biosynthesis and is currently approved for the oral treatment of type 1 GD. Using site-directed mutagenesis, we constructed plasmids containing wild-type and several mutations in glucocerebrosidase (GBA) gene. The plasmids were transfected into COS-7 cells and stable transfected cell lines were obtained by geneticin (G418) selection. Cells were cultured during 6 days with medium with or without 10 microM NB-DNJ. The addition of NB-DNJ to COS-7 cell medium leads to 1.3-, 2.1-, 2.3-, 3.6-, and 9.9-fold increase in the activity of S364R, wild-type, N370S, V15M, and M123T GC, respectively. However, no significant changes were observed in the activity of the L444P, L336P, and S465del mutated proteins, but a small decrease in the rare P266L variant was observed. These results suggest that NB-DNJ, in addition to the inhibitory effect on CSG, also works as a \"chemical chaperone\", increasing the activity of acid beta-glucosidase of wild-type and several GC mutated proteins, including the most frequent N370S mutation. The specific location of the Miglustat binding site in GC is unknown. Potential binding sites in the enzyme have been searched for using computational molecular docking. The searching strategy identified three potential GC binding sites for Miglustat, one being the substrate-binding site of the enzyme, which was the best-ranked site by AutoDock program. Therefore, it is possible that Miglustat exerts its chaperoning activity on acid beta-glucosidase by acting as an inhibitor bound at the active site. This increase on the activity of the acid beta-glucosidase would imply that Miglustat is not only a substrate reducer but also an inhibitor of the GC degradation, with very promising clinical implications for the treatment of GD patients.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 702,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 488,
                "text": "Hsp90"
            }
        },
        {
            "context": "Global DNA hypomethylation-induced ΔNp73 transcriptional activation in non-small cell lung cancer. p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic ΔΝp73 isoforms respectively. In this study, we investigated the DNA methylation status of both promoters as a means of epigenetic transcriptional control of their corresponding isoforms in 102 primary non-small cell lung carcinomas (NSCLCs). We demonstrated that while P1 hypermethylation-associated reduction of TAp73 mRNA levels is relatively infrequent, the P2 hypomethylation-associated over-expression of ΔΝp73 mRNA is a frequent event, particularly among squamous cell carcinomas. P2 hypomethylation strongly correlated with LINE-1 element hypomethylation, indicating that ΔΝp73 over-expression may be a passive consequence of global DNA hypomethylation.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 256,
                "text": "7"
            }
        },
        {
            "context": "Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. A single cell has the potential to kill an entire human being. Efforts to cure cancer are limited by survival of individual cancer cells despite immune surveillance and toxic therapies. Understanding the intricate network of pathways that maintain cellular homeostasis and mediate stress response or default into cell death is critical to the development of strategies to eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein response (UPR) are cellular pathways that degrade and recycle excess or damaged proteins to maintain cellular homeostasis and survival. This review will discuss autophagy and how it is integrated with proteasomal degradation and UPR to govern cell fate through restoration of cellular homeostasis or default into the apoptotic cell death pathway. The first response of autophagy is macroautophagy, which sequesters cytoplasm including organelles inside double-membraned autophagosome vesicles that fuse with lysosomes to degrade and recycle the contents. Ubiquitination patterns on proteins targeted for degradation determine whether adapter proteins will bring them to developing autophagosomes or to proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. These two processes and the lesser understood microautophagy, which involves direct engulfment of proteins into lysosomes, occur at basal and induced levels. Insufficient proteasome function or ER stress induction of UPR can induce autophagy, which can mitigate damage and stress. If this network is incapable of repairing the damage or overcoming continued stress, the default pathway of apoptosis is engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics has led to clinical trials investigating combinations of HCQ (hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. Further study of the complex integration of autophagy, proteasomal degradation, UPR and apoptosis is likely to provide additional targets for our fight against cancer. This article is part of a Special Issue entitled \"Apoptosis: Four Decades Later\".",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 1287,
                "text": "chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Fungal S-adenosylmethionine synthetase and the control of development and secondary metabolism in Aspergillus nidulans. The filamentous fungus Aspergillus nidulans carries a single gene for the S-adenosylmethionine (SAM) synthetase SasA, whereas many other organisms possess multiple SAM synthetases. The conserved enzyme catalyzes the reaction of methionine and ATP to the ubiquitous methyl group donor SAM. SAM is the main methyl group donor for methyltransferases to modify DNA, RNA, protein, metabolites, or phospholipid target substrates. We show here that the single A. nidulans SAM synthetase encoding gene sasA is essential. Overexpression of sasA, encoding a predominantly cytoplasmic protein, led to impaired development including only small sterile fruiting bodies which are surrounded by unusually pigmented auxiliary Hülle cells. Hülle cells are the only fungal cell type which does not contain significant amounts of SasA. Sterigmatocystin production is altered when sasA is overexpressed, suggesting defects in coordination of development and secondary metabolism. SasA interacts with various metabolic proteins including methionine or mitochondrial metabolic enzymes as well as proteins involved in fungal morphogenesis. SasA interaction to histone-2B might reflect a putative epigenetic link to gene expression. Our data suggest a distinct role of SasA in coordinating fungal secondary metabolism and development.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 409,
                "text": "SAM"
            }
        },
        {
            "context": "Incidence and anatomical variations of accessory navicular bone in patients with foot pain: A retrospective radiographic analysis. The accessory navicular (AN) is an accessory ossicle anatomically located on the medial side of the foot, proximal to the navicular and continuous with the tibialis posterior tendon. It is occasionally a source of pain and local tenderness. Knowledge of the AN and its morphological variations can help identify the source of a patient's symptoms and prevent misinterpreting them as fractures. Foot radiographs from 1,240 patients who presented in two centers with chronic foot pain, or persistent pain developed after trauma, were retrospectively reviewed to determine the incidence and variations of the AN in relation to gender. The AN was found in 20.9% (259/1240). Among 259 feet with AN, Type 1 was identified in 25.4% (66/259), Type 2 in 42.4% (110/259) (20.0% (52/259) Type 2 A and 22.4% (58/259) Type 2B), and Type 3 in 32.0% (83/259). After 13 patients with incomplete medical records had been excluded, the remaining records showed that foot pain was associated with an AN in 10.6% of patients (26/246). In 1.2% of cases, two additional ossicles were found proximal to the navicular, possibly the result of multiple ossification centers that did not unite at the time of development. Patient symptomatology was related to the presence of an AN in 2% of patients with chronic foot pain. The AN could vary morphologically. Our data can enhance our diagnostic skills in detecting these ossicles. Clin. Anat. 30:436-444, 2017. © 2017 Wiley Periodicals, Inc.",
            "question": "Where in the body would the navicular bone be found?",
            "answers": {
                "answer_start": 231,
                "text": "foot"
            }
        },
        {
            "context": "Structure-guided design of a methyl donor cofactor that controls a viral histone H3 lysine 27 methyltransferase activity. vSET (a viral SET domain protein) is an attractive polycomb repressive complex 2 (PRC2) surrogate to study the effect of histone H3 lysine 27 (H3K27) methylation on gene transcription, as both catalyze histone H3K27 trimethylation. To control the enzymatic activity of vSET in vivo with an engineered S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried out structure-guided design, synthesis, and characterization of orthogonal vSET methyltransferase mutant/SAM analogue pairs using a \"bump-and-hole\" strategy.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 609,
                "text": "SAM"
            }
        },
        {
            "context": "Characterisation of inflammatory response, coagulation, and radiological findings in Katayama fever: a report of three cases at the Medical University of Vienna, Austria. BACKGROUND: Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp. infection. It is predominantly reported in travellers from non-endemic regions. Whereas the immunological response to Schistosoma infection is well characterised, alterations in inflammatory markers and coagulation in response to acute infection are poorly understood. METHODS: Here we report the clinical, laboratory and radiological characteristics of three returning travellers with Katayama fever. Inflammatory markers and coagulation status were assessed repeatedly during follow-up to characterise the host response to infection. Radiographic findings were correlated with clinical and laboratory markers. RESULTS: Clinical symptoms were suggestive of a significant inflammatory response in all patients including high fever (>39°C), cough, and general malaise. Classical inflammatory markers including blood sedimentation rate, C-reactive protein, and serum amyloid A were only moderately elevated. Marked eosinophilia (33-42% of white blood cells) was observed and persisted despite anti-inflammatory and anthelminthic treatment for up to 32 weeks. Analysis of blood coagulation markers indicated increased coagulability reflected by elevated D-dimer values (0.57-1.17 μg/ml) and high thrombin generating potentials (peak thrombin activity: 311-384 nM). One patient showed particularly high levels of microparticle-associated tissue factor activity at initial presentation (1.64 pg/ml). Multiple pulmonary and hepatic opacities demonstrated by computed tomography (CT) scanning were associated with raised inflammatory markers in one patient. CONCLUSIONS: The characterisation of the inflammatory response, blood coagulation parameters and radiological findings in three patients adds to our current understanding of Katayama fever and serves as a starting point for further systematic investigations of the pathophysiology of this acute helminthic infection.",
            "question": "What causes Katayama Fever?",
            "answers": {
                "answer_start": 311,
                "text": "Schistosoma spp"
            }
        },
        {
            "context": "Structural biology of human H3K9 methyltransferases. UNLABELLED: SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 65,
                "text": "SET domain"
            }
        },
        {
            "context": "Jamaican vomiting sickness: a study of two adult cases. An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. Analyses of serum and urine samples were performed to compare the patterns of organic acidaemia and aciduria with those reported from childhood cases. The main conclusion from the comparison is that the toxic ackee constitutent, hypoglycin, produces essentially the same metabolic effects in adults as in children.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 148,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Early onset HER2-positive breast cancer is associated with germline TP53 mutations. BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 718,
                "text": "positive"
            }
        },
        {
            "context": "Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 414,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients. BACKGROUND: Gaucher disease (GD) is a heterogeneous disease characterized by an impaired activity of the lysosomal glucocerebrosidase. This heterogeneity is attributed in part to the existence of a large number of mutations in the corresponding gene. SUBJECTS AND METHODS: To establish genotype-phenotype relationships, we analyzed the residual enzyme activities of six naturally occurring mutations found in Spanish population in the glucocerebrosidase gene [c.160G > A (V15M), c.485T>C (M123T), c.914C>T (P266L), c.1124T>C (L336P), c.1207A>C (S364R) and c.1510-1512delTCT (S465del)]. The mutated genes were subcloned into the mammalian expression vector pCR 3.1 and expressed by transient transfection in COS cells. The enzymatic activity of the expressed protein were measured and compared with the wild-type human glucocerebrosidase cDNA. Also, two previously alleles, c.1226A>G (N370S) and c.1448T>C (L444P), were used for comparative purposes. RESULTS: The residual activity of the expressed proteins using the synthetic substrate (4-methylumbelliferyl-beta-D-glucopyranoside, 4MU-Glu) ranged from 5.5% (for the 3-bp deletion) to 42.7% (for S364R mutation) of the activity of the wild-type enzyme. CONCLUSION: The present analyses may help to better understand the molecular basis and the pathogenesis of Gaucher disease. However, results of expression of mutated enzymes are necessary but not sufficient to explain the ultimate clinical outcome of Gaucher disease.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 241,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 39,
                "text": "CD38"
            }
        },
        {
            "context": "Posterior spinal fusion for scoliosis in Ehlers-Danlos syndrome, kyphoscoliosis type. The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by articular hypermobility, skin extensibility, and tissue fragility. Surgical treatment of scoliosis associated with Ehlers-Danlos syndrome poses a challenge to spine surgeons because of the high risk of major complications. There is a paucity of evidence in the literature on surgical treatment for scoliosis in the Ehlers-Danlos syndrome patient.This article describes 3 adolescent patients diagnosed with Ehlers-Danlos syndrome, kyphoscoliosis type, which was treated by posterior spinal fusion only. After unsuccessful conservative treatment for at least 1 year, the patients underwent posterior spinal surgery for the correction of spinal deformity. A satisfactory correction in the spinal curve was achieved, with no obvious loss of correction during follow-up. No intra- or postoperative major complications were observed.Our experience supports that a satisfactory correction of scoliosis can be achieved by posterior spinal fusion only in patients with Ehlers-Danlos syndrome, kyphoscoliosis type.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 185,
                "text": "connective tissue"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 45,
                "text": "MRSA"
            }
        },
        {
            "context": "Rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) in diverse clinical specimens by the BD GeneOhm MRSA assay and comparison with culture. The efficacy of the BD GeneOhm methicillin-resistant Staphylococcus aureus (MRSA) assay was assessed by analyzing nasal swabs and swabs from other body sites for the presence of MRSA in a low-prevalence area. From 681 patients with a high risk for MRSA carriage, 1,601 specimens were collected and transported in Amies agar. After discordant analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of the BD GeneOhm MRSA assay were 84.3%, 99.2%, 88.4%, and 98.9%, respectively, compared to culture.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 118,
                "text": "MRSA"
            }
        },
        {
            "context": "Nucleotide excision repair and its interplay with transcription. Nucleotide excision repair (NER) is a multistep process capable to remove a variety of DNA distorting lesions from prokaryotic and eukaryotic genomes. In eukaryotic cells, the process requires more than 30 proteins to perform the different steps, i.e. recognition of DNA damage, single strand incisions and excision of the lesion-containing DNA fragment and DNA repair synthesis/ligation. NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes. Both in vivo as well as in cultured cells the fast removal of transcription blocking lesions by TCR is crucial to escape from lethal effects of inhibited transcription inhibition The most delicate step in NER is the recognition of the DNA lesions in their different chromatin context and the mechanism of damage recognition in GGR and TCR is principally different and requires specific proteins. In GGR, the XPC-HR23B is essential for the formation of the incision complex. In TCR the Cockayne syndrome (CS) gene products are key players in the recognition of a stalled RNA polymerase the presumed signaling structure for repair of transcribed strands. In this study, we show that the extent of recovery of UV-inhibited transcription and TCR strictly depends on the amount of CSB protein as well as the amount of DNA damage present in the cell. This indicates that the ratio between DNA damage frequency and CSB protein concentration in the cell is rather critical for acute cellular response, i.e. recovery of inhibited transcription upon DNA damage infliction, and hence cellular survival.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 643,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Overt and occult rheumatic diseases: the child with chronic fever. Identification of the genes involved in hereditary periodic fever syndromes has led to the recognition of a new pathophysiological category, the autoinflammatory disorders. The main non-hereditary autoinflammatory disease in childhood is systemic juvenile idiopathic arthritis (sJIA), others being the chronic infantile neurological cutaneous arthropathy (CINCA) syndrome and the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. Familial Mediterranean fever (FMF) has been traced to mutations in the MEFV gene. Mutations in the MVK gene, encoding the enzyme mevalonate kinase, cause the hyper-IgD periodic fever syndrome (HIDS). The tumour necrosis factor(TNF)-receptor-associated periodic syndromes (TRAPS) have been linked to mutations in theTNFRSF1A gene, encoding a TNF-alpha receptor, and the CIAS1 gene is mutated in familial cold autoinflammatory syndrome. We discuss how this knowledge has influenced diagnosis and treatment of these rare genetic disorders and how it might change our approach to the more common rheumatic diseases.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 600,
                "text": "MEFV gene"
            }
        },
        {
            "context": "[Chronic myeloid leukemia and imatinib: Experience at the Lome Campus teaching hospital (Togo)]. BACKGROUND: Chronic myeloid leukemia (CML) is a clonal malignant myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (t 9.22). Our main objective was to assess the efficacy of imatinib in CML patients, measured by their survival. METHODS: Over a six-year period (June 2003 through May 2009), 25 patients were seen regularly for CML at the Lomé Campus teaching hospital. Patients received imatinib after diagnosis and underwent regular laboratory monitoring (quantification of BCR-ABL ratio by RT-PCR). Patients' survival and treatment response were evaluated. RESULTS: Patients' mean age at diagnosis was 40 years (range: 9 to 72 years). Men predominated (17 compared with 7 women). Splenomegaly was found in 80% of cases. The mean leukocyte level was 188.71 g/L (24.4-350). Six patients (24%) had thrombocytosis with a mean platelet count of 491.15 g/L (108-2000). Six patients (24%) died after developing accelerated-phase CML or blast crisis. Estimated overall survival of patients at 6 years was 60%. Molecular biology monitoring detected a secondary G250E mutation with resistance to imatinib in one patient. Standard hematological side effects led to reduction in imatinib doses. The principal nonhematological side effects were weight gain and transient digestible disorders. CONCLUSIONS: At six years after diagnosis, imatinib was effective in treating patients with CML, even in sub-Saharan Africa. Mutation-induced resistance required regular molecular biological monitoring to determine the need to switch to later-generation tyrosine kinase inhibitors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 640,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 553,
                "text": "thyroid"
            }
        },
        {
            "context": "Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene. Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth impairment pre- and postnatally with abnormal glucose metabolism and a characteristic pattern of soft tissue overgrowth. We report a 5 day old neonate with refractory hyperglycemia and paradoxical hypoglycemia, severe intrauterine growth retardation, typical 'elfin' facies (hypertrichosis, large and low-set ears, broad nasal tip, flared nares, thick lips), reduced subcutaneous fat, distended abdomen, and enlarged external genitalia and nipples. Fasting serum insulin and C-peptide were severely elevated at >2,100 pmol/l and >2,331 pmol/l, respectively. In addition, hepatic, ovarian and renal enlargement was demonstrated by ultrasonography. The neonate died within two months secondary to hypoglycemia. Diplex PCR analysis of the insulin receptor gene revealed the neonate to be homozygous for deletion of exon 3. Both parents were heterozygous for this deletion but were metabolically healthy. As such a deletion has previously been reported in Israel, we suggest that it may show a founder effect in the Middle East.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 72,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Applying the discovery of the Philadelphia chromosome. The identification of the Philadelphia chromosome in cells from individuals with chronic myelogenous leukemia (CML) led to the recognition that the BCR-ABL tyrosine kinase causes CML. This in turn led to the development of imatinib mesylate, a clinically successful inhibitor of the BCR-ABL kinase. Incorporating the use of markers of BCR-ABL kinase inhibition into clinical trials led to the realization that imatinib-resistant kinase domain mutations are the major cause of relapse during imatinib therapy and the subsequent development of new inhibitors to treat CML patients. The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 338,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "BCR signaling in chronic lymphocytic leukemia and related inhibitors currently in clinical studies. Normal B lymphocytes receive signals from B-cell antigen receptor (BCR) that are triggered by binding of the BCR to an external antigen. Tonic signaling through the BCR provides growth and signals to chronic lymphocytic leukemia (CLL) cells, and plays an important role in the pathogenesis and progression of the disease. Antigen engagement of BCR is followed by intracellular recruitment and activation of BCR-associated kinases including spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk) and phosphatidylinositol 3-kinases (PI3K). Inhibition of signaling pathways downstream of the BCR induces disruption of chemokine-mediated CLL cell migration and cell killing. BCR signal transduction inhibitors represent a promising new strategy for targeted CLL treatment. A number of therapeutic agents have recently been developed with significant activity in CLL. The compounds that are currently investigated in patients with CLL include ibrutinib -inhibitor of Btk, fostamatinib-inhibitor of Syk and idelalisib (GS-1101) -a specific isoform of the PI3K (PI3K) inhibitor. The clinical activity of ibrutinib, GS-1101 and fostamatinib in patients with CLL is associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. Further studies are ongoing with single agents and their combinations with other targeted and conventional therapies. This article will review the preclinical rationale of BCR signaling inhibitors in the treatment of CLL, and the clinical evidence supporting the use of these agents in CLL patients.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1044,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 426,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Who, when, and how to reverse non-vitamin K oral anticoagulants. Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1261,
                "text": "factor Xa"
            }
        },
        {
            "context": "Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Riociguat (Adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 0,
                "text": "Riociguat"
            }
        },
        {
            "context": "Tolerance to oats in dermatitis herpetiformis. OBJECTIVES: Recent studies on coeliac disease have shown that oats can be included in a gluten-free diet without adverse effects on the small bowel. The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats. PATIENTS/METHODS: Eleven patients with dermatitis herpetiformis in remission on a gluten-free diet were challenged daily with 50 g oats for six months. Clinical symptoms were recorded, serum samples taken, and skin and small bowel biopsies performed before and after the oat challenge. A control group comprised of 11 patients with dermatitis herpetiformis on a conventional gluten-free diet was also studied. RESULTS: Eight patients challenged with oats remained asymptomatic, two developed a transient rash, and one withdrew because of the appearance of a more persistent but mild rash. Three of the 11 controls also developed a transient rash. IgA endomysial antibodies remained negative in all patients. The small bowel villous architecture, the densities of intraepithelial CD3 and alpha/beta and gamma/delta T cell receptor positive lymphocytes and crypt epithelial cell DR expression remained unaltered during the oat challenge. CONCLUSIONS: The results confirm the absence of oat toxicity on the gluten sensitive small bowel mucosa and suggest that the rash in patients with dermatitis herpetiformis is not activated by eating oats.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 1469,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 931,
                "text": "factor Xa"
            }
        },
        {
            "context": "Eosinophilic oesophagitis: epidemiology, pathogenesis and management. Eosinophilic oesophagitis (EE) is a clinico-pathological entity recognized with increased frequency in children and adults. It is an atopic disease involving ingested and inhaled allergens. A pathological eosinophilic infiltrate is diagnosed by finding > 15 eosinophils per high-powered field on oesophageal mucosal biopsies. This infiltrate may result in a narrowed oesophageal lumen. It does not involve the stomach or duodenum. Children commonly present with abdominal pain, vomiting and dysphagia. Presentation in adults is with dysphagia, heartburn, chest pain or impaction of a food bolus in the oesophagus. There is often a history of allergy (asthma, hay fever, eczema). A male predominance (70% in adults) is unexplained. Distinctive endoscopic features are linear furrows, mucosal rings and white papules, and the narrowed lumen may be appreciated. Although EE and gastro-oesophageal reflux disease are separate entities, there is a significant overlap of the conditions. Treatment options include nonpharmacological approaches including an elimination or elemental diet, and/ or medications, chiefly with corticosteroids. The topical administration of fluticasone propionate has been demonstrated to improve symptoms and mobilize the pathological infiltrate of eosinophils. There has been a variable effect with the leukotriene receptor antagonist montelukast and promising early results with mepolizumab, a monoclonal antibody against interleukin-5. The long-term efficacy of topical corticosteroids has not been well studied and most patients experience recurrent symptoms when treatment is completed. Currently, repeated short courses of topical corticosteroids are utilized. Acid suppression by a proton pump inhibitor may be considered in view of the overlap between EE and gastro-oesophageal reflux disease.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 1517,
                "text": "interleukin-5"
            }
        },
        {
            "context": "The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster. RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar(5G1) null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar(5G1) mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar(5G1) null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 4,
                "text": "ADAR"
            }
        },
        {
            "context": "Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (deltaN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not deltaNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 400,
                "text": "7"
            }
        },
        {
            "context": "Long-term remission in patients with dermatitis herpetiformis on a normal diet. BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. OBJECTIVES: To investigate the effects on long-term remission of dermatitis herpetiformis in patients who underwent a gluten challenge and subsequently reintroduced dietary gluten. PATIENTS AND METHODS: We studied 38 patients (14 male and 24 female) with biopsy-confirmed dermatitis herpetiformis. They had followed a gluten-free diet for a mean of 8 years, achieving clinical remission and intestinal normalization. The patients were asked to reintroduce gluten in their diet and agreed to undergo skin and intestinal biopsies during the follow-up. RESULTS: Of the 38 patients abandoning a gluten-free diet, 31 reported the onset of rash within an average of 2 months. Seven subjects (three males, mean age 15 years at challenge) experienced no clinical or histological relapses (median follow-up 12 years), and lost IgA immunoglobulin from the skin. The two series of patients differed in terms of age at diagnosis (mean age: 26.6 vs. 6 years), the use of dapsone (one of 31 vs. four of seven) and adherence to the gluten-free diet (strict compliance in 26 of 31 vs. none of seven). CONCLUSIONS: Our data suggest that the ingestion of small doses of gluten in childhood and/or the use of an anti-inflammatory drug may modify the immunological response inducing immune tolerance. We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 152,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Hyperalgesia in an animal model of multiple sclerosis. Many individuals with multiple sclerosis (MS) experience clinically significant pain, yet the underlying neural mechanisms for MS pain are not understood. Experimental autoimmune encephalomyelitis (EAE) is a well-studied disease in rodents that mimics many clinical and pathological features of MS, including central nervous system inflammation and demyelination. To determine whether EAE is an appropriate model for MS-related pain, nociceptive responses in both male and female SJL mice were measured before and after immunization with myelin proteolipid protein peptide 139-151 (PLP(139-151)) in complete Freund's adjuvant to induce 'active' EAE. To determine if changes in nociception were due to direct effects of encephalitogenic T cells, nociceptive responses in female SJL mice were measured following the transfer of activated, PLP(139-151) specific T cells to induce 'passive' EAE. Both forepaw and tail withdrawal latencies to a radiant heat stimulus were measured. In both active and passive EAE, there was an initial increase in tail withdrawal latency (hypoalgesia) that peaked several days prior to the peak in motor deficits during the acute disease phase. During the chronic disease phase, tail withdrawal latencies decreased and were significantly faster than control latencies for up to 38 days post-immunization. This hyperalgesia was seen in both sexes and in both active and passive EAE models. Forepaw withdrawal latencies remained within 1-2 s of baseline latencies for the entire testing period, indicating that the hypoalgesia and hyperalgesia were most pronounced in clinically affected body regions. These results suggest that both active and passive EAE are useful models of MS-related pain.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 210,
                "text": "Experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Lack of p53 affects the expression of several brain mitochondrial proteins: insights from proteomics into important pathways regulated by p53. The tumor suppressor protein p53 has been described \"as the guardian of the genome\" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals. Although p53 promotes longevity by decreasing the risk of cancer through activation of apoptosis or cellular senescence, several findings suggest that an increase of its activity may have deleterious effects leading to selected aspects of the aging phenotype and neurodegenerative diseases. There is the link between p53 and oxidative stress, the latter a crucial factor that contributes to neurodegenerative processes like Alzheimer disease (AD). In the present study, using a proteomics approach, we analyzed the impact of lack of p53 on the expression of several brain mitochondrial proteins involved in different pathways, and how lack of p53 may present a target to restore neuronal impairments. Our investigation on isolated brain mitochondria from p53((-/-)) mice also provides a better understanding of the p53-mitochondria relationship and its involvement in the development of many diseases.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 172,
                "text": "p53"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 388,
                "text": "phosphatase 2B"
            }
        },
        {
            "context": "Profiling of pre-micro RNAs and microRNAs using quantitative real-time PCR (qPCR) arrays. Quantitative real-time PCR (QPCR) has emerged as an accurate and valuable tool in profiling gene expression levels. One of its many advantages is a lower detection limit compared to other methods of gene expression profiling while using smaller amounts of input for each assay. Automated qPCR setup has improved this field by allowing for greater reproducibility. Its convenient and rapid setup allows for high-throughput experiments, enabling the profiling of many different genes simultaneously in each experiment. This method along with internal plate controls also reduces experimental variables common to other techniques. We recently developed a qPCR assay for profiling of pre-microRNAs (pre-miRNAs) using a set of 186 primer pairs. MicroRNAs have emerged as a novel class of small, non-coding RNAs with the ability to regulate many mRNA targets at the post-transcriptional level. These small RNAs are first transcribed by RNA polymerase II as a primary miRNA (pri-miRNA) transcript, which is then cleaved into the precursor miRNA (pre-miRNA). Pre-miRNAs are exported to the cytoplasm where Dicer cleaves the hairpin loop to yield mature miRNAs. Increases in miRNA levels can be observed at both the precursor and mature miRNA levels and profiling of both of these forms can be useful. There are several commercially available assays for mature miRNAs; however, their high cost may deter researchers from this profiling technique. Here, we discuss a cost-effective, reliable, SYBR-based qPCR method of profiling pre-miRNAs. Changes in pre-miRNA levels often reflect mature miRNA changes and can be a useful indicator of mature miRNA expression. However, simultaneous profiling of both pre-miRNAs and mature miRNAs may be optimal as they can contribute nonredundant information and provide insight into microRNA processing. Furthermore, the technique described here can be expanded to encompass the profiling of other library sets for specific pathways or pathogens.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 1020,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 734,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data. BACKGROUND: Identifying and tackling the social determinants of infectious diseases has become a public health priority following the recognition that individuals with lower socioeconomic status are disproportionately affected by infectious diseases. In many parts of the world, epidemiologically and genotypically defined community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged to become frequent causes of hospital infection. The aim of this study was to use spatial models with adjustment for area-level hospital attendance to determine the transmission niche of genotypically defined CA- and health-care-associated (HA)-MRSA strains across a diverse region of South East London and to explore a potential link between MRSA carriage and markers of social and material deprivation. METHODS AND FINDINGS: This study involved spatial analysis of cross-sectional data linked with all MRSA isolates identified by three National Health Service (NHS) microbiology laboratories between 1 November 2011 and 29 February 2012. The cohort of hospital-based NHS microbiology diagnostic services serves 867,254 usual residents in the Lambeth, Southwark, and Lewisham boroughs in South East London, United Kingdom (UK). Isolates were classified as HA- or CA-MRSA based on whole genome sequencing. All MRSA cases identified over 4 mo within the three-borough catchment area (n = 471) were mapped to small geographies and linked to area-level aggregated socioeconomic and demographic data. Disease mapping and ecological regression models were used to infer the most likely transmission niches for each MRSA genetic classification and to describe the spatial epidemiology of MRSA in relation to social determinants. Specifically, we aimed to identify demographic and socioeconomic population traits that explain cross-area extra variation in HA- and CA-MRSA relative risks following adjustment for hospital attendance data. We explored the potential for associations with the English Indices of Deprivation 2010 (including the Index of Multiple Deprivation and several deprivation domains and subdomains) and the 2011 England and Wales census demographic and socioeconomic indicators (including numbers of households by deprivation dimension) and indicators of population health. Both CA-and HA-MRSA were associated with household deprivation (CA-MRSA relative risk [RR]: 1.72 [1.03-2.94]; HA-MRSA RR: 1.57 [1.06-2.33]), which was correlated with hospital attendance (Pearson correlation coefficient [PCC] = 0.76). HA-MRSA was also associated with poor health (RR: 1.10 [1.01-1.19]) and residence in communal care homes (RR: 1.24 [1.12-1.37]), whereas CA-MRSA was linked with household overcrowding (RR: 1.58 [1.04-2.41]) and wider barriers, which represent a combined score for household overcrowding, low income, and homelessness (RR: 1.76 [1.16-2.70]). CA-MRSA was also associated with recent immigration to the UK (RR: 1.77 [1.19-2.66]). For the area-level variation in RR for CA-MRSA, 28.67% was attributable to the spatial arrangement of target geographies, compared with only 0.09% for HA-MRSA. An advantage to our study is that it provided a representative sample of usual residents receiving care in the catchment areas. A limitation is that relationships apparent in aggregated data analyses cannot be assumed to operate at the individual level. CONCLUSIONS: There was no evidence of community transmission of HA-MRSA strains, implying that HA-MRSA cases identified in the community originate from the hospital reservoir and are maintained by frequent attendance at health care facilities. In contrast, there was a high risk of CA-MRSA in deprived areas linked with overcrowding, homelessness, low income, and recent immigration to the UK, which was not explainable by health care exposure. Furthermore, areas adjacent to these deprived areas were themselves at greater risk of CA-MRSA, indicating community transmission of CA-MRSA. This ongoing community transmission could lead to CA-MRSA becoming the dominant strain types carried by patients admitted to hospital, particularly if successful hospital-based MRSA infection control programmes are maintained. These results suggest that community infection control programmes targeting transmission of CA-MRSA will be required to control MRSA in both the community and hospital. These epidemiological changes will also have implications for effectiveness of risk-factor-based hospital admission MRSA screening programmes.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 622,
                "text": "MRSA"
            }
        },
        {
            "context": "Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. The nuclear factor of activated T cells (NFAT) group of transcription factors is retained in the cytoplasm of quiescent cells. NFAT activation is mediated in part by induced nuclear import. This process requires calcium-dependent dephosphorylation of NFAT caused by the phosphatase calcineurin. The c-Jun amino-terminal kinase (JNK) phosphorylates NFAT4 on two sites. Mutational removal of the JNK phosphorylation sites caused constitutive nuclear localization of NFAT4. In contrast, JNK activation in calcineurin-stimulated cells caused nuclear exclusion of NFAT4. These findings show that the nuclear accumulation of NFAT4 promoted by calcineurin is opposed by the JNK signal transduction pathway.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 360,
                "text": "calcineurin"
            }
        },
        {
            "context": "The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies. Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 31,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 941,
                "text": "thyroid"
            }
        },
        {
            "context": "Expression and regulation of antimicrobial peptide psoriasin (S100A7) at the ocular surface and in the lacrimal apparatus. PURPOSE: Psoriasin, originally isolated from psoriasis as an overexpressed molecule of unknown function, has recently been identified as a principal Escherichia coli-killing antimicrobial peptide of healthy skin. The purpose of this study was to investigate the expression and antimicrobial role of psoriasin at the ocular surface and in the lacrimal apparatus. METHODS: Different tissues of the lacrimal apparatus and ocular surface were systematically analyzed by means of RT-PCR, Western blot, and immunohistochemistry for their ability to express and produce psoriasin. The inducibility and regulation of psoriasin were studied in human corneal as well as conjunctival epithelial cell lines after challenge with ocular pathogens and proinflammatory cytokines. Real-time RT-PCR was performed to evaluate the expression and induction of psoriasin. In addition, tear fluid obtained from different healthy volunteers was examined by ELISA for its psoriasin concentration. RESULTS: RT-PCR and Western blot analyses revealed a constitutive expression of psoriasin in cornea, conjunctiva, nasolacrimal ducts, and lacrimal gland. Immunohistochemistry showed strong staining of meibomian glands for psoriasin. No induction of psoriasin was observed after stimulation with supernatants of E. coli, whereas supernatants of Staphylococcus aureus and Haemophilus influenzae significantly increased the psoriasin mRNA expression. Stimulation with IL-1β and VEGF also strongly increased psoriasin transcription. The highest amounts of psoriasin protein were detected in the tear fluid (~170 ng/mL) of healthy volunteers. CONCLUSIONS: The results suggest that psoriasin is produced by the structures of the ocular surface and is part of the innate immune system at the ocular surface and tear film.",
            "question": "In which condition was protein S100A7 originally identified?",
            "answers": {
                "answer_start": 168,
                "text": "psoriasis"
            }
        },
        {
            "context": "Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient diamond-Blackfan anemia improves following RPS19 gene transfer. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 1195,
                "text": "DBA"
            }
        },
        {
            "context": "A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.",
            "question": "Which amino acid residue appears mutated in most of the cases reported with  cadasil syndrome?",
            "answers": {
                "answer_start": 602,
                "text": "cysteine"
            }
        },
        {
            "context": "Altered RNA binding activity underlies abnormal thyroid hormone metabolism linked to a mutation in selenocysteine insertion sequence-binding protein 2. The expression of selenoproteins requires the translational recoding of the UGA stop codon to selenocysteine. In eukaryotes, this requires an RNA stem loop structure in the 3'-untranslated region, termed a selenocysteine insertion sequence (SECIS), and SECIS-binding protein 2 (SBP2). This study implicates SBP2 in dictating the hierarchy of selenoprotein expression, because it is the first to show that SBP2 distinguishes between SECIS elements in vitro. Using RNA electrophoretic mobility shift assays, we demonstrate that a naturally occurring mutation in SBP2, which correlates with abnormal thyroid hormone function in humans, lies within a novel, bipartite RNA-binding domain. This mutation alters the RNA binding affinity of SBP2 such that it no longer stably interacts with a subset of SECIS elements. Assays performed under competitive conditions to mimic intracellular conditions suggest that the differential affinity of SBP2 for various SECIS elements will determine the expression pattern of the selenoproteome. We hypothesize that the selective loss of a subset of selenoproteins, including some involved in thyroid hormone homeostasis, is responsible for the abnormal thyroid hormone metabolism previously observed in the affected individuals.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 393,
                "text": "SECIS"
            }
        },
        {
            "context": "TFEB regulates lysosomal proteostasis. Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 839,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.",
            "question": "Which methyl-CpG-binding protein when mutant becomes the hallmark for Rett syndrome?",
            "answers": {
                "answer_start": 230,
                "text": "methyl-CpG-binding protein 2 (MeCP2)"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 1096,
                "text": "CAGEr"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 383,
                "text": "TYR"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1125,
                "text": "CO2"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 655,
                "text": "miR-7"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 217,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Gender differences in Latin-American patients with rheumatoid arthritis. BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a large population with unique characteristics, including high admixture. OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in LAC. METHODS: This was a 2-phase study. First we conducted a cross-sectional and analytical study in which 1128 consecutive Colombian patients with RA were assessed. Second, a systematic review of the literature was done to evaluate the effect of gender in LAC patients with RA. RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man. Colombian women with RA are more at risk of having an early age at onset and developing polyautoimmunity and abdominal obesity, and they perform more household duties than their male counterparts. However, male gender was associated with the presence of extra-articular manifestations. Of a total of 641 potentially relevant articles, 38 were considered for final analysis, in which several factors and outcomes related to gender were identified. CONCLUSIONS: RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 738,
                "text": "women"
            }
        },
        {
            "context": "The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men. AIMS: To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODS: Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTS: The aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONS: Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 178,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Ser67-phosphorylated inhibitor 1 is a potent protein phosphatase 1 inhibitor. Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase. Nonphosphorylated I-1 is inactive, whereas phosphorylated I-1 is a potent PP1 inhibitor. I-1 is phosphorylated in vivo on Thr(35) and Ser(67). Thr(35) is phosphorylated by cAMP-dependent protein kinase (A kinase), and Thr(35)-phosphorylated I-1 inhibits PP1. Until now the kinase that phosphorylates Ser(67) had not been identified and the physiological role of Ser(67) phosphorylation was unknown. In this study we detected a high level of kinase activity in brain extract when a glutathione S-transferase (GST) fusion I-1 mutant containing an Ala substituted for Thr(35) [GST-I-1(T35A)] was used as the substrate. GST-I-1(T35A) kinase and neuronal cdc2-like protein kinase (NCLK) in the brain extract could not be separated from each other by a series of sequential chromatographies. GST-I-1(T35A) kinase immunoprecipitated with anti-NCLK antibody from kinase-active column fractions. Purified NCLK-phosphorylated GST-I-1(T35A) and I-1 (0.7 mole of phosphate per mole of I-1). HPLC phosphopeptide mapping, amino acid sequencing, and site-directed mutagenesis determined that NCLK phosphorylates Ser(67) of I-1. NCLK-phosphorylated I-1 and I-1(T35A) inhibited PP1 with IC(50) values approximately 9.5 and 13. 8 nM, respectively. When compared, A kinase-phosphorylated I-1 was only approximately 1.2 times more inhibitory than NCLK-phosphorylated I-1. Our data indicate that NCLK is a potential in vivo I-1 kinase and that Thr(35) and Ser(67) phosphorylation independently activate I-1.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 21,
                "text": "inhibitor 1"
            }
        },
        {
            "context": "Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 0,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "OCA1 in different ethnic groups of india is primarily due to founder mutations in the tyrosinase gene. Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 354,
                "text": "tyr"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 1328,
                "text": "IgG4"
            }
        },
        {
            "context": "Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 gene in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 426,
                "text": "FBN1"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 416,
                "text": "CaN"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 75,
                "text": "Xa"
            }
        },
        {
            "context": "Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated restriction of HIV-1. The deoxynucleoside triphosphohydrolase SAMHD1 restricts retroviral replication in myeloid cells. Human immunodeficiency virus type 2 (HIV-2) and a simian immunodeficiency virus from rhesus macaques (SIVmac) encode Vpx, a virion-packaged accessory protein that counteracts SAMHD1 by inducing its degradation. SAMHD1 is thought to work by depleting the pool of intracellular deoxynucleoside triphosphates but has also been reported to have exonuclease activity that could allow it to degrade the viral genomic RNA or viral reverse-transcribed DNA. To induce the degradation of SAMHD1, Vpx co-opts the cullin4a-based E3 ubiquitin ligase, CRL4. E3 ubiquitin ligases are regulated by the covalent attachment of the ubiquitin-like protein Nedd8 to the cullin subunit. Neddylation can be prevented by MLN4924, a drug that inhibits the nedd8-activating enzyme. We report that MLN4924 inhibits the neddylation of CRL4, blocking Vpx-induced degradation of SAMHD1 and maintaining the restriction. Removal of the drug several hours postinfection released the block. Similarly, Vpx-containing virus-like particles and deoxynucleosides added to the cells more than 24 h postinfection released the SAMHD1-mediated block. Taken together, these findings support deoxynucleoside triphosphate pool depletion as the primary mechanism of SAMHD1 restriction and argue against a nucleolytic mechanism, which would not be reversible.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 928,
                "text": "nedd8-activating enzyme"
            }
        },
        {
            "context": "Evaluation of the Recognition of Stroke in the Emergency Room (ROSIER) scale in Chinese patients in Hong Kong. BACKGROUND AND PURPOSE: The objective of this study was to determine the performance of the Recognition Of Stroke In the Emergency Room (ROSIER) scale in risk-stratifying Chinese patients with suspected stroke in Hong Kong. METHODS: This was a prospective cohort study in an urban academic emergency department (ED) over a 7-month period. Patients over 18 years of age with suspected stroke were recruited between June 2011 and December 2011. ROSIER scale assessment was performed in the ED triage area. Logistic regression analysis was used to estimate the impacts of diagnostic variables, including ROSIER scale, past history and ED characteristics. FINDINGS: 715 suspected stroke patients were recruited for assessment, of whom 371 (52%) had acute cerebrovascular disease (302 ischaemic strokes, 24 transient ischaemic attacks (TIA), 45 intracerebral haemorrhages), and 344 (48%) had other illnesses i.e. stroke mimics. Common stroke mimics were spinal neuropathy, dementia, labyrinthitis and sepsis. The suggested cut-off score of>0 for the ROSIER scale for stroke diagnosis gave a sensitivity of 87% (95%CI 83-90), a specificity of 41% (95%CI 36-47), a positive predictive value of 62% (95%CI 57-66), and a negative predictive value of 75% (95%CI 68-81), and the AUC was 0.723. The overall accuracy at cut off>0 was 65% i.e. (323+141)/715. INTERPRETATION: The ROSIER scale was not as effective at differentiating acute stroke from stroke mimics in Chinese patients in Hong Kong as it was in the original studies, primarily due to a much lower specificity. If the ROSIER scale is to be clinically useful in Chinese suspected stroke patients, it requires further refinement.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 33,
                "text": "Stroke"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 386,
                "text": "NCX"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 827,
                "text": "53BP1"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 196,
                "text": "MRSA"
            }
        },
        {
            "context": "Pigmentary changes in a patient treated with imatinib. Imatinib mesylate (STI 571; Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) is an orally available tyrosine kinase inhibitor that targets a constitutively activated BCR-ABL tyrosine kinase with additional inhibitory effects on platelet derived growth factor (PDGF) receptors alpha and beta, and KIT. It has revolutionized the treatment of adult and pediatric patients with Philadelphia chromosome positive chronic myelogenous leukemia (CML) and is also FDA-approved for KIT-positive advanced gastrointestinal tumor (GIST) and dermatofibrosarcoma protuberans. A wide spectrum of dermatologic toxicities has been associated with this agent, among which a maculopapular rash is the most common event. In addition, a variety of pigmentary abnormalities of the skin and mucosal surfaces have been reported. Hypopigmentation is a well-recognized adverse effect. In contrast, paradoxical hyperpigmentation has only rarely been documented. In this case report we describe imatinib-induced cutaneous hyperpigmentation and graying of hair occurring in the same patient with dermatofibrosarcoma protuberans treated with imatinib.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 227,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle? BACKGROUND: The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy. OBJECTIVE: We describe controversies regarding the use of idarucizumab therapy in patients with dabigatran-associated bleeding. DISCUSSION: Although existing clinical studies show a rapid reversal of coagulation assays, these studies did not describe a corresponding improvement in mortality or rapid cessation of hemorrhage. It is questionable how heavily clinicians can rely upon the use of the surrogate endpoints in clinical studies, such as ecarin clotting time and dilute thrombin time. Another issue is whether patients exhibiting re-elevation of coagulation assays would benefit from an additional dose of idarucizumab, because this has not been studied. It is currently unclear if blood products must be given in addition to idarucizumab can be used as monotherapy. CONCLUSIONS: The initial data suggest a definite role for idarucizumab in treatment of bleeding associated with dabigatran. As more clinical practice experience is gained with the agent and the remaining data on its use are released, clinicians can better guide the clinical use of idarucizumab. At present, there is currently not enough evidence for idarucizumab to be used as monotherapy.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 410,
                "text": "dabigatran"
            }
        },
        {
            "context": "Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 810,
                "text": "mTOR"
            }
        },
        {
            "context": "[Analysis of mutations of ribosomal protein genes in 21 cases of Diamond-Blackfan anemia]. This study was aimed to explore the mutations of ribosomal protein (RP) genes in patients with Diamond Blackfan anemia (DBA). Twenty-one cases of DBA admitted in our hospital from Dec 2008 to Aug 2012 were screened by PCR for mutations in the nine known genes associated with DBA: RPS19, RPS24, RPS17, RPL5, RPL11, RPS7, RPL35a, RPS10 and RPS26. The results found that 8 patients (38.1%) with DBA had mutations in the genes coding for ribosomal protein, in which RPS19 mutation was identified in 3 patients, RPS24, RPS7, RPL5, RPL11 and RPL35A mutations were identified respectively in 1 of the patient. No mutations were detected in RPS17, RPS10 or RPS26 genes. Thumb anomalies were found in 2 patients with RPL11 or RPL5 mutation, and hypospadias was found in 1 patient with RPS19 mutation. It is concluded that the mutation frequency of the genes coding for ribosomal protein in the patients with DBA here is lower than that in western countries. The hypospadias can be observed in some patients with RPS19 mutation and some dactyl anomalies are associated with RPL11 and RPL5 mutations.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 484,
                "text": "DBA"
            }
        },
        {
            "context": "Monitoring and reversal strategies for new oral anticoagulants. Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and edoxaban form a new class of non-vitamin K antagonist oral anticoagulants and have been extensively studied in patients with venous thromboembolism and atrial fibrillation. They offer anticoagulation that is as effective and at least as safe compared to warfarin without the need for routine laboratory monitoring; however, no reversal strategies are currently validated in case of a non-vitamin K antagonist oral anticoagulant-associated bleed. In emergency situations, laboratory drug measurement and well-defined management for non-vitamin K antagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. In this review, the merits and limitations of the routine coagulation tests and some of the more specific laboratory assays are compared. Furthermore, prohemostatic measures are reviewed and the recommended strategies in case of bleeding are summarized. Specific reversal agents are currently under development (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and PER977 for both Xa- and thrombin inhibitors), which will facilitate clinical management of severe bleeding and emergency surgery.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1129,
                "text": "Xa"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa. BACKGROUND: Many studies have found disturbances of serotonin (5-HT) activity in anorexia nervosa (AN). Because little is known about 5-HT receptor function in AN, positron emission tomography (PET) imaging with 5-HT receptor-specific radioligands was used to characterize 5-HT1A and 5-HT2A receptors. METHODS: Fifteen women ill with AN (ILL AN) were compared with 29 healthy control women (CW); PET and [11C]WAY100635 were used to assess binding potential (BP) of the 5-HT1A receptor, and [18F]altanserin was used to assess postsynaptic 5-HT2A receptor BP. [15O] water and PET were used to assess cerebral blood flow. RESULTS: The ILL AN women had a highly significant (30%-70%) increase in [11C]WAY100635 BP in prefrontal and lateral orbital frontal regions, mesial and lateral temporal lobes, parietal cortex, and dorsal raphe nuclei compared with CW. The [18F]altanserin BP was normal in ILL AN but was positively and significantly related to harm avoidance in suprapragenual cingulate, frontal, and parietal regions. Cerebral blood flow was normal in ILL AN women. CONCLUSIONS: Increased activity of 5-HT1A receptor activity may help explain poor response to 5-HT medication in ILL AN. This study extends data suggesting that 5-HT function, and, specifically, the 5-HT2A receptor, is related to anxiety in AN.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 635,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family? AIM: to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. METHODS: this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. RESULTS: during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. CONCLUSION: the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 74,
                "text": "MRSA"
            }
        },
        {
            "context": "A first-in-class NAE inhibitor, MLN4924, blocks lentiviral infection in myeloid cells by disrupting neddylation-dependent Vpx-mediated SAMHD1 degradation. MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells. SAMHD1 is required for MLN4924-mediated SIVmac inhibition. Our findings indicate the potential efficacy of inhibiting neddylation as an antiretroviral strategy and identify the readily available anticancer drug MLN4924 as a candidate agent for that purpose.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 213,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.",
            "question": "How is OCT3 associated with serotonin?",
            "answers": {
                "answer_start": 367,
                "text": "serotonin clearance"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 478,
                "text": "Xa"
            }
        },
        {
            "context": "Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin. Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Here we report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 260,
                "text": "GAN gene"
            }
        },
        {
            "context": "New insights into pri-miRNA processing and accumulation in plants. MicroRNAs (miRNAs) regulate many biological processes such as development, metabolism, and others. They are processed from their primary transcripts called primary miRNA transcripts (pri-miRNAs) by the processor complex containing the RNAse III enzyme, DICER-LIKE1 (DCL1), in plants. Consequently, miRNA biogenesis is controlled through altering pri-miRNA accumulation and processing, which is crucial for plant development and adaptation to environmental changes. Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins. Here, we summarize recent progresses related to pri-miRNA transcription, stability, and processing in plants.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 582,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Diagnosis of pneumoperitoneum on supine abdominal radiographs. A blinded, retrospective study was performed to determine the value of supine abdominal radiographs in diagnosing pneumoperitoneum. Supine films from 44 cases of pneumoperitoneum were randomly interspersed among supine films from 87 control subjects without free air, and the films were reviewed for the presence or absence of various signs of pneumoperitoneum, including Rigler's sign (gas on both sides of the bowel wall), the falciform ligament sign (gas outlining the falciform ligament), the football sign (gas outlining the peritoneal cavity), the inverted-V sign (gas outlining the medial umbilical folds), and the right-upper-quadrant gas sign (localized gas in the right upper quadrant). One or more of these signs were present in 26 cases (59%) of pneumoperitoneum, including the right-upper-quadrant gas sign in 18 cases (41%), Rigler's sign in 14 cases (32%), and the falciform ligament and football signs in one case each (2%). Unfortunately, there were frequent errors in the interpretation of the right-upper-quadrant gas sign and Rigler's sign, with a total of 11 false-positive cases (13%). Further analysis of the true-positive right-upper-quadrant gas signs showed that these gas collections were always triangular or linear with an inferolateral to superomedial orientation and, if triangular, a concave superolateral border. In the true-positive Rigler's signs, the bowel wall thickness ranged from 1 to 8 mm, whereas the false positives all had a bowel wall thickness of 1 mm or less. Proper interpretation of the various signs of pneumoperitoneum on supine films should lead to more accurate diagnosis of this condition.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 407,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "Genetics of rheumatoid arthritis - a comprehensive review. The \"Bermuda triangle\" of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11-37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci - Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively - have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.",
            "question": "How many genes outside of the MHC locus have been genetically associated to Rheumatoid Arthritis through GWAS?",
            "answers": {
                "answer_start": 999,
                "text": "more than 30"
            }
        },
        {
            "context": "Epidural blood patch for headache after lumboperitoneal shunt placement. Headaches complicating lumboperitoneal (LP) shunt placement have been attributed to shunt failure with resultant high intracranial pressure or to overdrainage with resultant low intracranial pressure. In this case, a 17-yr-old girl had symptoms of a low-pressure headache after LP shunt placement alleviated by an epidural blood patch. The success of this therapy suggests postdural puncture as a possible cause for low-pressure headache after LP shunt placement. Epidural blood patch may be an alternative initial therapy for some low-pressure headaches after LP shunt placement.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 387,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "The properties of a tRNA-specific adenosine deaminase from Drosophila melanogaster support an evolutionary link between pre-mRNA editing and tRNA modification. Pre-mRNA editing involving the conversion of adenosine to inosine is mediated by adenosine deaminases that act on RNA (ADAR1 and ADAR2). ADARs contain multiple double-stranded RNA(dsRNA)-binding domains in addition to an adenosine deaminase domain. An adenosine deaminase acting on tRNAs, scTad1p (also known as scADAT1), cloned from Saccharomyces cerevisiae has a deaminase domain related to the ADARs but lacks dsRNA-binding domains. We have identified a gene homologous to scADAT1 in the region of Drosophila melanogaster Adh chromosome II. Recombinant Drosophila ADAT1 (dADAT1) has been expressed in the yeast Pichia pastoris and purified. The enzyme has no activity on dsRNA substrates but is a tRNA deaminase with specificity for adenosine 37 of insect alanine tRNA. dADAT1 shows greater similarity to vertebrate ADARs than to yeast Tad1p, supporting the hypothesis of a common evolutionary origin for ADARs and ADATs. dAdat1 transcripts are maternally supplied in the egg. Zygotic expression is widespread initially and later concentrates in the central nervous system.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 1068,
                "text": "ADAR"
            }
        },
        {
            "context": "Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 444,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single-center study. Our objective was to evaluate the efficacy of influenza and meningococcal vaccinations in healthy subjects exposed to the anti-interleukin-17A (IL-17A) monoclonal antibody (MAb) secukinumab. We used an open-label, parallel-group, randomized single-center study of 50 healthy subjects. Subjects received a single 150-mg dose of secukinumab or no treatment, followed by vaccination with inactivated trivalent subunit influenza virus and conjugate group C meningococcal vaccine (Agrippal and Menjugate, respectively) 2 weeks later. Primary efficacy variables were responses of > 4-fold increases in antibody titer (hemagglutination inhibition [HI; for influenza virus] and serum bactericidal assay [SBA; for Neisseria meningitides]) for meningococcus and influenza (at least two out of three serotypes), both at 4 weeks postvaccination. All subjects randomized to secukinumab (n = 25) or the control (n = 25) completed the study. Antibody responses to vaccinations measured at 4 weeks were comparable in both groups, with > 4-fold increased responses following influenza virus vaccination of 20/25 (80%) for both groups and following meningococcal vaccination of 19/25 (76%) for the secukinumab group and 18/25 (72%) for the control group. Differences between groups were 0% (90% confidence intervals [CI], 19 and 19%) and 4% (90% CI, 16 and 24%) for influenza virus and meningococcal vaccines, respectively. Antibody responses were comparable between the 2 groups at different time points. Headache was the most frequently reported adverse effect. No deaths or serious adverse events were reported. Blockade of IL-17A by secukinumab does not appear to interfere with efficacy of influenza and meningococcal vaccinations, as assessed by the achievement of protective antibody levels. A protective ( > 4-fold) immune response to both vaccinations at 4 weeks was achieved in 80 and 76% of subjects exposed to secukinumab and the control, respectively.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 19,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "Detection of long repeat expansions from PCR-free whole-genome sequence data. Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.",
            "question": "Which algorithm is used for detection of long repeat expansions?",
            "answers": {
                "answer_start": 422,
                "text": "ExpansionHunter"
            }
        },
        {
            "context": "Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Riociguat (Adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 0,
                "text": "Riociguat"
            }
        },
        {
            "context": "Global DNA hypomethylation-induced ΔNp73 transcriptional activation in non-small cell lung cancer. p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic ΔΝp73 isoforms respectively. In this study, we investigated the DNA methylation status of both promoters as a means of epigenetic transcriptional control of their corresponding isoforms in 102 primary non-small cell lung carcinomas (NSCLCs). We demonstrated that while P1 hypermethylation-associated reduction of TAp73 mRNA levels is relatively infrequent, the P2 hypomethylation-associated over-expression of ΔΝp73 mRNA is a frequent event, particularly among squamous cell carcinomas. P2 hypomethylation strongly correlated with LINE-1 element hypomethylation, indicating that ΔΝp73 over-expression may be a passive consequence of global DNA hypomethylation.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 100,
                "text": "7"
            }
        },
        {
            "context": "Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study. BACKGROUND AND OBJECTIVES: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS: Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses > 2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS: Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01955720.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 286,
                "text": "dabigatran"
            }
        },
        {
            "context": "The p47phox- and NADPH oxidase organiser 1 (NOXO1)-dependent activation of NADPH oxidase 1 (NOX1) mediates endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction in a streptozotocin-induced murine model of diabetes. AIMS/HYPOTHESIS: We have previously shown that NADPH oxidase (NOX) lies upstream of uncoupled endothelial nitric oxide synthase (eNOS), which is known to occur in diabetic endothelium. However, it remains unclear which specific NOX isoform(s) is responsible for eNOS uncoupling and endothelial dysfunction in diabetic mouse models. The aim of the present study was to test the hypothesis that one or more NOX isoform(s) mediate(s) diabetic uncoupling of eNOS, which has been shown to occur in patients with diabetes to contribute to endothelial dysfunction. METHODS: Diabetes was induced by streptozotocin administration. The N (ω)-nitro-L-arginine methyl ester (L-NAME)-sensitive superoxide production of aortic segments, reflective of eNOS uncoupling activity, was determined by electron spin resonance. RESULTS: The L-NAME-sensitive superoxide production was more than doubled in wild-type diabetic mice, implicating uncoupling of eNOS. This was abolished in diabetic p47 ( phox-/-) (also known as Ncf1 (-/-)) mice, but preserved in Nox2 (-/y) (also known as Cybb (-/-)) mice made diabetic. The eNOS uncoupling activity was markedly attenuated in diabetic mice transfected with Nox1 or Nox1 organiser 1 (Noxo1) short interfering RNA (siRNA), and abolished in Nox1 (-/y) diabetic mice. Diabetes-induced impairment in endothelium-dependent vasorelaxation was also significantly attenuated in the Nox1 (-/y) mice made diabetic. By contrast, Nox4 siRNA, or inhibition of mitochondrial complex I or III with rotenone or siRNA, respectively, had no effect on diabetic uncoupling of eNOS. Overexpression of Dhfr, or oral administration of folic acid to improve dihydrofolate reductase (DHFR) function, recoupled eNOS in diabetes to improve endothelial function. CONCLUSIONS/INTERPRETATION: Our data demonstrate for the first time that the p47(phox) and NOXO1-dependent activation of NOX1, but not that of NOX2, NOX4 or mitochondrion, mediates diabetic uncoupling of eNOS. NOX1-null mice are protected from diabetic endothelial dysfunction. Novel approaches to inhibit NOX1 and/or improve DHFR function, may prove to have therapeutic potential for diabetic endothelial dysfunction.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 92,
                "text": "NOX1"
            }
        },
        {
            "context": "Primary Care Management of Plantar Fasciitis. Plantar fasciitis (PF) is present in 10% of the population and is the most common cause of plantar heel pain. PF is painful, can alter daily activities and presents as a sharp pain localized to the plantar foot and medial heel. The underlying etiology involves microtrauma to the plantar fascia, specifically at its insertion point on the calcaneus. Successful management of plantar fasciitis is typically achieved with the conservative therapy approaches discussed.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 145,
                "text": "heel pain"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 1325,
                "text": "OikoBase"
            }
        },
        {
            "context": "Pregnancy outcome after oocyte donation in patients with Turner's syndrome: Clinical experience and management. Turner's syndrome (TS) is a chromosomal defect with partial or total absence of the X chromosome. Our objective is to report our experience in Greece with patients suffering from TS and trying to conceive; therefore, we present four patients with TS, who underwent In vitro fertilization (ICSI) with donor oocytes in order to get pregnant. Three out of four patients managed to conceive and bring pregnancy to completion. It was shown that patients diagnosed in childhood or adolescence with TS have the possibility to undergo hormone replacement therapy (HRT) and thus, secondary sexual characteristics as well as uterus of almost normal size can develop. Assisted reproduction techniques (ART), predominantly with donated oocytes, could give these patients the possibility to have children.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 196,
                "text": "X"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2234,
                "text": "stroke"
            }
        },
        {
            "context": "Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye. Gaucher disease (GD) is the most common of the lysosomal storage disorders and is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase). The accumulation of its substrate, glucocylceramide (GlcCer) is considered the main cause of GD. We found here that the expression of human mutated GlcCerase gene (hGBA) that is associated with neuronopathy in GD patients causes neurodevelopmental defects in Drosophila eyes. The data indicate that endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate a novel mechanism of neurodevelopmental defects mediated by ER stress through expression of mutants of human GBA gene in the eye of Drosophila.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 240,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Mitochondria in cells comprise a tubulovesicular network shaped continuously by complementary fission and fusion events. The mammalian Drp1 protein plays a key role in fission, while Mfn1, Mfn2, and OPA1 are required for fusion. Shifts in the balance between these opposing processes can occur rapidly, indicating that modifications to these proteins may regulate mitochondrial membrane dynamics. We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized. This dynamin-related GTPase undergoes a number of steps to mediate mitochondrial fission, including translocation from cytoplasm to the mitochondrial outer membrane, higher-order assembly into spirals, GTP hydrolysis associated with a conformational change and membrane deformation, and ultimately disassembly. Many of these steps may be influenced by covalent modification of Drp1. We discuss the dynamic nature of Drp1 modifications and how they contribute not only to the normal regulation of mitochondrial division, but also to neuropathologic processes.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 551,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.",
            "question": "Which hormone deficiency is implicated in the Costello syndrome ?",
            "answers": {
                "answer_start": 1305,
                "text": "growth hormone deficiency"
            }
        },
        {
            "context": "Semi-synthesis of cyclosporins. BACKGROUND: Since its isolation in 1970, and discovery of its potent inhibitory activity on T-cell proliferation, cyclosporin A (CsA) has been shown to play a significant role in diverse fields of biology. Furthermore, chemical modification of CsA has led to analogs with distinct biological activities associated with its protein receptor family, cyclophilins. SCOPE OF REVIEW: This review systematically collates the synthetic chemistry performed at each of the eleven amino acids, and provides examples of the utility of such transformations. The various modifications of CsA are traced from early, modest chemistry performed at the unique Bmt residue, through the remarkable use of a polyanion enolate that can be stereoselectively manipulated, and onto application of more recently developed olefin metathesis chemistry to prepare new CsA derivatives with unexpected biological activity. MAJOR CONCLUSIONS: The myriad biological activities of CsA and its synthetic derivatives have inspired the development of new approaches to modify the CsA ring. In turn, these new CsA derivatives have served as tools in the discovery of new roles for cyclophilins. GENERAL SIGNIFICANCE: This review provides information on the types of cyclosporin derivatives that are available to the many biologists working in this field, and should be of value to the medicinal chemist trying to discover drugs based on CsA. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.",
            "question": "Which is the receptor for the immunosuppressive drug cyclosporin A (CsA)?",
            "answers": {
                "answer_start": 380,
                "text": "cyclophilin"
            }
        },
        {
            "context": "MicroRNA transcription start site prediction with multi-objective feature selection. MicroRNAs (miRNAs) are non-coding, short (21-23nt) regulators of protein-coding genes that are generally transcribed first into primary miRNA (pri-miR), followed by the generation of precursor miRNA (pre-miR). This finally leads to the production of the mature miRNA. A large amount of information is available on the pre- and mature miRNAs. However, very little is known about the pri-miRs, due to a lack of knowledge about their transcription start sites (TSSs). Based on the genomic loci, miRNAs can be categorized into two types --intragenic (intra-miR) and intergenic (inter-miR). While it is already an established fact that intra-miRs are commonly transcribed in conjunction with their host genes, the transcription machinery of inter-miRs is poorly understood. Although it is assumed that miRNA promoters are similar in structure to gene promoters, since both are transcribed by RNA polymerase II (Pol II), computational validations exhibit poor performance of gene promoter prediction methods on miRNAs. In this paper, we concentrate on the problem of TSS prediction for miRNAs. The present study begins with the identification of positive and negative promoter samples from recently published data stemming from RNA-sequencing studies. From these samples of experimentally validated miRNA TSSs, a number of standard sequence features are extracted. Furthermore, to account for potential footprints related to promoter regulation by CpG dinucleotide targeted DNA methylation, a number of novel features are defined. We develop a support vector machine (SVM) with RBF kernel for the prediction of miRNA TSSs trained on human miRNA promoters. A novel feature reduction technique based on archived multi-objective simulated annealing (AMOSA) identifies the final set of features. The resulting model trained on miRNA promoters shows improved performance over the one trained on protein-coding gene promoters in terms of classification accuracy, sensitivity and specificity. Results are also reported for a completely independent biologically validated test set. In a part of the investigation, the proposed approach is used to predict protein-coding gene TSSs. It shows a significantly improved performance when compared to previously published gene TSS prediction methods.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 972,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "First case of X-linked dystonia-parkinsonism (\"Lubag\") to demonstrate a response to bilateral pallidal stimulation. \"Lubag\" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 127,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Alteration in composition of keratin intermediate filaments in a model of breast cancer progression and the potential to reverse hallmarks of metastasis. BACKGROUND: In breast cancer the development of metastasis is a major turning point in the treatment and outcome of the disease. Throughout tumour development, and especially in the development of metastasis, epithelial mesenchymal transition takes place. During this transformation into a mesenchymal phenotype, the tumour cells undergo a series of structural changes. The loss of structural integrity and adoption of mesenchymal filaments enables cells to detach from the epithelial cell layer and metastasise. Keratins form the intermediate filaments of the cytoskeleton and provide scaffold structures within cells. During cancer progression the intermediate filaments are reorganised, and dramatic changes are seen in their protein components. Keratins K8, K18, K19 and vimentin are intermediate filament proteins with altered expression profiles during tumour development. METHOD: We have used in vivo and in vitro models to analyse changes in intermediate filament proteins. Antibody-based methods were used to study K8 levels and proteomic analysis to profile the protein content of metastatic breast cancer cell variants. RESULTS: K8 expression declines as human breast tumours progress into an invasive phenotype. Analysis of IF proteins indicated altered expression profiles of K8, K18, K19 and vimentin, with K8, K18, K19 expressed in high levels in the T47D and MCF-7 cell lines, whereas the highly metastatic cell lines expressed lower levels of K8 and K18 and no detectable K19. Vimentin showed reverse expression profile with T47D and MCF-7 cells having no detectable vimentin expression whereas the highly metastatic MDA-MB-231 and MDA-MB-436 showed high levels. Analysis of acetylation status using specific antibodies suggested acetylation occurred within the central coiled domain in the MCF-7 and T47D cells. Inhibition of tumour growth by tissue factor (TF) shRNA resulted in a dramatic re-elevation of expression of K8 in xenographs of the highly metastatic MDA-MB-436 line. CONCLUSION: Intermediate filament expression alters during epithelial mesenchymal transition. Identified post translational modifications may play a role in alterations seen in the organisation, solubility and stability of these filaments. Epithelial mesenchymal transition can be reversed and an epithelial phenotype re-established.",
            "question": "What are the structures formed when keratin molecules come together?",
            "answers": {
                "answer_start": 685,
                "text": "intermediate filaments"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1093,
                "text": "53BP1"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 902,
                "text": "53BP1"
            }
        },
        {
            "context": "Alternative splicing and expression analysis of bovine DNA methyltransferase 1. Methylation of specific CG residues in the mammalian genome results in tissue-specific patterns of gene expression, which are critical for cell differentiation. Embryos that fail to establish and maintain proper DNA methylation patterns show severe developmental abnormalities as is the case of DNA methyltransferase 1 (Dnmt1) -deficient embryos. Dnmt1 is the main maintenance methyltransferase in the mouse and its expression is regulated by a splicing mechanism that dictates the expression of stage-specific isoforms. Little is known about Dnmt1 expression in the cow and isoforms of Dnmt1 are yet unknown in this species. Here we demonstrate that the previously described bovine Dnmt1 transcript is ubiquitously expressed in embryos and fetal tissue. In addition, we report the identification of a splice variant of the bovine Dnmt1, which shows a ubiquitous expression pattern. This new transcript was detected using 5'RACE and genomic mapping and its expression pattern was shown to be consistent with a tissue-specific mode of regulation. Furthermore, our analysis shows that the expression of an oocyte-specific isoform of Dnmt1 is unlikely to occur in cattle. The newly reported isoform of Dnmt1 was demonstrated to be, similarly to Dnmt1a, polyadenylated and if translated possess the functional domains necessary for maintenance and de novo methyltransferase activity.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 427,
                "text": "Dnmt1"
            }
        },
        {
            "context": "[Selective estrogen receptor modulators (SERMs)]. Selective estrogen receptor modulators (SERMs) bind to estrogen receptor (ER) and develop tissue-selective actions as estrogen agonists or antagonists. As such, SERMs have been developed to exert estrogen-like beneficial effects against some disorders including osteoporosis, while reducing estrogen-related risks, including breast cancer. Prevention of vertebral fractures by a SERM, raloxifene (RLX), in osteoporotic postmenopausal women has been well established. RLX does not increase or decrease cardiovascular events, overall mortality, cardiovascular mortality or the overall number of strokes, but there appears to be a small increase in stroke mortality. Both RLX and tamoxifen similarly reduce the risk of ER-positive invasive breast cancer. At the same time, RLX treatment is associated with 36% fewer uterine cancer incidence and 29% less thromboembolic events. Keeping these results in mind, it is our responsibility to critically evaluate and decide timing and length of treatment, as well as subjects with benefits or risks for the treatment of osteoporosis by SERMs.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 1,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Upregulation of amyloid precursor protein isoforms containing Kunitz protease inhibitor in dementia with Lewy bodies. Amyloid precursor protein (APP) is involved in the accumulation of alpha-synuclein, the main component of Lewy bodies. It is currently unknown, however, whether any of the APP isoforms is instrumental in alpha-synuclein deposition in dementia with Lewy bodies (DLB). Using real-time RT-PCR, we have studied relative mRNA expression levels of APP isoforms in frozen postmortem frontal cortices of DLB patients, Alzheimer disease (AD) patients, and control subjects. Of the three main APP isoforms, the two with a Kunitz protease inhibitory (KPI) motif (APP770 and APP751) were found to be specifically overexpressed in the frontal cortices of DLB patients when compared with controls and AD patients. These findings suggest a specific role of APP isoforms containing Kunitz protease inhibitor in DLB pathogenesis.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 185,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Delayed L-DOPA-induced hyperalgesia. Previously we reported on L-DOPA's antinociceptive effect on substance P-induced nociceptive behaviors in mice [Shimizu T, Iwata S, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of L-DOPA. Pain 2004;110;246-9.]. Since significant hyperalgesia was noted following antinociception, our study was designed to investigate the mechanism of this hyperalgesia. Nociceptive behaviors were enhanced 2 h after L-DOPA administration. L-DOPA induced hyperalgesia occurred after conversion to dopamine because co-administration of benserazide, a DOPA decarboxylase inhibitor, completely abolished the L-DOPA-induced hyperalgesia. The D2 receptor agonist, quinpirole, depressed these behaviors entirely, while the D1 antagonist, SCH23390, inhibited the enhancement of these behaviors by L-DOPA. The D2 receptor antagonist, sulpiride, which induced hyperalgesia of the substance P-induced behaviors in naive mice, did not have any effects on L-DOPA-induced hyperalgesia. Spinal cord dopamine content increased rapidly after L-DOPA administration, exhibiting levels 100 times greater than baseline, and then returned to control after 1 h. These results suggested that the dopaminergic inhibitory system for pain sensation was temporarily impaired by excess amounts of exogenous dopamine that were derived from L-DOPA and both D1 and D2 receptors were involved in L-DOPA-induced hyperalgesia.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 648,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Filamentous polymers induced by overexpression of a novel centrosomal protein, Cep135. A novel 135 kDa centrosomal component (Cep135) was identified by immunoscreening of a mammalian expression library with monoclonal antibodies raised against clam centrosomes. It is predicted to be a highly coiled-coil protein with an extensive alpha-helix, suggesting that Cep135 is a structural component of the centrosome. To evaluate how the protein is arranged in the centrosomal structure, we overexpressed Cep135 polypeptides in CHO cells by transient transfection. HA- or GFP-tagged full (amino acids 1-1144) as well as truncated (#10, 29-1144; Delta3, 29-812) polypeptides become localized at the centrosome and induce cytoplasmic dots of various size and number in CHO cells. Centrosomes are associated with massive approximately 7 nm filaments and dense particles organized in a whorl-like arrangement in which parallel-oriented dense lines appear with a regular approximately 7 nm periodicity. The same filamentous aggregates are also detected in cytoplasmic dots, indicating that overexpressed Cep135 can assemble into elaborate higher-ordered structures in and outside the centrosome. Sf9 cells infected with baculovirus containing Cep135 sequences induce filamentous polymers which are distinctive from the whorl seen in CHO cells; #10 forms highly packed spheroids, but the Delta3-containing structure looks loose. Both structures show an internal repeating unit of dense and less dense stripes. Although the distance between the outer end of two adjacent dense lines is similar between two types of polymers ( approximately 120 nm), the dense stripe of Delta3 polymers ( approximately 40 nm) is wider than #10 ( approximately 30 nm). The light band of Delta3 ( approximately 40 nm) is thus narrower than #10 ( approximately 60 nm). Since thin fibers are frequently seen to extend from one dense line to the next, the coiled-coil rod of Cep135 may span the light band. These results suggest that overexpressed Cep135 assemble into distinctive polymers in a domain-specific manner.",
            "question": "Where in the cell do we find the protein Cep135?",
            "answers": {
                "answer_start": 400,
                "text": "centrosome"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 465,
                "text": "ADAR"
            }
        },
        {
            "context": "Phase I study protocol for ex-vivo lentiviral gene therapy for the inherited skin disease, Netherton Syndrome. Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). Patients with NS have defective keratinization, hair shaft defects, recurrent infections, atopy and a predisposition to skin malignancies. Historically, one in ten infants has died before their first birthday. Currently there are no proven treatments to cure this condition. A SIN-lentiviral vector encoding the codon optimized SPINK5 gene under the control of a 572bp element derived from the human involucrin promoter (INVO) can confer compartment specific LEKTI expression in NS keratinocytes with restoration of normal skin architecture. Here we detail a study protocol for a phase I trial for feasibility and safety evaluations of autologous epidermal sheets generated from ex-vivo gene corrected keratinocyte stem cells, which will be grafted onto patients with mutation proven NS.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 305,
                "text": "lymphoepithelial Kazal type-related inhibitor"
            }
        },
        {
            "context": "Genetic and molecular aspects of acromelic dysplasia. The acromelic dysplasia group includes three rare disorders: Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) all characterized by short stature, short hands and stiff joints. The clinical overlap between the three disorders is striking. Indeed, in addition to the diagnostic criteria, they all share common features including delayed bone age, cone shaped epiphyses, thick skin and heart disease. In contrast, a microspherophakic lens seems to be a characteristic feature of WMS whereas hepatomegaly and a severe outcome are encountered only in the most severe forms of GD. Finally, WMS is transmitted either by an autosomal dominant or an autosomal recessive (AR) mode of inheritance, GD by an autosomal recessive mode of inheritance and AD by an autosomal dominant mode of inheritance. Using genetic approaches, we have identified the molecular basis of WMS and GD which both involved the same superfamily of proteins, the ADAMTS [A Disintegrin-like And Metalloproteinase domain (reprolysin type) with ThromboSpondin type 1 repeats (TSR)]. We have found ADAMTS10 mutations in the recessive form of WMS and Fibrillin 1 mutations in the dominant form of WMS. More recently, we have identified ADAMTSL2 mutations in GD. The function of ADAMTS1 0 and AD AMTSL 2 are unknown. But the findings of FBN1 and ADAMTS10 mutations in WMS suggest a direct link between the two proteins. Using a yeast double hybrid screen, we have identified LTBP1 (Latent TGFbeta Binding protein 1) as a partner of ADAMTSL2. The combination of these findings suggests that ADAMTS10 and ADAMTSL2 are both involved in the microfibrillar network.",
            "question": "What is the mode of inheritance of Acromicric dysplasia?",
            "answers": {
                "answer_start": 844,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Effector Gene Suites in Some Soil Isolates of Fusarium oxysporum Are Not Sufficient Predictors of Vascular Wilt in Tomato. Seventy-four Fusarium oxysporum soil isolates were assayed for known effector genes present in an F. oxysporum f. sp. lycopersici race 3 tomato wilt strain (FOL MN-25) obtained from the same fields in Manatee County, Florida. Based on the presence or absence of these genes, four haplotypes were defined, two of which represented 96% of the surveyed isolates. These two most common effector haplotypes contained either all or none of the assayed race 3 effector genes. We hypothesized that soil isolates with all surveyed effector genes, similar to FOL MN-25, would be pathogenic toward tomato, whereas isolates lacking all effectors would be nonpathogenic. However, inoculation experiments revealed that presence of the effector genes alone was not sufficient to ensure pathogenicity on tomato. Interestingly, a nonpathogenic isolate containing the full suite of unmutated effector genes (FOS 4-4) appears to have undergone a chromosomal rearrangement yet remains vegetatively compatible with FOL MN-25. These observations confirm the highly dynamic nature of the F. oxysporum genome and support the conclusion that pathogenesis among free-living populations of F. oxysporum is a complex process. Therefore, the presence of effector genes alone may not be an accurate predictor of pathogenicity among soil isolates of F. oxysporum.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 260,
                "text": "tomato"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1461,
                "text": "XA"
            }
        },
        {
            "context": "Site and sequence specific DNA methylation in the neurofibromatosis (NF1) gene includes C5839T: the site of the recurrent substitution mutation in exon 31. CpG dinucleotides provide hotspots for transitional mutations in a variety of genes, some leading to genetic diseases in humans. Although this phenomenon is attributed to cytosine methylation at such sites, direct and specific observations of CpG methylation at the sites of recurrent mutations are lacking. We have used a bisulfite genomic sequencing method to analyze DNA methylation within three representative exons from the neurofibromatosis type 1 (NF1) gene, well recognized for its high frequency of spontaneous mutations. We observed that the cytosine methylation within NF1 exons 28, 29, and 31 is restricted to CpG dinucleotides, including the CpG dinucleotide present at the site of the recurrent NF1 mutation (C5839T; also referred to as R1947X). At several sites, clone-specific methylation differences were also observed. Our results provide experimental evidence for the hypothesis that methylatable CpGs in the NF1 gene contribute to spontaneous germline mutations associated with this gene, by showing that DNA methylation does occur at all CpGs contained within these representative NF1 exons. As well, the DNA methylation seen at the common mutation site in exon 31 may explain why this site is frequently mutated. Methylation-dependent mutagenesis may also provide a basis for some somatic (second hit) mutations which disable the normal allele and result in the development of NF1 associated symptoms.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 611,
                "text": "NF1"
            }
        },
        {
            "context": "[DNA methyltransferases: classification, functions and research progress]. DNA methylation is a postreplicative modification occurred in most prokaryotic and eukaryotic genomes, which has a variety of important biological functions including regulation of gene expression, gene imprinting, preservation of chromosomal integrity, and X-chromosome inactivation. According to their structure and functions, DNA methyltransferases (Dnmts) are divided into two major families in mammalian cells: maintenance methyltransferase (Dnmt1) and de novo methyltransferases (Dnmt3a, Dnmt3b, and Dnmt3L). In addition, Dnmt2 also displays weak DNA methyltransferase catalytic activity, but newly founded function is to methylate cytosine 38 in the anti-codon loop of tRNAAsp. These Dnmts are crucial for mammalian growth and development. Dnmts deficiency will lead to embryonic development defects, cancer, and other diseases. Therefore, Dnmts could be important therapeutical targets. This article summarizes the classification, function, and recent research progress in DNA methyltransferases.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 522,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 881,
                "text": "thyroid"
            }
        },
        {
            "context": "The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster. RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar(5G1) null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar(5G1) mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar(5G1) null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 4,
                "text": "ADAR"
            }
        },
        {
            "context": "Twiddler's syndrome in a patient with a deep brain stimulation device for generalized dystonia. Deep brain stimulation (DBS) is the technique of neurostimulation of deep brain structures for the treatment of conditions such as essential tremor, dystonia, Parkinson's disease and chronic pain syndromes. The procedure uses implanted deep brain stimulation electrodes connected to extension leads and an implantable pulse generator (IPG). Hardware failure related to the DBS procedure is not infrequent, and includes electrode migration and disconnection. We describe a patient who received bilateral globus pallidus internus DBS for dystonia with initially good clinical response, but the device eventually failed. Radiographs showed multiple twisting of the extension leads with disconnection from the brain electrodes and a diagnosis of Twiddler's syndrome was made. Twiddler's syndrome was first described in patients with cardiac pacemakers. Patients with mental disability, elderly and obese patients are at increased risk. Twiddler's syndrome should be suspected whenever there is a failure of the DBS device to relieve symptoms previously responsive to stimulation. Surgical correction is usually required.",
            "question": "Neurostimulation of which nucleus is used for treatment of dystonia?",
            "answers": {
                "answer_start": 599,
                "text": "globus pallidus internus"
            }
        },
        {
            "context": "New insights into pri-miRNA processing and accumulation in plants. MicroRNAs (miRNAs) regulate many biological processes such as development, metabolism, and others. They are processed from their primary transcripts called primary miRNA transcripts (pri-miRNAs) by the processor complex containing the RNAse III enzyme, DICER-LIKE1 (DCL1), in plants. Consequently, miRNA biogenesis is controlled through altering pri-miRNA accumulation and processing, which is crucial for plant development and adaptation to environmental changes. Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins. Here, we summarize recent progresses related to pri-miRNA transcription, stability, and processing in plants.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 582,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells. The mechanisms underlying lithium's therapeutic efficacy in the chronic treatment of bipolar disorder are not clearly understood. Useful insights can be obtained by identifying genes that are differentially regulated during chronic lithium treatment. Toward this end, we have used microarray technology to identify mRNAs that are differentially expressed in a human neuronal cell line that has been continuously maintained in therapeutic levels of lithium for 33 days. Significantly, unlike other transcriptomes where predominantly rodent cells were used and a limited number of genes probed, we have used human cells probed with more extensive 44,000 gene microarrays. A total of 671 differentially regulated transcripts, after correcting for false discovery rates, were identified, of which 347 and 324, respectively, were found to be up- and downregulated. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the most downregulated, implying a beneficial effect of lithium on neuronal cells. Several of the most highly regulated genes are novel, uncharacterized and encode proteins of unknown function. Differentially expressed genes associated with phosphoinositide metabolism include those encoding phosphatidyl inositol 4-phosphate 5-kinase type II alpha (PIP5K2A), WD repeat domain, phosphoinositide interacting 1 protein (WIPI49), tribbles homolog 3 (TRB3) and sorting nexin 14 (SNX14). A protein interactome using some of the saliently regulated genes identified protein kinase C (PKC) as a major target for lithium action while a global analysis of all 671 differentially expressed genes identified the mitogen-activated protein kinase pathway as the most regulated. The list of highly regulated genes, besides encoding putative targets for antimanic agents, should prove useful in defining novel pathways, or to better understand the mechanisms, underlying the mood stabilization process.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 1010,
                "text": "antioxidant"
            }
        },
        {
            "context": "Cytarabine-induced destabilization of a model Okazaki fragment. Cytarabine is a potent anticancer drug that interferes with elongation of the lagging strand at the replication fork during DNA synthesis. The effects of cytarabine substitution on the structural and thermodynamic properties of a model Okazaki fragment were investigated using UV hyperchromicity and 1H NMR spectroscopy to determine how cytarabine alters the physicochemical properties of Okazaki fragments that are intermediates during DNA replication. Two model Okazaki fragments were prepared corresponding to a primary initiation site for DNA replication in the SV40 viral genome. One model Okazaki fragment consisted of five ribo- and seven deoxyribonucleotides on the hybrid strand, together with its complementary (DNA) strand. The second model Okazaki fragment was identical to the first with the exception of cytarabine substitution for deoxycytidine at the third DNA nucleotide of the hybrid strand. Thermodynamic parameters for the duplex to single strand transition for each model Okazaki fragment were calculated from the concentration dependence of the T m at 260 nm. Cytarabine significantly decreased the stability of this model Okazaki fragment, decreasing the melting temperature from 46.8 to 42.4 degrees C at a concentration of 1.33 x 10(-5) M. The free energy for the duplex to single strand transition was 1.2 kcal/mol less favorable for the cytarabine-substituted Okazaki fragment relative to the control at 37 degrees C. Analysis of the temperature dependence of the imino1H resonances for the two duplexes demonstrated that cytarabine specifically destabilized the DNA:DNA duplex portion of the model Okazaki fragment. These results are consistent with inhibition of lagging strand DNA synthesis by cytarabine substitution resulting from destabilization of the DNA:DNA duplex portion of Okazaki fragments in vivo .",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 501,
                "text": "DNA replication"
            }
        },
        {
            "context": "Augmentation of restless leg syndrome (Willis-Ekbom disease) during long-term dopaminergic treatment. Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common sensorimotor disorder that can generally be effectively managed in the primary care clinic. However, some treatment complications may arise. According to the recommendations of the International Restless Legs Syndrome Study Group, non-ergot dopamine-receptor agonists have over the past years been one of the first-line treatments for patients with RLS/WED requiring pharmacological therapy. Augmentation is the main complication of long-term dopaminergic treatment of RLS/WED and is defined as an overall worsening of symptoms beyond pretreatment levels in patients who experienced an initial positive therapeutic response. Once identified on the basis of its characteristic clinical features, augmentation requires careful management. In order to provide clinicians with a comprehensive understanding of this common treatment complication, this review discusses the clinical features of augmentation, and its differentiation from morning rebound, symptom fluctuations and natural disease progression. Reported incidences of augmentation in clinical trials of dopaminergic RLS/WED therapies are summarized. Finally, the hypothetical pathophysiology of augmentation and the current recommendations for management of patients with augmented RLS/WED symptoms are discussed.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 102,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "Designing calcium release channel inhibitors with enhanced electron donor properties: stabilizing the closed state of ryanodine receptor type 1. New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 456,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage. OBJECTIVES: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. METHODS: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activity was measured, along with that of other LCP initiators (mannose-binding lectin, ficolin-2, and ficolin-1), C3 activation products, and soluble C5b-9 terminal complex, in a prospective cohort of 39 patients with SAH and 20 healthy controls. The following parameters were recorded: SAH severity, assessed using the World Federation of Neurosurgical Societies grading scale; vasospasm, defined as neuro-worsening with angiographic confirmation of vessel narrowing; cerebral ischemia, defined as hypodense lesion on CT scan performed before discharge; and 6-month outcome, assessed using the Glasgow Outcome Scale. RESULTS: In patients, no changes were detected for ficolin-3 compared with controls. Notably, however, ficolin-3-mediated functional LCP activity was reduced. Low levels of plasma ficolin-3 and ficolin-3-mediated functional LCP activity were related to SAH severity, vasospasm, and cerebral ischemia. Moreover, ficolin-3 functional LCP activity was decreased in patients with unfavorable outcome. CONCLUSION: Our data provide evidence that LCP is activated after SAH and that the actual plasma concentrations of ficolin-3 reflect the severity of brain injury as evaluated by clinical and structural parameters. These results support the idea that ficolin-3-mediated functional LCP activity may be targeted to control injury progression in SAH.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 19,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "FullSSR: Microsatellite Finder and Primer Designer. Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. The software was tested with 2000 sequences of Oryza sativa shotgun sequencing project from the National Center of Biotechnology Information Trace Archive and with partial genome sequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla platensis, and Zilchiopsis collastinensis. FullSSR performance was compared against other similar SSR search programs. The results of the use of this kind of approach depend on the parameters set by the user. In addition, results can be affected by the analyzed sequences because of differences among the genomes. FullSSR simplifies the detection of SSRs and primer design on a big data set. The command line interface of FullSSR was intended to be used as part of genomic analysis tools pipeline; however, it can be used as a stand-alone program because the results are easily interpreted for a nonexpert user.",
            "question": "Which tool exists for microsatellite (SSR) loci detection and primer design?",
            "answers": {
                "answer_start": 0,
                "text": "FullSSR"
            }
        },
        {
            "context": "Microsporidia infection in a mexican kidney transplant recipient. Microorganisms of the microsporidia group are obligated intracellular protozoa that belong to the phylum Microspora; currently they are considered to be related or belong to the fungi reign. It is considered an opportunistic infection in humans, and 14 species belonging to 8 different genera have been described. Immunocompromized patients such as those infected with human immunodeficiency virus (HIV), also HIV serum-negative asymptomatic patients, with poor hygienic conditions, and recipients of bone marrow or solid organ transplantation are susceptible to develop deinfection. Sixty transplanted patients with renal microsporidia infection have been reported worldwide. The aim of this paper is to inform about the 2nd case of kidney transplant and microsporidia infection documented in Mexico.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 244,
                "text": "fungi"
            }
        },
        {
            "context": "Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 6,
                "text": "NF1"
            }
        },
        {
            "context": "Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 113,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "JAMM: a peak finder for joint analysis of NGS replicates. MOTIVATION: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets. RESULTS: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy. AVAILABILITY AND IMPLEMENTATION: JAMM is available for free and can run on Linux machines through the command line: http://code.google.com/p/jamm-peak-finder.",
            "question": "Which peak calling algorithm employs mixture model clustering under the hood?",
            "answers": {
                "answer_start": 908,
                "text": "JAMM"
            }
        },
        {
            "context": "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in > 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 154,
                "text": "CD38"
            }
        },
        {
            "context": "A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina. Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 135,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 444,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 29,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling. BACKGROUND: Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling. METHODS AND RESULTS: Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1-PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1. CONCLUSIONS: Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1-PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.",
            "question": "Which protein phosphatase has been found to interact with the heat shock protein, HSP20?",
            "answers": {
                "answer_start": 1763,
                "text": "PP1"
            }
        },
        {
            "context": "Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone. Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 287,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Idarucizumab for Dabigatran Reversal. BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 227,
                "text": "dabigatran"
            }
        },
        {
            "context": "Suvorexant, a dual orexin receptor antagonist for the management of insomnia. Suvorexant, a dual orexin receptor antagonist for the management of insomnia.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 19,
                "text": "orexin"
            }
        },
        {
            "context": "Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome. The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 639,
                "text": "FBN1"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 551,
                "text": "chromDraw"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 0,
                "text": "LARVA"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 780,
                "text": "CD38"
            }
        },
        {
            "context": "SeqArray-a storage-efficient high-performance data format for WGS variant calls. Motivation: Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Results: Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. Availability and Implementation: http://www.bioconductor.org/packages/SeqArray. Contact: zhengx@u.washington.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm has been proposed for efficient storage of WGS variant calls?",
            "answers": {
                "answer_start": 0,
                "text": "SeqArray"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 977,
                "text": "BRG1"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 57,
                "text": "CO2"
            }
        },
        {
            "context": "Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.",
            "question": "What do nerve-associated peripheral glial progenitors give rise to?",
            "answers": {
                "answer_start": 18,
                "text": "Parasympathetic neurons"
            }
        },
        {
            "context": "Mutations in MED12 cause X-linked Ohdo syndrome. Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.",
            "question": "What is the genetic basis of Ohdo syndrome?",
            "answers": {
                "answer_start": 0,
                "text": "Mutations in MED12"
            }
        },
        {
            "context": "Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys. Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses > 3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 29,
                "text": "CYP17A1"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2234,
                "text": "stroke"
            }
        },
        {
            "context": "Association of restless legs syndrome variants in Korean patients with restless legs syndrome. STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS. DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci. MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters. CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 255,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "[Dialectical behavior therapy approaches with disruptive behavior disorders]. Disruptive behaviour disorders comprise the diagnosis conduct disorder (CD) and in adults the diagnosis antisocial personality disorder (APD). CD is seen as a difficult-to-treat disorder with a high risk for persistent behavioral problems. In addition, CD is seen as the precursor to antisocial personality disorder (Kretschmer et al., 2014). Dialectical behavior therapy (DBT) was originally developed by Marsha Linehan (1991) for the treatment of borderline personality disorder, but because of the core deficits in emotion regulation in disruptive behavior disorders, DBT is also increasingly being recommended for the treatment of CD and APD. This review presents DBT adaptions for the forensic setting and for the treatment of CD/APD. Clinical implications are discussed.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 527,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. OBJECTIVES: Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. DESIGN: Prospective analysis. PATIENTS: 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses. SETTING: All analyses were performed in a large German laboratory specialised in genetic diagnostics. RESULTS: 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. CONCLUSIONS: On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 2142,
                "text": "MITF"
            }
        },
        {
            "context": "Dermatitis herpetiformis: close to unravelling a disease. Dermatitis herpetiformis is characterised by granular IgA precipitates in the papillary dermis. In contrast to other autoimmune blistering diseases, where tissue-deposited and circulating autoantibodies recognise the same target within the skin, in dermatitis herpetiformis a serum IgA reacting with a component of the healthy papillary dermis has not been detected. Recently, the antigenic specificity of pathognomic skin-bound IgA has been clarified: the immune precipitates contain epidermal transglutaminase, an enzyme not previously detected in the papillary region of normal skin. Furthermore, serum IgA in dermatitis herpetiformis has been found to bind epidermal transglutaminase. These findings may relate to the fact, that dermatitis herpetiformis is associated with gluten sensitive enteropathy, coeliac disease, which is characterised by IgA type autoantibodies to a closely related enzyme, tissue transglutaminase. The two transglutaminases are highly homologous, and therefore, cross reactivity of the two antibodies might explain why patients with gluten sensitive enteropathy, with or without skin disease, generally have serum autoantibodies to both enzymes. There is growing evidence that dermatitis herpetiformis should be considered as the skin manifestation of gluten sensitivity developing in those patients with mild coeliac disease, who produce epidermal transglutaminase autoantibodies of high avidity and affinity. Both the skin and the small bowel diseases are gluten dependent and are strongly associated with HLA DQ with no genetic differences to explain the two phenotypes. The question should be asked whether the rash in dermatitis herpetiformis is a classic autoimmune blistering disease or whether it has an immune complex basis, which is the most likely alternative.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 1265,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Deep brain stimulation in critical care conditions. Some neurological conditions require admission to an intensive care unit (ICU) where deep sedation and mechanical ventilation are administered to improve the patient's condition. Nevertheless, these treatments are not always helpful in disease control. At this stage, deep brain stimulation (DBS) could become a viable alternative in the treatment of critical neurological conditions with long-lasting clinical benefit. The value of deep brain stimulation has been investigated in the treatment of patients who had undergone surgical electrode implants as an emergency procedure to treat acute life-threatening conditions requiring admission to neurological ICU (NICU). A before-and-after perspective study was examined of seven patients who were treated with DBS for status dystonicus (SD) and post-stroke severe hemiballismus. Bilateral globus pallidus internus (GPi) DBS was performed in five SD patients and unilateral ventralis oralis anterior and posterior (Voa/Vop) nucleus of the thalamus DBS in two post-stroke hemiballismus patients. Bilateral GPi-DBS allowed SD resolution in a time lapse varying from 1 week to 3 months. No clear improvements compared to the baseline clinical condition were observed. Unilateral Voa/Vop-DBS intervention controlled hemiballismus after 10 h, and the patient was discharged in 2 days. The other patient was transferred from the NICU to the neurosurgery ward after 13 days. No surgical complications were observed in any of the above procedures. Neurostimulation procedures could represent a valuable choice in critical care conditions, when involuntary movements are continuous, life-threatening and refractory to intensive care procedures. DBS is feasible, safe and effective in selected cases.",
            "question": "Neurostimulation of which nucleus is used for treatment of dystonia?",
            "answers": {
                "answer_start": 891,
                "text": "globus pallidus internus"
            }
        },
        {
            "context": "HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity. BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 1244,
                "text": "liver"
            }
        },
        {
            "context": "Maintenance of DNA methylation: Dnmt3b joins the dance. DNA methylation mostly occurs within the context of CpG dinucleotides and is essential for embryonic development and gene repression. It is generally accepted that DNA methyltransferases carry out specific and non-overlapping functions, Dnmt3a and Dnmt3b being responsible for the establishment of methylation around the time of implantation and Dnmt1 ensuring that methylation is faithfully copied to daughter cells via what has come to be known as \"maintenance methylation.\" This longstanding view has been challenged over the years with the observation that Dnmt1 alone is incapable of perfect maintenance methylation. A new model is emerging that takes into account a contribution of the de novo enzymes Dnmt3a and Dnmt3b in the maintenance of the DNA methylation. We recently showed that certain germ line genes are specific targets of Dnmt3b, and that Dnmt3b remains bound to their promoter regions in somatic cells via interaction with the transcriptional repressor E2F6. It is tempting to consider an ongoing role for Dnmt3b in the methylation of germ line genes in somatic cells. We propose here observations in support of the hypothesis that the maintenance of methylation and subsequent silencing of a handful of germ line genes requires Dnmt3b but not Dnmt1. In addition to suggesting a new role for Dnmt3b in the protection of somatic cells against the promiscuous expression of the germ line program, these observations are of particular interest in the field of carcinogenesis, given that the expression of catalytically inactive Dnmt3b isoforms and aberrant expression of germ line genes are commonly observed in cancer cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 402,
                "text": "Dnmt1"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 19,
                "text": "Stroke"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1491,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. The p53 guardian of the genome is inactivated in the majority of cancers, mostly through missense mutations that cause single residue changes in the DNA binding core domain of the protein. Not only do such mutations result in the abrogation of wild-type p53 activity, but the expressed p53 mutant proteins also tend to gain oncogenic functions, such as interference with wild-type p53-independent apoptosis. Because p53 mutants are highly expressed in cancer cells and not in normal cells, their reactivation to wild-type p53 function may eliminate the cancer by apoptosis or another p53-dependent mechanism. Several studies that embarked on this quest for reactivation have succeeded in restoring wildtype p53 activity to several p53 mutants. However, mutants with more extensive structural changes in the DNA binding core domain may be refractory to reactivation to the wild-type p53 phenotype. Therefore, understanding the structure and functions of oncogenic p53 mutants may lead to more potent reactivation modalities or to the ability to eliminate mutant p53 gain of function.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 27,
                "text": "p53"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 985,
                "text": "xa"
            }
        },
        {
            "context": "Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 702,
                "text": "NGF"
            }
        },
        {
            "context": "Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 251,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 55,
                "text": "tyr"
            }
        },
        {
            "context": "Imaging of plantar fascia disorders: findings on plain radiography, ultrasound and magnetic resonance imaging. Plantar fascia (PF) disorders commonly cause heel pain and disability in the general population. Imaging is often required to confirm diagnosis. This review article aims to provide simple and systematic guidelines for imaging assessment of PF disease, focussing on key findings detectable on plain radiography, ultrasound and magnetic resonance imaging (MRI). Sonographic characteristics of plantar fasciitis include PF thickening, loss of fibrillar structure, perifascial collections, calcifications and hyperaemia on Doppler imaging. Thickening and signal changes in the PF as well as oedema of adjacent soft tissues and bone marrow can be assessed on MRI. Radiographic findings of plantar fasciitis include PF thickening, cortical irregularities and abnormalities in the fat pad located deep below the PF. Plantar fibromatosis appears as well-demarcated, nodular thickenings that are iso-hypoechoic on ultrasound and show low-signal intensity on MRI. PF tears present with partial or complete fibre interruption on both ultrasound and MRI. Imaging description of further PF disorders, including xanthoma, diabetic fascial disease, foreign-body reactions and plantar infections, is detailed in the main text. Ultrasound and MRI should be considered as first- and second-line modalities for assessment of PF disorders, respectively. Indirect findings of PF disease can be ruled out on plain radiography. Teaching Points • PF disorders commonly cause heel pain and disability in the general population.• Imaging is often required to confirm diagnosis or reveal concomitant injuries.• Ultrasound and MRI respectively represent the first- and second-line modalities for diagnosis.• Indirect findings of PF disease can be ruled out on plain radiography.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 156,
                "text": "heel pain"
            }
        },
        {
            "context": "In vitro characterization of mutant yeast RNA polymerase II with reduced binding for elongation factor TFIIS. We have reported previously the isolation and genetic characterization of mutations in the gene encoding the largest subunit of yeast RNA polymerase II (RNAPII), which lead to 6-azauracil (6AU)-sensitive growth. It was suggested that these mutations affect the functional interaction between RNAPII and transcription-elongation factor TFIIS because the 6AU-sensitive phenotype of the mutant strains was similar to that of a strain defective in the production of TFIIS and can be suppressed by increasing the dosage of the yeast TFIIS-encoding gene, PPR2, RNAPIIs were purified and characterized from two independent 6AU-sensitive yeast mutants and from wild-type (wt) cells. In vitro, in the absence of TFIIS, the purified wt polymerase and the two mutant polymerases showed similar specific activity in polymerization, readthrough at intrinsic transcriptional arrest sites and nascent RNA cleavage. In contrast to the wt polymerase, both mutant polymerases were not stimulated by the addition of a 3-fold molar excess of TFIIS in assays of promoter-independent transcription, readthrough or cleavage. However, stimulation of the ability of the mutant RNAPIIs to cleave nascent RNA and to read through intrinsic arrest sites was observed at TFIIS:RNAPII molar ratios greater than 600:1. Consistent with these findings, the binding affinity of the mutant polymerases for TFIIS was found to be reduced by more than 50-fold compared with that of the wt enzyme. These studies demonstrate that TFIIS has an important role in the regulation of transcription by yeast RNAPII and identify a possible binding site for TFIIS on RNAPII.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 103,
                "text": "TFIIS"
            }
        },
        {
            "context": "Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled repair. BACKGROUND: In eukaryotic cells, there are two sub-pathways of nucleotide excision repair (NER), the global genome (gg) NER and the transcription-coupled repair (TCR). TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA. This strand-specific repair in a suitable restriction fragment is usually determined by alkaline gel electrophoresis followed by Southern blotting transfer and hybridization with an indirect end-labeled single-stranded probe. Here we describe a new method of TCR assay based on strand-specific-PCR (SS-PCR). Using this method, we have investigated the role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related protein kinases (PIKK) family, in the TCR pathway of UV-induced DNA damage. RESULTS: Although depletion of DNA-PKcs sensitized HeLa cells to UV radiation, it did not affect the ggNER efficiency of UV-induced cyclobutane pyrimidine dimers (CPD) damage. We postulated that DNA-PKcs may involve in the TCR process. To test this hypothesis, we have firstly developed a novel method of TCR assay based on the strand-specific PCR technology with a set of smart primers, which allows the strand-specific amplification of a restricted gene fragment of UV radiation-damaged genomic DNA in mammalian cells. Using this new method, we confirmed that siRNA-mediated downregulation of Cockayne syndrome B resulted in a deficiency of TCR of the UV-damaged dihydrofolate reductase (DHFR) gene. In addition, DMSO-induced silencing of the c-myc gene led to a decreased TCR efficiency of UV radiation-damaged c-myc gene in HL60 cells. On the basis of the above methodology verification, we found that the depletion of DNA-PKcs mediated by siRNA significantly decreased the TCR capacity of repairing the UV-induced CPDs damage in DHFR gene in HeLa cells, indicating that DNA-PKcs may also be involved in the TCR pathway of DNA damage repair. By means of immunoprecipitation and MALDI-TOF-Mass spectrometric analysis, we have revealed the interaction of DNA-PKcs and cyclin T2, which is a subunit of the human transcription elongation factor (P-TEFb). While the P-TEFb complex can phosphorylate the serine 2 of the carboxyl-terminal domain (CTD) of RNA polymerase II and promote transcription elongation. CONCLUSION: A new method of TCR assay was developed based the strand-specific-PCR (SS-PCR). Our data suggest that DNA-PKcs plays a role in the TCR pathway of UV-damaged DNA. One possible mechanistic hypothesis is that DNA-PKcs may function through associating with CyclinT2/CDK9 (P-TEFb) to modulate the activity of RNA Pol II, which has already been identified as a key molecule recognizing and initializing TCR.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 363,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519. A newly synthesized 1,4-benzothiazipine derivate, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2,3,4,5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) mediated multidrug resistance (MDR) in K562/MDR and KB/MRP cells, respectively. JTV-519 at 3 microM reversed the resistance of K562/MDR cells to vincristine (VCR), taxol, etoposide (VP16), adriamycin (ADM) and actinomycin D and at 0.5 or 1 microM reversed their resistance to STI571. JTV-519 at 10 microM enhanced the accumulation of ADM in K562/MDR cells to the level in parental K562 cells and inhibited the efflux of ADM from K562/MDR cells. Photoaffinity labeling of P-gp with 3H-azidopine was almost completely inhibited by 500 microM JTV-519. JTV-519 at 3 microM also partially reversed the resistance of KB/MRP cells to VCR and at 500 microM partially inhibited the photoaffinity labeling of MRP1 with (125)I-II-azidophenyl agosterol A (125I-azidoAG-A). These results suggest that JTV-519 reversed the resistance to the anti-cancer agents in P-gp and MRP1 overexpressing multidrug-resistant cells by directly binding to P-gp and MRP1, and competitively inhibiting transport of the anti-cancer agents.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 246,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 504,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Physiological Roles of Adipokines, Hepatokines, and Myokines in Ruminants. Since the discovery of leptin secreted from adipocytes, specialized tissues and cells have been found that secrete the several peptides (or cytokines) that are characterized to negatively and positively regulate the metabolic process. Different types of adipokines, hepatokines, and myokines, which act as cytokines, are secreted from adipose, liver, and muscle tissue, respectively, and have been identified and examined for their physiological roles in humans and disease in animal models. Recently, various studies of these cytokines have been conducted in ruminants, including dairy cattle, beef cattle, sheep, and goat. Interestingly, a few cytokines from these tissues in ruminants play an important role in the post-parturition, lactation, and fattening (marbling) periods. Thus, understanding these hormones is important for improving nutritional management in dairy cows and beef cattle. However, to our knowledge, there have been no reviews of the characteristics of these cytokines in beef and dairy products in ruminants. In particular, lipid and glucose metabolism in adipose tissue, liver tissue, and muscle tissue are very important for energy storage, production, and synthesis, which are regulated by these cytokines in ruminant production. In this review, we summarize the physiological roles of adipokines, hepatokines, and myokines in ruminants. This discussion provides a foundation for understanding the role of cytokines in animal production of ruminants.",
            "question": "From which cell type is leptin secreted?",
            "answers": {
                "answer_start": 119,
                "text": "adipocytes"
            }
        },
        {
            "context": "Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications. Protein phosphorylation by kinases plays a central role in the regulation and coordination of multiple biological processes. In general, knowledge on kinase specificity is restricted to substrates identified in the context of specific cellular responses, but kinases are likely to have multiple additional substrates and be integrated in signaling networks that might be spatially and temporally different, and in which protein complexes and subcellular localization can play an important role. In this report the substrate specificity of atypical human vaccinia-related kinases (VRK1 and VRK2) using a human peptide-array containing 1080 sequences phosphorylated in known signaling pathways has been studied. The two kinases identify a subset of potential peptide targets, all of them result in a consensus sequence composed of at least four basic residues in peptide targets. Linear peptide arrays are therefore a useful approach in the characterization of kinases and substrate identification, which can contribute to delineate the signaling network in which VRK proteins participate. One of these target proteins is coilin; a basic protein located in nuclear Cajal bodies. Coilin is phosphorylated in Ser184 by both VRK1 and VRK2. Coilin colocalizes and interacts with VRK1 in Cajal bodies, but not with the mutant VRK1 (R358X). VRK1 (R358X) is less active than VRK1. Altered regulation of coilin might be implicated in several neurological diseases such as ataxias and spinal muscular atrophies.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1283,
                "text": "coilin"
            }
        },
        {
            "context": "Molluscum contagiosum virus interleukin-18 (IL-18) binding protein is secreted as a full-length form that binds cell surface glycosaminoglycans through the C-terminal tail and a furin-cleaved form with only the IL-18 binding domain. Some poxviruses and their mammalian hosts encode homologous proteins that bind interleukin-18 (IL-18) with high affinity and inhibit IL-18-mediated immune responses. MC54L, the IL-18 binding protein of the human poxvirus that causes molluscum contagiosum, is unique in having a C-terminal tail of nearly 100 amino acids that is dispensable for IL-18 binding. When recombinant MC54L was expressed and purified via a C-terminal six-histidine tag, a shorter fragment was detected in addition to the full-length protein. This C-terminal fragment resulted from the cleavage of MC54L by cellular furin, as it was greatly diminished when furin was specifically inhibited or when a furin-deficient cell line was used for expression. Furthermore, the N- and C-terminal fragments of MC54L were generated by cleavage of the recombinant protein with furin in vitro. The furin cleavage site was mapped within a 32-amino-acid segment that is C terminal to the IL-18 binding domain. Full-length MC54L, but not the N-terminal IL-18 binding fragment, bound to cells and to purified heparin and other glycosaminoglycans that are commonly found on the cell surface and in the extracellular matrix. MC54L bound to heparin with a nanomolar K(d) and could simultaneously bind to IL-18. Their different glycosaminoglycan and cell binding properties may allow the long and short forms of MC54L to inactivate IL-18 near the site of infection and at more distal locations, respectively.",
            "question": "Which virus type causes Molluscum contagiosum?",
            "answers": {
                "answer_start": 439,
                "text": "human poxvirus"
            }
        },
        {
            "context": "Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790: implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8%. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 388,
                "text": "EGFR"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 959,
                "text": "NCX"
            }
        },
        {
            "context": "Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome. Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C>T, CGA>TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein's BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 99,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 651,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "TFEB links autophagy to lysosomal biogenesis. Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 451,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1264,
                "text": "7"
            }
        },
        {
            "context": "Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease. It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-β (Aβ)-induced apoptosis. Therefore, blocking GSK3β-induced Drp1 phosphorylation may be an effective way to protect neurons from Aβ toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3β-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aβ-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aβ burden and rescued the memory deficits in AD transgenic mice. Although Aβ has multiple targets to exert its neurotoxicity, our findings suggested that GSK3β-induced mitochondrial fragmentation was, at least partially, mediated by Aβ toxicity and contribute to the pathogenesis of AD. Taken together, GSK3β-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 248,
                "text": "Mitochondrial fission"
            }
        },
        {
            "context": "NOXO1 phosphorylation on serine 154 is critical for optimal NADPH oxidase 1 assembly and activation. Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 60,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "Ophthalmic findings in patients with arterial tortuosity syndrome and carriers: A case series. INTRODUCTION: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disease hallmarked by tortuosity, stenosis, and aneurysm development of large- and medium-sized arteries. Mutations in SLC2A10, a gene that encodes the facilitative glucose transporter GLUT10, cause ATS. Several case reports have noted associated ophthalmic findings such as keratoconus, keratoglobus, and myopia without detailed descriptions or standardized examinations. We report the ophthalmic findings in a cohort of compound heterozygous ATS patients and heterozygous carriers of SLC2A10 mutations. METHODS: Five ATS patients and three carriers were identified through an ATS specialty clinic at the Arkansas Children's Hospital in Little Rock, Arkansas. Patients underwent complete eye examinations, including corneal pachymetry, topography, and optical coherence tomography when indicated. RESULTS: All five patients with ATS had myopia and thin corneas with an average central corneal thickness of 426 µm, and three had corneal ectasia, two with early keratoconus and one with keratoglobus and deep stromal corneal opacities. One patient had bilateral high irregular astigmatism, and one had unilateral high regular astigmatism. All carriers had myopia, one had corneal thinning, and one developed keratectasia in one eye many years after laser-assisted in situ keratomileusis (LASIK) surgery. CONCLUSION: We document a spectrum of ophthalmic manifestations of ATS with universal findings of myopia, corneal thinning, and a propensity for corneal ectasia leading to keratoconus or keratoglobus. Heterozygous carriers may develop keratectasia after corneal refractive surgery. Our data support regular eye examinations for all patients carrying SLC2A10 mutations with follow-up tailored to clinical findings.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 293,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 299,
                "text": "dabigatran"
            }
        },
        {
            "context": "Styrylbenzimidazoles. Synthesis and biological activity - part 3. As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 microM; among them, compound 17 was the most active, with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active against RSV with EC(50)= 1 microM and represents a new lead compound.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 330,
                "text": "three"
            }
        },
        {
            "context": "Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. T cell DNA methylation levels decline with age, activating genes such as KIR and TNFSF7 (CD70), implicated in lupus-like autoimmunity and acute coronary syndromes. The mechanisms causing age-dependent DNA demethylation are unclear. Maintenance of DNA methylation depends on DNA methyltransferase 1 (Dnmt1) and intracellular S-adenosylmethionine (SAM) levels, and is inhibited by S-adenosylhomocysteine (SAH). SAM levels depend on dietary micronutrients including folate and methionine. SAH levels depend on serum homocysteine concentrations. T cell Dnmt1 levels also decline with age. We hypothesized that age-dependent Dnmt1 decreases synergize with low folate, low methionine or high homocysteine levels to demethylate and activate methylation-sensitive genes. T cells from healthy adults ages 22-81, stimulated and cultured with low folate, low methionine, or high homocysteine concentrations showed demethylation and overexpression of KIR and CD70 beginning at age approximately 50 and increased further with age. The effects were reproduced by Dnmt1 knockdowns in T cells from young subjects. These results indicate that maintenance of T cell DNA methylation patterns is more sensitive to low folate and methionine levels in older than younger individuals, due to low Dnmt1 levels, and that homocysteine further increases aberrant gene expression. Thus, attention to proper nutrition may be particularly important in the elderly.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 503,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Sequence analysis of the human kallikrein gene locus identifies a unique polymorphic minisatellite element. Minisatellites are repetitive sequences of DNA that are present throughout the genome. Although the origin and function of these minisatellites is still unknown, they found clinical applications as markers of many diseases, including cancer. Also, they are useful tools for DNA fingerprinting and linkage analysis. Kallikreins are serine proteases that appear to be involved in many diseases including brain disorders and malignancy. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. In this study, we examined the kallikrein locus ( approximately 300 Kb) for all known repeat elements. About 50% of this genomic area is occupied by different repeat elements. We also identified unique minisatellite elements that are restricted to chromosome 19q13. Ten clusters of these minisatellites are distributed along the locus on either DNA strand. The clusters are located in the promoters and enhancers of genes, in introns, and in untranslated regions of the mRNA. Analysis of these elements indicates that they are polymorphic, thus they can be useful in linkage analysis and DNA fingerprinting. Our preliminary results indicate also that the distribution of the different alleles of these minisatellites might be associated with malignancy.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 643,
                "text": "15"
            }
        },
        {
            "context": "A New Less Invasive Technique for Multiple-Level Spontaneous Spinal Epidural Hematomas: Wash-and-Go Technique. Aim Spinal epidural hematomas are rare entity in neurosurgery practice. Most of them are spontaneous due to anticoagulant therapy and called spontaneous spinal epidural hematomas (SSEHs). Laminectomy or hemilaminectomy for affected levels is still the first choice in the operative treatment of an SSEH. We describe a new less invasive surgical technique, performing single-level laminectomy and washing with 0.9% sodium chloride through a thin soft catheter for a 12-level thoracic-cervical SSEH in a patient under anticoagulant therapy. Patient and Operative Technique A 55-year-old woman was brought to the emergency department with a rapid onset of pain in her upper back and both legs with weakness of her lower extremities. An urgent magnetic resonance imaging (MRI) of the whole spine showed a SEH. During the operation, after T2 laminectomy, a thin soft catheter was epidurally placed under the T1 lamina and gently pushed forward rostrally. Then continuous saline irrigation was utilized and aspiration made via the catheter to wash out the hematoma. Drainage of blood was observed. The procedure was performed for 15 minutes. Then the catheter was epidurally placed under the T3 lamina, and the procedure for the hematoma in the lower segment was repeated. Decompression of spinal cord and nerve roots was observed. Result Postoperative early MRI of the thoracic-cervical spine showed gross total evacuation of the SEH. Accordingly, the patient's muscle strength improved. Conclusion Although multiple laminectomy or hemilaminectomy for affected levels to evacuate the hematoma and decompress the spinal cord is the main choice of surgical treatment, single-level laminectomy and irrigation plus aspiration via a thin soft catheter can be performed successfully with good results in SSEH.",
            "question": "What drug treatment can cause a spinal epidural hematoma?",
            "answers": {
                "answer_start": 219,
                "text": "anticoagulant therapy"
            }
        },
        {
            "context": "Can the FAST and ROSIER adult stroke recognition tools be applied to confirmed childhood arterial ischemic stroke? BACKGROUND: Stroke recognition tools have been shown to improve diagnostic accuracy in adults. Development of a similar tool in children is needed to reduce lag time to diagnosis. A critical first step is to determine whether adult stoke scales can be applied in childhood stroke.Our objective was to assess the applicability of adult stroke scales in childhood arterial ischemic stroke (AIS) METHODS: Children aged 1 month to < 18 years with radiologically confirmed acute AIS who presented to a tertiary emergency department (ED) (2003 to 2008) were identified retrospectively. Signs, symptoms, risk factors and initial management were extracted. Two adult stroke recognition tools; ROSIER (Recognition of Stroke in the Emergency Room) and FAST (Face Arm Speech Test) scales were applied retrospectively to all patients to determine test sensitivity. RESULTS: 47 children with AIS were identified. 34 had anterior, 12 had posterior and 1 child had anterior and posterior circulation infarcts. Median age was 9 years and 51% were male. Median time from symptom onset to ED presentation was 21 hours but one third of children presented within 6 hours. The most common presenting stroke symptoms were arm (63%), face (62%), leg weakness (57%), speech disturbance (46%) and headache (46%). The most common signs were arm (61%), face (70%) or leg weakness (57%) and dysarthria (34%). 36 (78%) of children had at least one positive variable on FAST and 38 (81%) had a positive score of > 1 on the ROSIER scale. Positive scores were less likely in children with posterior circulation stroke. CONCLUSION: The presenting features of pediatric stroke appear similar to adult strokes. Two adult stroke recognition tools have fair to good sensitivity in radiologically confirmed childhood AIS but require further development and modification. Specificity of the tools also needs to be determined in a prospective cohort of children with stroke and non-stroke brain attacks.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 823,
                "text": "Stroke"
            }
        },
        {
            "context": "RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene ERCC6. Transcription-coupled repair (TCR) is a universal sub-pathway of the nucleotide excision repair (NER) system that is limited to the transcribed strand of active structural genes. It accomplishes the preferential elimination of transcription-blocking DNA lesions and permits rapid resumption of the vital process of transcription. A defect in TCR is responsible for the rare hereditary disorder Cockayne syndrome (CS). Recently we found that mutations in the ERCC6 repair gene, encoding a putative helicase, underly the repair defect of CS complementation group B. Here we report the cloning and characterization of the Saccharomyces cerevisiae homolog of CSB/ERCC6, which we designate RAD26. A rad26 disruption mutant appears viable and grows normally, indicating that the gene does not have an essential function. In analogy with CS, preferential repair of UV-induced cyclobutane pyrimidine dimers in the transcribed strand of the active RBP2 gene is severely impaired. Surprisingly, in contrast to the human CS mutant, yeast RAD26 disruption does not induce any UV-, cisPt- or X-ray sensitivity, explaining why it was not isolated as a mutant before. Recovery of growth after UV exposure was somewhat delayed in rad26. These findings suggest that TCR in lower eukaryotes is not very important for cell survival and that the global genome repair pathway of NER is the major determinant of cellular resistance to genotoxicity.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 211,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 663,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 1124,
                "text": "LARVA"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 605,
                "text": "AD"
            }
        },
        {
            "context": "Cell-cycle regulation of cohesin stability along fission yeast chromosomes. Sister chromatid cohesion is mediated by cohesin, but the process of cohesion establishment during S-phase is still enigmatic. In mammalian cells, cohesin binding to chromatin is dynamic in G1, but becomes stabilized during S-phase. Whether the regulation of cohesin stability is integral to the process of cohesion establishment is unknown. Here, we provide evidence that fission yeast cohesin also displays dynamic behavior. Cohesin association with G1 chromosomes requires continued activity of the cohesin loader Mis4/Ssl3, suggesting that repeated loading cycles maintain cohesin binding. Cohesin instability in G1 depends on wpl1, the fission yeast ortholog of mammalian Wapl, suggestive of a conserved mechanism that controls cohesin stability on chromosomes. wpl1 is nonessential, indicating that a change in wpl1-dependent cohesin dynamics is dispensable for cohesion establishment. Instead, we find that cohesin stability increases at the time of S-phase in a reaction that can be uncoupled from DNA replication. Hence, cohesin stabilization might be a pre-requisite for cohesion establishment rather than its consequence.",
            "question": "During which stage of the cell cycle is cohesin deposited on the yeast genome?",
            "answers": {
                "answer_start": 1033,
                "text": "S-phase"
            }
        },
        {
            "context": "The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma. The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-α alone had little effect on cell viability in vitro. However, the combination of ixazomib with IFN-α significantly enhanced ixazomib's ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-α also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-α-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-α-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-α for the treatment of advanced BRAF V600E mutant melanoma.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 365,
                "text": "proteasome"
            }
        },
        {
            "context": "Chaperone-mediated autophagy components are upregulated in sporadic inclusion-body myositis muscle fibres. AIMS: Sporadic inclusion-body myositis (s-IBM) is an age-associated degenerative muscle disease. Characteristic features are muscle-fibre vacuolization and intramuscle-fibre accumulations of multiprotein aggregates, which may result from the demonstrated impairments of the 26S proteasome and autophagy. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif. Lysosome-associated membrane protein type 2A (LAMP2A) and the heat-shock cognate protein 70 (Hsc70) constitute specific CMA components. Neither CMA components nor CMA activity has been studied in normal or disease human muscle, to our knowledge. METHODS: We studied CMA components by immunocytochemistry, immunoblots, real-time PCR and immunoprecipitation in: (a) 16 s-IBM, nine aged-matched normal and nine disease control muscle biopsies; and (b) cultured human muscle fibres (CHMFs) with experimentally inhibited activities of either the 26S proteasome or autophagy. RESULTS: Compared with age-matched controls, in s-IBM muscle, LAMP2A and Hsc70 were on a given transverse section accumulated as aggregates in approximately 5% of muscle fibres, where they (a) colocalized with each other and α-synuclein (α-syn), a CMA-targeted protein; and (b) were bound to each other and to α-syn by immunoprecipitation. By immunoblots, LAMP2A was increased sevenfold P < 0.001 and Hsc70 2.6-fold P < 0.05. LAMP2A mRNA was increased 4.4-fold P < 0.001 and Hsc70 mRNA 1.9-fold P < 0.05. In CHMFs inhibition of either the 26S proteasome or autophagy induced CMA, evidenced by a significant increase of both LAMP2A and Hsc70. CONCLUSIONS: Our study demonstrates, for the first time, up-regulation of CMA components in s-IBM muscle, and it provides further evidence that altered protein degradation is likely an important pathogenic aspect in s-IBM.",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 411,
                "text": "Chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine. BACKGROUND: A pivotal phase III study of the RTS,S/AS01 malaria candidate vaccine is ongoing in several research centres across Africa. The development and establishment of quality systems was a requirement for trial conduct to meet international regulatory standards, as well as providing an important capacity strengthening opportunity for study centres. METHODS: Standardized laboratory methods and quality assurance processes were implemented at each of the study centres, facilitated by funding partners. RESULTS: A robust protocol for determination of parasite density based on actual blood cell counts was set up in accordance with World Health Organization recommendations. Automated equipment including haematology and biochemistry analyzers were put in place with standard methods for bedside testing of glycaemia, base excess and lactacidaemia. Facilities for X-rays and basic microbiology testing were also provided or upgraded alongside health care infrastructure in some centres. External quality assurance assessment of all major laboratory methods was established and method qualification by each laboratory demonstrated. The resulting capacity strengthening has ensured laboratory evaluations are conducted locally to the high standards required in clinical trials. CONCLUSION: Major efforts by study centres, together with support from collaborating parties, have allowed standardized methods and robust quality assurance processes to be put in place for the phase III evaluation of the RTS, S/AS01 malaria candidate vaccine. Extensive training programmes, coupled with continuous commitment from research centre staff, have been the key elements behind the successful implementation of quality processes. It is expected these activities will culminate in healthcare benefits for the subjects and communities participating in these trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 120,
                "text": "malaria"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 134,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 535,
                "text": "CD38"
            }
        },
        {
            "context": "McEnhancer: predicting gene expression via semi-supervised assignment of enhancers to target genes. Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.",
            "question": "Which method has been developed for assignment of enhancers to target genes?",
            "answers": {
                "answer_start": 0,
                "text": "McEnhancer"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 396,
                "text": "stroke"
            }
        },
        {
            "context": "Phase II trial of syncopated thalidomide, lenalidomide, and weekly dexamethasone in patients with newly diagnosed multiple myeloma. UNLABELLED: Thalidomide and lenalidomide, in combination with dexamethasone, provide response rates ranging from 63%-79% after 4 cycles of therapy. Because of toxicities such as neuropathy and myelosuppression for thalidomide and lenalidomide, respectively, dose escalation has not been pursued. We evaluated a syncopated regimen of alternating weeks of thalidomide and lenalidomide to determine if a modified schedule allows for fewer dose reductions and, subsequently, superior efficacy. Although well tolerated, this phase II trial did not show superior efficacy compared with conventional dosing and scheduling of these agents. INTRODUCTION: Over the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity. PATIENTS AND METHODS: Twenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy. RESULTS: The median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity. CONCLUSION: We conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 912,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 230,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T(3), which binds to nuclear receptors. Recently, a transporter specific for T(3), MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan-Herndon-Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T(3), low to below normal serum levels of free T(4), and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with cognitive impairment, congenital hypotonia, and generalized muscle weakness.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 853,
                "text": "thyroid"
            }
        },
        {
            "context": "Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchange. The histone variant H2AZ is incorporated preferentially at specific locations in chromatin to modulate chromosome functions. In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by the multiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Here, we define interactions between SWR1 components and H2AZ, revealing a link between the ATPase domain of Swr1 and three subunits required for the binding of H2AZ. We discovered that Swc2 binds directly to and is essential for transfer of H2AZ. Swc6 and Arp6 are necessary for the association of Swc2 and for nucleosome binding, whereas other subunits, Swc5 and Yaf9, are required for H2AZ transfer but neither H2AZ nor nucleosome binding. Finally, the C-terminal alpha-helix of H2AZ is crucial for its recognition by SWR1. These findings provide insight on the initial events of histone exchange.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 306,
                "text": "SWR1"
            }
        },
        {
            "context": "Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine. OBJECTIVE: To evaluate the efficacy and tolerability of telcagepant when co-administered with ibuprofen or acetaminophen for the acute treatment of migraine. BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. METHODS: Randomized, double-blind, placebo-controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N =170), or placebo (N = 171). The primary efficacy endpoint was 2-hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. RESULTS: The percentages of patients with 2-hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by > 4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. CONCLUSIONS: The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 281,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 1623,
                "text": "SMA"
            }
        },
        {
            "context": "NOXO1 phosphorylation on serine 154 is critical for optimal NADPH oxidase 1 assembly and activation. Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 145,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa. BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 2164,
                "text": "HIV"
            }
        },
        {
            "context": "Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 444,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "New anticoagulants: focus on venous thromboembolism. Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 909,
                "text": "xa"
            }
        },
        {
            "context": "Involvement of the Na(+)/Ca(2+) exchanger in the automaticity of guinea-pig pulmonary vein myocardium as revealed by SEA0400. We examined the involvement of the Na(+)/Ca(2+) exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca(2+) transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca(2+) transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na(+)/Ca(2+) exchanger underlies the automaticity of the pulmonary vein myocardium.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 161,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Decreased expression of lysyl hydroxylase 2 (LH2) in skin fibroblasts from three Ehlers-Danlos patients does not result from mutations in either the coding or proximal promoter region of the LH2 gene. The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized by tissue fragility, hyperelasticity of the skin and joint hypermobility. This phenotype, accompanied by kyphoscoliosis and/or ocular fragility, is present in patients with the autosomal recessive type VI form of EDS. These patients have significantly decreased levels of lysyl hydroxylase (LH) activity, due to mutations in the LH1 gene. LH hydroxylates specific lysine residues in the collagen molecule that are precursors for the formation of cross-links which provide collagen with its tensile strength. No disorder has been directly linked to decreased expression of LH2 and LH3, two other isoforms of LH. This study describes 3 patients with mixed phenotypes of EDS, who have significantly decreased mRNAs for LH2, but normal levels of LH1 and LH3 mRNAs, in their skin fibroblasts. In contrast to the effect of LH1 deficiency in EDS VI patients, the decreased expression of LH2 does not affect LH activity, bifunctional collagen cross-links (measured after reduction as dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL)), or helical lysine hydroxylation in these cell lines. Sequence analysis of full length LH2 cDNAs and 1kb of the promoter region of LH2 does not show mutations that could explain the decreased expression of LH2. These results suggest that the deficiency of LH2 in these fibroblasts may be caused by changes in other factors required for the expression of LH2.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 274,
                "text": "connective tissue"
            }
        },
        {
            "context": "Characterization of hCINAP, a novel coilin-interacting protein encoded by a transcript from the transcription factor TAFIID32 locus. Coilin is a marker protein for the Cajal body, a subnuclear domain acting as a site for assembly and maturation of nuclear RNA-protein complexes. Using a yeast two-hybrid screen to identify coilin-interacting proteins, we have identified hCINAP (human coilin interacting nuclear ATPase protein), a nuclear factor of 172 amino acids with a P-loop nucleotide binding motif and ATPase activity. The hCINAP protein sequence is highly conserved across its full-length from human to plants and yeast and is ubiquitously expressed in all human tissues and cell lines tested. The yeast orthologue of CINAP is a single copy, essential gene. Tagged hCINAP is present in complexes containing coilin in mammalian cells and recombinant, Escherichia coli expressed hCINAP binds directly to coilin in vitro. The 214 carboxyl-terminal residues of coilin appear essential for the interaction with hCINAP. Both immunofluorescence and fluorescent protein tagging show that hCINAP is specifically nuclear and distributed in a widespread, diffuse nucleoplasmic pattern, excluding nucleoli, with some concentration also in Cajal bodies. Overexpression of hCINAP in HeLa cells results in a decrease in the average number of Cajal bodies per nucleus, consistent with it affecting either the stability of Cajal bodies and/or their rate of assembly. The hCINAP mRNA is an alternatively spliced transcript from the TAF9 locus, which encodes the basal transcription factor subunit TAFIID32. However, hCINAP and TAFIID32 mRNAs are translated from different ATG codons and use distinct reading frames, resulting in them having no identity in their respective protein sequences.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 133,
                "text": "Coilin"
            }
        },
        {
            "context": "Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [(3)H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [(3)H]S107 per RyR1 tetramer with EC(50) ∼52 µM and Hillslope ∼2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 µM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 419,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. UNLABELLED: We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 554,
                "text": "SAM"
            }
        },
        {
            "context": "McEnhancer: predicting gene expression via semi-supervised assignment of enhancers to target genes. Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.",
            "question": "Which method has been developed for assignment of enhancers to target genes?",
            "answers": {
                "answer_start": 318,
                "text": "McEnhancer"
            }
        },
        {
            "context": "Dermatitis herpetiformis: close to unravelling a disease. Dermatitis herpetiformis is characterised by granular IgA precipitates in the papillary dermis. In contrast to other autoimmune blistering diseases, where tissue-deposited and circulating autoantibodies recognise the same target within the skin, in dermatitis herpetiformis a serum IgA reacting with a component of the healthy papillary dermis has not been detected. Recently, the antigenic specificity of pathognomic skin-bound IgA has been clarified: the immune precipitates contain epidermal transglutaminase, an enzyme not previously detected in the papillary region of normal skin. Furthermore, serum IgA in dermatitis herpetiformis has been found to bind epidermal transglutaminase. These findings may relate to the fact, that dermatitis herpetiformis is associated with gluten sensitive enteropathy, coeliac disease, which is characterised by IgA type autoantibodies to a closely related enzyme, tissue transglutaminase. The two transglutaminases are highly homologous, and therefore, cross reactivity of the two antibodies might explain why patients with gluten sensitive enteropathy, with or without skin disease, generally have serum autoantibodies to both enzymes. There is growing evidence that dermatitis herpetiformis should be considered as the skin manifestation of gluten sensitivity developing in those patients with mild coeliac disease, who produce epidermal transglutaminase autoantibodies of high avidity and affinity. Both the skin and the small bowel diseases are gluten dependent and are strongly associated with HLA DQ with no genetic differences to explain the two phenotypes. The question should be asked whether the rash in dermatitis herpetiformis is a classic autoimmune blistering disease or whether it has an immune complex basis, which is the most likely alternative.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 791,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Fetal exposure to diesel exhaust affects X-chromosome inactivation factor expression in mice. Several studies have shown effects of diesel exhaust (DE) on the central nervous system, but the mechanism is unclear. Fetal mice were exposed to whole DE (contains gases and particles) in an inhalation chamber, and cerebrum gene expression changes were examined by gene assay (microarray and quantitative real-time PCR). By microarray, upregulation of Xist, B-raf and Drwms2 were detected. Especially, mRNA expression of Xist was increased in a concentration-dependent manner in male and female mice. Xist (X-inactive specific transcript) is a major effector of the X-inactivation process, and X-linked genes are highly expressed in brain tissue and consistent with a role in brain developments. By quantitative real-time PCR, Tsix (crucial noncoding antisense partner of Xist) and other X-linked genes (Mecp2, Hprt1, and Sts) were examined; Tsix was upregulated, and other X-linked genes were unaffected in the male and female mice. Our findings suggest that exposure to DE increases Xist and Tsix gene expression in utero without influencing X-linked gene expression. An examination of Xist gene expression changes may provide an important biomarker for DE-induced effects. The possibility of avoiding X-chromosome inactivation (XCI) mechanisms by minimizing exposure to DE is expected.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 596,
                "text": "Xist"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 395,
                "text": "FSHD"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 887,
                "text": "53BP1"
            }
        },
        {
            "context": "Necrobiosis lipoidica diabeticorum: a clinicopathologic study. Necrobiosis lipoidica diabeticorum is an unusual dermatologic condition with a characteristic clinical appearance and a clear association with diabetes mellitus. There is currently no treatment that reverses the atrophic changes associated with this lesion. We have carried out a clinicopathologic study on 15 subjects and, in addition, have reviewed 10 further biopsy specimens of necrobiosis lipoidica diabeticorum. We found a frequent association of necrobiosis lipoidica diabeticorum with other chronic complications of diabetes mellitus, including limited joint mobility. It is possible that nonenzymatic glucosylation or other changes in collagen may be important in the etiology of necrobiosis lipoidica diabeticorum and the limited joint mobility. We confirmed that cutaneous anesthesia is usually present in the necrobiosis lipoidica diabeticorum lesions. With the use of an antibody to S100 protein and an immunohistochemical method, there was an apparent decreased number of nerves in the skin lesions. We suggest that sensory loss results from local destruction of cutaneous nerves by the inflammatory process. Finally, in six elliptical biopsies extending into clinically normal skin, we demonstrated that the inflammatory infiltrate of necrobiosis lipoidica diabeticorum extended from the lesion into apparently normal skin surrounding clinically active lesions. Thus, intradermal steroids might be administered to perilesional areas surrounding active lesions in the hope of halting progression.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 206,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 299,
                "text": "dabigatran"
            }
        },
        {
            "context": "Modified Mallampati Score Improves Specificity of STOP-BANG Questionnaire for Obstructive Sleep Apnea. BACKGROUND: An accurate, clinical screening tool for obstructive sleep apnea (OSA) that identifies patients for further diagnostic testing would assist in the diagnosis of this comorbidity. One example, the STOP-BANG questionnaire (SBQ), has been validated as a screening tool with high sensitivity. However, its specificity may result in a high false-positive rate. The aim of this study to determine if addition of the Modified Mallampati score to the SBQ improves its specificity. METHODS: The authors studied 162 patients referred to the Sleep Disorders Clinic at Yedikule Chest Disease Education and Research Hospital. All patients were prospectively screened for risk of OSA using the SBQ, their oral anatomy was assessed by Modified Mallampati scoring, and sleep quality characterized by polysomnography. Polysomnography results were reviewed when available and the predictive performance of the SBQ and the modified SBQ scoring models were compared. RESULTS: In the authors' study an SBQ score > 3 yielded sensitivities of 0.85, 0.86, and 0.91 for Apnea-Hypopnea Index (AHI) > 5/h, AHI > 15/h, and AHI > 30/h, respectively, and specificities of 0.09, 0.10, and 0.18. The modified SBQ with a cutoff of > 4 (>3) points for AHI levels of >5, >15, and >30 yielded respective sensitivities of 0.84, 0.86, and 0.91 and specificities of 0.25, 0.26, and 0.27. CONCLUSIONS: The author's results from indicated the modified SBQ with a cutoff of >3 points in this study was more specific than the standard SBQ but no less sensitive, and may be used in identifying OSA patients for further diagnostic evaluation or avoiding unnecessary testing.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 78,
                "text": "Obstructive Sleep Apnea"
            }
        },
        {
            "context": "Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 34,
                "text": "malaria"
            }
        },
        {
            "context": "Chromosome condensation and sister chromatid pairing in budding yeast. We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 740,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome. Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened snout (often skewed) with dental malocclusion was observed in a minority of heterozygotes and many homozygotes. Development of this incompletely penetrant skull phenotype was dependent on genetic background and sex, with males more often affected. However, these cranial abnormalities were rarely attributable to craniosynostosis, which was only present in 2/364 mutants; more commonly, we found fusion of the premaxillary and/or zygomatic sutures. We also found decreased cortical thickness and bone mineral densities in long bones. We conclude that although both cranial and long bone development is variably affected by the murine Fgfr3(P244R) mutation, coronal craniosynostosis is not reliably reproduced.",
            "question": "Which gene is associated with Muenke syndrome?",
            "answers": {
                "answer_start": 178,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1-Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway.",
            "question": "Which type of GTPases is required for amino acid-dependent activation of mTORC1?",
            "answers": {
                "answer_start": 302,
                "text": "heterodimeric Rag GTPases"
            }
        },
        {
            "context": "Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance. The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC(2)(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 904,
                "text": "H3K4"
            }
        },
        {
            "context": "Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. BACKGROUND: The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. METHODS: In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged > 18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. FINDINGS: Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8·8%; 95% CI -17·6 to 4·2). The lower bound of the 95% CI of -17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). INTERPRETATION: Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. FUNDING: Genzyme, a Sanofi company.",
            "question": "Which disease is treated with Eliglustat?",
            "answers": {
                "answer_start": 55,
                "text": "Gaucher's disease type 1"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 406,
                "text": "Stroke"
            }
        },
        {
            "context": "Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 777,
                "text": "flumazenil"
            }
        },
        {
            "context": "Diversity and evolution of multiple orc/cdc6-adjacent replication origins in haloarchaea. BACKGROUND: While multiple replication origins have been observed in archaea, considerably less is known about their evolutionary processes. Here, we performed a comparative analysis of the predicted (proved in part) orc/cdc6-associated replication origins in 15 completely sequenced haloarchaeal genomes to investigate the diversity and evolution of replication origins in halophilic Archaea. RESULTS: Multiple orc/cdc6-associated replication origins were predicted in all of the analyzed haloarchaeal genomes following the identification of putative ORBs (origin recognition boxes) that are associated with orc/cdc6 genes. Five of these predicted replication origins in Haloarcula hispanica were experimentally confirmed via autonomous replication activities. Strikingly, several predicted replication origins in H. hispanica and Haloarcula marismortui are located in the distinct regions of their highly homologous chromosomes, suggesting that these replication origins might have been introduced as parts of new genomic content. A comparison of the origin-associated Orc/Cdc6 homologs and the corresponding predicted ORB elements revealed that the replication origins in a given haloarchaeon are quite diverse, while different haloarchaea can share a few conserved origins. Phylogenetic and genomic context analyses suggested that there is an original replication origin (oriC1) that was inherited from the ancestor of archaea, and several other origins were likely evolved and/or translocated within the haloarchaeal species. CONCLUSION: This study provides detailed information about the diversity of multiple orc/cdc6-associated replication origins in haloarchaeal genomes, and provides novel insight into the evolution of multiple replication origins in Archaea.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 493,
                "text": "Multiple"
            }
        },
        {
            "context": "ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies. BACKGROUND: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson's disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies. RESULTS: In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition. CONCLUSIONS: Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 1252,
                "text": "α-synuclein"
            }
        },
        {
            "context": "Virus-associated small satellite RNAs and viroids display similarities in their replication strategies. Since the discovery of non-coding, small, highly structured, satellite RNAs (satRNAs) and viroids as subviral pathogens of plants , have been of great interest to molecular biologists as possible living fossils of pre-cellular evolution in an RNA world. Despite extensive studies performed in the last four decades, there is still mystery surrounding the origin and evolutionary relationship between these subviral pathogens. Recent technical advances revealed some commonly shared replication features between these two subviral pathogens. In this review, we discuss our current perception of replication and evolutionary origin of these petite RNA pathogens.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 194,
                "text": "viroids"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 128,
                "text": "CD38"
            }
        },
        {
            "context": "[Genetic investigations in facioscapulohumeral muscular dystrophy: a preliminary report]. Facioscapulohumeral muscular dystrophy (FSHD) is a primary muscle disorder with autosomal dominant inheritance. FSHD was mapped to chromosome 4 locus q35, but the gene is not yet known. It is characterised by progressive, often asymmetric, selective muscular weakness and great clinical variability. The aim of the study was to analyze 62 FSHD cases from 44 Polish families in which the diagnosis was confirmed by DNA analyses. FSHD diagnosis was based on the clinical findings and standardized investigations confirming primary muscular involvement (EMG, muscle biopsy). DNA analysis was based on EcoRI/BlnI restriction enzyme digestion followed by hybridization with P13E-11 molecular probe. In our material, we have found a relatively large percentage (41%) of big deletions (EcoRI/BlnI fragment of 10-15 kb [kilo bases]), which in the majority of cases (67%) was present in isolated cases. In 10 families (23%) the phenotype was assessed as severe. These are cases with the onset before the age of 10 and fast progression. \"Middle sized\" deletions (EcoRI/BlnI fragment of 16-29 kb) were prevalent in familial cases and present in 57% of families. \"Small\" deletion was found in one family (EcoRI/BlnI fragment of 30 kb). Somatic mosaicism was confirmed in one case. De novo mutations were shown in 11% of the examined families. The results of this study indicate that the bigger the deletion, the more severe the FSHD course, however there are some exceptions. A similar relationship has been shown by previous research. Molecular analyses are particularly important in atypical and sporadic cases. It is the first genetic presentation of a group of patients' with this kind of dystrophy in the Polish population.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 170,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Mitochondria in cells comprise a tubulovesicular network shaped continuously by complementary fission and fusion events. The mammalian Drp1 protein plays a key role in fission, while Mfn1, Mfn2, and OPA1 are required for fusion. Shifts in the balance between these opposing processes can occur rapidly, indicating that modifications to these proteins may regulate mitochondrial membrane dynamics. We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized. This dynamin-related GTPase undergoes a number of steps to mediate mitochondrial fission, including translocation from cytoplasm to the mitochondrial outer membrane, higher-order assembly into spirals, GTP hydrolysis associated with a conformational change and membrane deformation, and ultimately disassembly. Many of these steps may be influenced by covalent modification of Drp1. We discuss the dynamic nature of Drp1 modifications and how they contribute not only to the normal regulation of mitochondrial division, but also to neuropathologic processes.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 22,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Global gene expression profile progression in Gaucher disease mouse models. BACKGROUND: Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure. RESULTS: To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns ( > ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation. CONCLUSIONS: Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 127,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 462,
                "text": "Stroke"
            }
        },
        {
            "context": "Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation. BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 35,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "The importance of IgG4 in the predictive model of thyroiditis. UNLABELLED: Immunoglobulin (Ig)G4-related sclerosing disease (IgG4-RSD) is a new disease entity first proposed with regard to autoimmune pancreatitis. A 67-year-old male patient was examined because of weight loss and an abdominal pain. Based on the clinical characteristics, laboratory parameters and ultrasound features, we identified the diagnosis of the IgG4-related systemic disease (IgG4-RSD), that was confirmed by the histopathological analysis after the biopsy of the head of pancreas. After confirmation, we started with the corticosteroid therapy with a good clinical, biochemical and morphological response. During the previous therapy, the disturbance of glucoregulation appeared, so we had to change the modality of treatment. We decided to add Azathioprine to the therapy in a dose of 150 mg/day. We achieved a stable phase of the disease with IgG 4.37 g/l and IgG4 0.179 g/l, and with no side effects from the therapy. LEARNING POINTS: There are potential clinical applications of identifying subsets of patients with IgG4 thyroiditis (FVHT and Riedel thyroiditis).A trial of immunosuppressive therapy should be included if a resection is deemed inadvisable.In particular, cases of FVHT that mimic malignancy, tissue and serum IgG4 may provide supportive diagnostic information.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 18,
                "text": "IgG4"
            }
        },
        {
            "context": "Metastatic extrapleural malignant solitary fibrous tumor presenting with hypoglycemia (Doege-Potter syndrome). We report a rare case of metastatic malignant solitary fibrous tumor (SFT) that presented with hypoglycemia because of insulin growth factor-2 production. Initial workup included computed tomography imaging that revealed a large, partially necrotic liver mass, a hypervascular pancreatic head lesion, and 2 renal lesions. Following hepatic resection, pancreatic head resection and nephrectomy, all these lesions demonstrated pathological findings that were consistent with SFT. The patient also had a history of an intracranial mass that had been previously resected and treated with gamma knife therapy at an outside institution, which was found to also be SFT. Six months after initial pancreatic head resection, the patient developed a new lesion involving the pancreatic tail that was found to represent recurrent metastatic SFT. This case emphasizes the highly aggressive nature of extrapleural SFT, while rare, and the role of imaging in follow-up for disease recurrence.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 73,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 297,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Impaired ribosome biogenesis in Diamond-Blackfan anemia. The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBA-related genes may be involved in the synthesis of the ribosomal subunits.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 134,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 95,
                "text": "xa"
            }
        },
        {
            "context": "\"Emplotted Narratives\" and Structured \"Behavioral Observations\" Supporting the Diagnosis of Willis-Ekbom Disease/Restless Legs Syndrome in Children with Neurodevelopmental Conditions. BACKGROUND: Willis-Ekbom disease/restless legs syndrome (WED/RLS) seems to be a frequent cause of intractable chronic insomnia (ICI) but is under-recognized in children/adolescents with neurodevelopmental conditions (NDCs), as many patients do not have the ability to express the underlying \"urge-to-move\". In light of this, we aim to develop a protocol for behavioral observations supporting the diagnosis of WED/RLS. METHODS: We investigated 26 pediatric patients (age 1-16 years, median 8) with NDCs, ICI and evidence of familial WED/RLS employing (1) \"emplotted narratives\" for description of the various \"urge-to-move\" presentations and (2) self-description and \"behavioral observations\" during a \"suggested clinical immobilization test\" (SCIT). RESULTS: Parental narratives reflected typical WED/RLS-related \"urge-to-move\" symptoms during day-, bed-, and nighttime in all patients. Fifteen out of 26 patients could describe the \"urge-to-move\" during the SCIT. Ten out of 26 patients, unable to describe their symptoms due to cognitive disabilities, showed patterns of \"relieving-movements\" upon observation. Sensory processing abnormalities were reported in all patients, with tactile sensitivities (26/26) (including shifted pain threshold) as the most common sensory domain. CONCLUSION: \"Emplotted narratives\" and structured \"behavioral observations\" support recognition of familial WED/RLS associated movement patterns and provide a useful tool for the diagnosis of WED/RLS in children with NDCs in a clinical office setting.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 217,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia. Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 910,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Is Wilson's disease caused by a controller gene mutation resulting in perpetuation of the fetal mode of copper metabolism into childhood? Wilson's disease is an inborn error of copper metabolism, characterised by raised liver-copper concentrations and low serum levels of copper and caeruloplasmin. The autosomal recessive mode of inheritance strongly suggests that mutation of a single gene causes the impairment of both caeruloplasmin synthesis and biliary copper excretion. The normal infant is born with the biochemical features of Wilson's disease (very high liver-copper levels and low serum copper and caeruloplasmin). Induction of normal copper metabolism after birth results in a fall in liver-copper concentrations and rise in serum caeruloplasmin. The repression of normal copper metabolism in the fetus and its induction after birth is probably regulated by a controller gene. It is suggested that mutation of a controller rather than a structural gene underlies the pathogenesis of Wilson's disease and that the disease results from failure to switch from the positive copper balance of the fetus to the normal copper balance of the child.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 303,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, approximately equal to 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate to carbamazepine or whose ECG shows abnormalities typical to those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 521,
                "text": "flumazenil"
            }
        },
        {
            "context": "Should the annular tendon of the eye be named 'annulus of Zinn' or 'of Valsalva'? The annular tendon is commonly named 'annulus of Zinn', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755). This structure, however, had been previously discovered not by Zinn, but by Antonio Maria Valsalva (1666-1723) some decades before the publication of Zinn, in his Dissertatio anatomica prima and Dissertatio anatomica altera (First and Second Anatomical Dissertations), inside Valsalva's Opera omnia published in 1740. We advance that this structure could be re-named such as 'annulus of Valsalva-Zinn' because Valsalva, even making a mistake in its functional interpretation, first described this anatomical structure. Likewise, Valsalva, with his discovery, advanced a revolutionary idea for that time on the usefulness of anatomy for clinic and pathology.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 33,
                "text": "eye"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 321,
                "text": "SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein)"
            }
        },
        {
            "context": "[Gaucher's disease uncovered late]. Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta glucocerebrosidase. This disease is usually diagnosed in the first or second decade of life with the arising of bone pains, splenomegaly and hemorragic manifestations due to thrombocytopenia. When the enlarged spleen is not evident, or after splenectomy, patients may be mis-identified as having Gaucher's disease. We present here two cases of elderly patients aged 70 and 46 years respectively, in whom the disease was a surprising finding of bone marrow examination, during check up for pancytopenia.",
            "question": "Which enzyme is deficient in Gaucher's disease?",
            "answers": {
                "answer_start": 157,
                "text": "beta glucocerebrosidase"
            }
        },
        {
            "context": "Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases. BACKGROUND: Genetic FBN1 testing is pivotal for confirming the clinical diagnosis of Marfan syndrome. In an effort to evaluate variant causality, FBN1 databases are often used. We evaluated the current databases regarding FBN1 variants and validated associated phenotype records with a new Marfan syndrome geno-phenotyping tool called the Marfan score. METHODS AND RESULTS: We evaluated four databases (UMD-FBN1, ClinVar, the Human Gene Mutation Database (HGMD), and Uniprot) containing 2,250 FBN1 variants supported by 4,904 records presented in 307 references. The Marfan score calculated for phenotype data from the records quantified variant associations with Marfan syndrome phenotype. We calculated a Marfan score for 1,283 variants, of which we confirmed the database diagnosis of Marfan syndrome in 77.1%. This represented only 35.8% of the total registered variants; 18.5-33.3% (UMD-FBN1 versus HGMD) of variants associated with Marfan syndrome in the databases could not be confirmed by the recorded phenotype. CONCLUSION: FBN1 databases can be imprecise and incomplete. Data should be used with caution when evaluating FBN1 variants. At present, the UMD-FBN1 database seems to be the biggest and best curated; therefore, it is the most comprehensive database. However, the need for better genotype-phenotype curated databases is evident, and we hereby present such a database.Genet Med advance online publication 01 December 2016.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 77,
                "text": "FBN1"
            }
        },
        {
            "context": "Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 368,
                "text": "PLN"
            }
        },
        {
            "context": "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.",
            "question": "How does increased GDF15 affect body weight?",
            "answers": {
                "answer_start": 373,
                "text": "reduces body weight"
            }
        },
        {
            "context": "A genome-wide study on the perception of the odorants androstenone and galaxolide. Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h (2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.",
            "question": "Which olfactory gene senses androsterone?",
            "answers": {
                "answer_start": 669,
                "text": "OR7D4"
            }
        },
        {
            "context": "New approaches to treating and preventing bone metastases. PURPOSE OF REVIEW: Treatment and prevention of bone metastases is a major problem in patients with cancer. New treatment of bone metastases are needed to maintain the quality of life of our patients with metastastic bone disease. In addition, promising preliminary results suggest that bone-directed therapies may be able to prevent both skeletal and extraskeletal metastases RECENT FINDINGS: For the past decade intravenous bisphosphonates have been the mainstay of treatment of patients with bone metastases. New therapies such as the antibody to RANKL (denosumab) are undergoing phase III clinical testing. In addition, confirmatory studies suggesting that bisphosphonates can prevent metastatic disease are underway. SUMMARY: Understanding the biology of bone metastases has uncovered many new potential therapies for the treatment and prevention of bone metastases. Many of these potential new approaches are discussed in the enclosed article.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 608,
                "text": "RANKL"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 541,
                "text": "7"
            }
        },
        {
            "context": "The bone-anchor sub-urethral sling for the treatment of iatrogenic male incontinence: subjective and objective assessment after 41 months of mean follow-up. OBJECTIVES: To evaluate retrospectively the objective and subjective parameters in 42 male patients who underwent bone anchored sub-urethral sling positioning (BAUS) for SUI (stress urinary incontinence) due to ISD (intrinsic sphincter deficiency). METHODS: Patients with SUI due to radical retropubic prostatectomy (36 patients), transurethral resection of prostate (5 patients) and open simple prostatectomy (1 patient) underwent BAUS positioning between July 1999 and September 2005 (mean FU = 41 months). Before and after surgery, the patients were evaluated by physical examination, urethrocystoscopy, urodynamics, 1 h pad test and QoL questionnaire. Surgical technique involved perineal implantation to the pubic rami using four anchors of a sub-urethral sling made of synthetic (26 patients), biological (4 patients) or mixed (12 patients) material. Patients were stratified into three groups: (1) Cured: dry patients at stress test, pad weight 0-1 g. (2) Improved: patients with mild-moderate incontinence, pad weight 2-50 g. (3) Failed: unchanged patients, pad weight > 50 g. RESULTS: At the final follow-up visit cured, improved and failed patients were 26 (62%), 4 (8%) and 12 (30%), respectively. Mean pad weight significantly decreased from 104.6 to 47.3 g (55%) and mean total questionnaire score significantly increased to 50.7 (66%). Mean ALPP significantly increased to 50.4 cmH2O (44.8%). Better results were seen with synthetic slings. Main complications were perineal pain (76%), detrusor overactivity (12%) and sling infection (4.8%). CONCLUSIONS: BAUS implantation is a safe, effective, minimally invasive option for iatrogenic male incontinence due to ISD. It compares favourably with AUS.",
            "question": "What is the gold standard treatment for Iatrogenic male incontinence?",
            "answers": {
                "answer_start": 1865,
                "text": "AUS"
            }
        },
        {
            "context": "Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness. The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 167,
                "text": "15"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. Alpha interferon (IFN-α) controls homeostasis of hematopoietic stem cells, regulates antiviral resistance, inhibits angiogenesis, and suppresses tumor growth. This cytokine is often used to treat cancers and chronic viral infections. The extent of cellular responses to IFN-α is limited by the IFN-induced ubiquitination and degradation of the IFN-α/β receptor chain 1 (IFNAR1) chain of the cognate receptor. IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand. Here we report identification of protein kinase D2 (PKD2) as a kinase that mediates the ligand-inducible phosphorylation of IFNAR1 degron and enables binding of βTrcp to the receptor. Treatment of cells with IFN-α induces catalytic activity of PKD2 and stimulates its interaction with IFNAR1. Expression and kinase activity of PKD2 are required for the ligand-inducible stimulation of IFNAR1 ubiquitination and endocytosis and for accelerated proteolytic turnover of IFNAR1. Furthermore, inhibition or knockdown of PKD2 robustly augments intracellular signaling induced by IFN-α and increases the efficacy of its antiviral effects. The mechanisms of the ligand-inducible elimination of IFNAR1 are discussed, along with the potential medical significance of this regulation.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 547,
                "text": "βTrcp"
            }
        },
        {
            "context": "Ficolins and the lectin pathway of complement in patients with systemic lupus erythematosus. The complement system plays a pathophysiological role in systemic lupus erythematosus (SLE). This study aims to investigate whether an association exists between the ficolins that are part of the lectin complement pathway and SLE. EDTA plasma samples from 68 Danish SLE patients and 29 healthy donors were included in the study. Plasma concentrations of Ficolin-1, -2, and -3 were determined in specific sandwich ELISAs. Lectin pathway activity via Ficolin-3 was measured in ELISA on acetylated bovine serum albumin (acBSA) and measured as Ficolin-3 binding and deposition of C4, C3 and the terminal complement complex (TCC). SLE patients had increased levels of Ficolin-3, 21.6μg/ml as compared to 17.0μg/ml in healthy controls (P=0.0098). The Ficolin-1 plasma concentration was negatively correlated with SLE Disease Activity Index (SLEDAI) (Rho=-0.29, P=0.015) and positively correlated to the [Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index] (SDI) (Rho=0.27, P=0.026). The Ficolin-1 concentration was also associated with the occurrence of arterial (P=0.0053) but not venous thrombosis (P=0.42). Finally, deposition of C4, C3 and TCC in the Ficolin-3 pathway were all correlated to SLEDAI, respectively (P<0.0076). The Ficolin-1 association to SLEDAI and SDI as well as arterial thrombosis shown in this study suggests that Ficolin-1 may be a potential new biomarker for patients with SLE. Furthermore, Ficolin-3 mediated complement activation may be valuable in monitoring disease activity in SLE patients due to the high sensitivity for complement consumption in the assay independent of the Ficolin-3 concentration.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 289,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 28,
                "text": "CDK4/6"
            }
        },
        {
            "context": "McLeod neuroacanthocytosis: genotype and phenotype. McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 94,
                "text": "XK"
            }
        },
        {
            "context": "Co-morbidity in Gaucher's disease results of a nationwide enquiry in Spain. SHORT INTRODUCTION: Gaucher's disease (GD) is an autosomal recessive disease produced by mutations of the Glucocerebrosidase gene. Carriers are considered to be healthy subjects because there is no manifestation of the disease, but they show signs of macrophage disfunction. The aim of the study was to determine if GD patients and non affected carriers risk suffering other diseases when compared to healthy non-carrier relatives. DESIGN: Epidemiologic study of historic cohorts. The fact that they have one or two mutated alleles has been considered to be the risk factor leading to other conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart disease, Non rheumatic valvular disease, Cancer hematological and non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and Schizophrenia). All people, patients, carriers and healthy controls shared the same genetical background and environmental influence. - Patients and relatives enrolled on the Spanish Gaucher Disease Registry were evaluated. STATISTICS: For the Relative-Risk calculation the Mantel-Haenszel test was applied. Yates' correction was used when size sample was too small. A value of p <0.05 was accepted for statistical significance. RESULTS: 370 people, from 79 different families, were surveyed. We received evaluable information from 45 families (56%), totalling 258 people (69%): 59 healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132 carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p 0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of suffering any disease with regard to sex was 3.96 for female patients (CI 1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68). CONCLUSION: As a group, Gaucher's patients seem to have a greater risk of suffering other common unrelated diseases than carriers or healthy relatives. This excess of risk is particularly higher among female patients and can not be explained in terms of differences in age. Carrier status doesn't seem to highten the risk of suffering other diseases.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 182,
                "text": "Glucocerebrosidase"
            }
        },
        {
            "context": "In vitro production and nuclear transfer affect dosage compensation of the X-linked gene transcripts G6PD, PGK, and Xist in preimplantation bovine embryos. Equal expression of X-linked genes such as G6PD and PGK in females and males and the initiation of X-chromosome inactivation are critically dependent on the expression of the X-inactive specific transcript (Xist). The objective of the present study was to determine the effects of in vitro production (IVP) and nuclear transfer (NT) on the relative abundance (RA) of the X-linked transcripts G6PD, PGK, and Xist in preimplantation bovine embryos. In experiment 1, sex-determined IVP or in vivo-produced embryos were analyzed for mRNA expression of the 3 genes. The sex ratio was 36% vs. 64% in IVP blastocysts and thus deviated significantly from the expected ratio of 50% in the vivo control group. The RA of G6PD transcripts was significantly higher in female IVP embryos than in male embryos. In contrast, no significant differences were seen between in vivo-derived female embryos and their male counterparts. At the morula stage, female IVP embryos transcribed significantly more PGK mRNA than did male embryos. However, blastocysts did not exhibit significant differences in PGK transcripts. No differences were observed for in vivo-derived embryos with regard to the RA of PGK transcripts. The RA of Xist mRNA was significantly higher in all female embryos than in their male counterparts. In experiment 2, IVP, in vivo-developed, NT-derived, and parthenogenetic embryos carrying two X chromosomes of either maternal and paternal origin or of maternal origin only (parthenogenotes) were analyzed for the RA of the 3 genes. In NT-derived morulae, the RA of G6PD transcripts was significantly increased compared with their IVP and in vivo-generated counterparts. G6PD transcript levels were significantly increased in IVP blastocysts compared with in vivo-generated and parthenogenetic embryos. At the morula stage, PGK transcripts were similar in all groups, but the RA of PGK transcripts was significantly higher in IVP blastocysts than in their in vivo-generated, parthenogenetic, and NT-derived counterparts. The RA of Xist was significantly elevated in NT-derived morulae compared with IVP, in vivo-generated, and parthenogenetic embryos. NT-derived blastocysts showed an increased Xist expression compared with that of IVP, in vivo-generated, and parthenogenetic embryos. Results of the present study show for the first time that differences in X-chromosome-linked gene transcript levels are related to a perturbed dosage compensation in female and male IVP and female NT-derived embryos. This finding warrants further studies to improve IVP systems and NT protocols to ensure the production of embryos with normal gene expression patterns.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 363,
                "text": "Xist"
            }
        },
        {
            "context": "Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat. Using a rat model of L-DOPA-induced dyskinesia (LID), the contributions of dopamine D1 and D2 receptors to axial, limb, and orolingual (ALO) abnormal involuntary movements (AIMs) elicited by L-DOPA were examined. Chronic L-DOPA-treated rats received the D1 receptor antagonist SCH23390 (0.01, 0.1, and 1.0 mg/kg; i.p.), the D2 receptor antagonist Eticlopride (0.01, 0.1, and 1.0 mg/kg; i.p.), a mixture of both antagonists (0.01, 0.1, 1.0 mg/kg each; i.p.), or vehicle 30 min prior to L-DOPA (6 mg/kg; i.p.)+Benserazide (15 mg/kg; i.p.). SCH23390 (0.1 and 1.0 mg/kg) significantly reduced axial and limb AIMs, while the same doses of Eticlopride significantly decreased axial, limb, and orolingual AIMs. Co-administration of SCH23390+Eticlopride significantly reduced axial (0.01, 0.1 and 1.0 mg/kg), limb (0.1 and 1.0 mg/kg), and orolingual (0.1 and 1.0 mg/kg) AIMs. These results indicate the importance of D1 and D2 receptors to LID and further validate the rat AIMs model.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 322,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons. The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. We have compared the chromosomal mobilization efficiency and insertion site preference of the two transposons mobilized from the same donor site in mouse embryonic stem (ES) cells under conditions in which there were no selective constraints on the transposons' insertion sites. Compared with Sleeping Beauty, PiggyBac exhibits higher transposition efficiencies, no evidence for local hopping and a significant bias toward reintegration in intragenic regions, which demonstrate its utility for insertional mutagenesis. Although Sleeping Beauty had no detectable genomic bias with respect to insertions in genes or intergenic regions, both Sleeping Beauty and PiggyBac transposons displayed preferential integration into actively transcribed loci.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 521,
                "text": "PiggyBac"
            }
        },
        {
            "context": "Inhibition of calcineurin phosphatase activity by a calcineurin B homologous protein. Calcineurin, a Ca(2+)/calmodulin-stimulated protein phosphatase, plays a key role in T-cell activation by regulating the activity of NFAT (nuclear factor of activated T cells), a family of transcription factors required for the synthesis of several cytokine genes. Calcineurin is the target of the immunosuppressive drugs cyclosporin A and FK506 complexed with their cytoplasmic receptors cyclophilin and FKBP12, respectively. In this study we report that calcineurin is also the target of a recently identified Ca(2+)-binding protein, CHP (for calcineurin homologous protein), which shares a high degree of homology with the regulatory B subunit of calcineurin and with calmodulin. In Jurkat and HeLa cells, overexpression of CHP specifically impaired the nuclear translocation and transcriptional activity of NFAT but had no effect on AP-1 transcriptional activity and only a small (<25%) inhibitory effect on the transcriptional activity of NFkappaB. Further study indicated that CHP inhibits calcineurin activity. In cells overexpressing CHP, the phosphatase activity of immunoprecipitated calcineurin was inhibited by approximately 50%; and in a reconstituted assay, the activity of purified calcineurin was inhibited up to 97% by the addition of purified recombinant CHP in a dose-dependent manner. Moreover, prolonged activation of Jurkat cells was associated with a decreased abundance of CHP, suggesting a possible regulatory mechanism allowing activation of calcineurin. CHP, therefore, is a previously unrecognized endogenous inhibitor of calcineurin activity.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 86,
                "text": "Calcineurin"
            }
        },
        {
            "context": "Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, the B-cell receptor (BCR) and nuclear factor- κB (NF-κB) pathways are activated in the lymph node (LN) microenvironment. Thus, model systems mimicking tumor-host interactions are important tools to study CLL biology and pathogenesis. We investigated whether the recently established NOD/scid/γc(null) (NSG) mouse xenograft model can recapitulate the effects of the human microenvironment. We assessed, therefore, tumor characteristics previously defined in LN-resident CLL cells, including proliferation, and activation of the BCR and NF-κB pathways. We found that the murine spleen (SP) microenvironment supported CLL cell proliferation and activation to a similar degree than the human LN, including induction of BCR and NF-κB signaling in the xenografted cells. Next, we used this model to study ibrutinib, a Bruton's tyrosine kinase inhibitor in clinical development. Ibrutinib inhibited BCR and NF-κB signaling induced by the microenvironment, decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, recapitulate the role of the human LN for CLL cells. In addition, we show that ibrutinib effectively disrupts tumor-host interactions essential for CLL cell proliferation and survival in vivo.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1063,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 204,
                "text": "childhood chordomas"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 1342,
                "text": "naloxone"
            }
        },
        {
            "context": "Apixaban: first global approval. Apixaban (Eliquis™), an oral direct factor Xa inhibitor, is being developed by Bristol-Myers Squibb and Pfizer as a therapy for the prevention and/or treatment of thrombotic disorders. Apixaban has been approved in the EU for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A rolling submission for approval of apixaban for the prevention of stroke in patients with atrial fibrillation has also been initiated in the US. Worldwide phase III development of apixaban is underway for the prevention and treatment of VTE, and prevention of stroke in patients with atrial fibrillation. Development for acute coronary syndromes has been stopped following the discontinuation of the phase III APPRAISE-II trial. This article summarizes the milestones in the development of apixaban leading to this first approval for the prevention of VTE after hip or knee replacement.",
            "question": "What is the drug target for Eliquis (Apixaban)?",
            "answers": {
                "answer_start": 69,
                "text": "factor Xa"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 433,
                "text": "xa"
            }
        },
        {
            "context": "Kell and XK immunohistochemistry in McLeod myopathy. The McLeod syndrome is an X-linked neuroacanthocytosis manifesting with myopathy and progressive chorea. It is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein of yet unknown function. In erythroid tissues, XK forms a functional complex with the Kell glycoprotein. Here, we present an immunohistochemical study in skeletal muscle of normal controls and a McLeod patient with a XK gene point mutation (C977T) using affinity-purified antibodies against XK and Kell proteins. Histological examination of the affected muscle revealed the typical pattern of McLeod myopathy including type 2 fiber atrophy. In control muscles, Kell immunohistochemistry stained sarcoplasmic membranes. XK immunohistochemistry resulted in a type 2 fiber-specific intracellular staining that was most probably confined to the sarcoplasmic reticulum. In contrast, there was only a weak background signal without a specific staining pattern for XK and Kell in the McLeod muscle. Our results demonstrate that the lack of physiological XK expression correlates to the type 2 fiber atrophy in McLeod myopathy, and suggest that the XK protein represents a crucial factor for the maintenance of normal muscle structure and function.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 191,
                "text": "XK"
            }
        },
        {
            "context": "MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 297,
                "text": "MITF"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 369,
                "text": "SMA"
            }
        },
        {
            "context": "Regulation of Nox1 activity via protein kinase A-mediated phosphorylation of NoxA1 and 14-3-3 binding. Nox activator 1 (NoxA1) is a homologue of p67(phox) that acts in conjunction with Nox organizer 1 (NoxO1) to regulate reactive oxygen species (ROS) production by the NADPH oxidase Nox1. The phosphorylation of cytosolic regulatory components by multiple kinases plays important roles in assembly and activity of the phagocyte NADPH oxidase (Nox2) system, but little is known about regulation by phosphorylation in the Nox1 system. Here we identify Ser(172) and Ser(461) of NoxA1 as phosphorylation sites for protein kinase A (PKA). A consequence of this phosphorylation was the enhancement of NoxA1 complex formation with 14-3-3 proteins. Using both a transfected human embryonic kidney 293 cell Nox1 model system and endogenous Nox1 in colon cell lines, we showed that the elevation of cAMP inhibits, whereas the inhibition of PKA enhances, Nox1-dependent ROS production through effects on NoxA1. Inhibition of Nox1 activity was intensified by the availability of 14-3-3zeta protein, and this regulatory interaction was dependent on PKA-phosphorylatable sites at Ser(172) and Ser(461) in NoxA1. We showed that phosphorylation and 14-3-3 binding induce the dissociation of NoxA1 from the Nox1 complex at the plasma membrane, suggesting a mechanism for the inhibitory effect on Nox1 activity. Our data establish that PKA-phosphorylated NoxA1 is a new binding partner of 14-3-3 protein(s) and that this forms the basis of a novel mechanism regulating the formation of ROS by Nox1 and, potentially, other NoxA1-regulated Nox family members.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 283,
                "text": "Nox1"
            }
        },
        {
            "context": "[Restless-leg syndrome--possible unrecognized cause for insomnia and irritability in children]. Restless legs syndrome (RLS) has gradually been recognized as a cause for insomnia in adults, but there have been few reports about children with RLS in Japan. Here we described seven pediatric RLS patients. All of the parents of our patients had difficult times to make their children sleep due to irritability, restlessness, and demanding bedtime routines. All patients had asked their parents to rub their feet in bed, and it took more than half an hour to soothe them until they fell asleep. Their mothers had been exhausted from this night-time routine. However, they did not consider the routine abnormal, as it had been their habitual behavior since infancy. Some parents were too distressed or embarrassed to describe the symptoms of their child properly. Five patients had clear family history and none had obvious periodic leg movements during sleep. All patients showed low levels of ferritin and iron supplementation was effective in five cases. In the severest two cases, pramipexole, but not iron, was dramatically effective. Both patients started to show RLS symptoms in the early days of infancy, which may suggest more severe hereditary dopaminergic dysfunction. RLS does occur in childhood and pediatricians should bear it in mind as one of the differential diagnoses when seeing children who are irritated and/or having difficulty in initiating their sleep.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1004,
                "text": "iron"
            }
        },
        {
            "context": "Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review. BACKGROUND: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene. CASE PRESENTATION: We describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data. CONCLUSIONS: Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 883,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (deltaN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not deltaNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 384,
                "text": "7"
            }
        },
        {
            "context": "Mechanistic studies of substrate-assisted inhibition of ubiquitin-activating enzyme by adenosine sulfamate analogues. Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate intermediate and catalyzes its transfer to a ubiquitin-conjugating enzyme (E2). MLN4924 is an adenosine sulfamate analogue that was identified as a selective, mechanism-based inhibitor of NEDD8-activating enzyme (NAE), another E1 enzyme, by forming a NEDD8-MLN4924 adduct that tightly binds at the active site of NAE, a novel mechanism termed substrate-assisted inhibition (Brownell, J. E., Sintchak, M. D., Gavin, J. M., Liao, H., Bruzzese, F. J., Bump, N. J., Soucy, T. A., Milhollen, M. A., Yang, X., Burkhardt, A. L., Ma, J., Loke, H. K., Lingaraj, T., Wu, D., Hamman, K. B., Spelman, J. J., Cullis, C. A., Langston, S. P., Vyskocil, S., Sells, T. B., Mallender, W. D., Visiers, I., Li, P., Claiborne, C. F., Rolfe, M., Bolen, J. B., and Dick, L. R. (2010) Mol. Cell 37, 102-111). In the present study, substrate-assisted inhibition of human UAE (Ube1) by another adenosine sulfamate analogue, 5'-O-sulfamoyl-N(6)-[(1S)-2,3-dihydro-1H-inden-1-yl]-adenosine (Compound I), a nonselective E1 inhibitor, was characterized. Compound I inhibited UAE-dependent ATP-PP(i) exchange activity, caused loss of UAE thioester, and inhibited E1-E2 transthiolation in a dose-dependent manner. Mechanistic studies on Compound I and its purified ubiquitin adduct demonstrate that the proposed substrate-assisted inhibition via covalent adduct formation is entirely consistent with the three-step ubiquitin activation process and that the adduct is formed via nucleophilic attack of UAE thioester by the sulfamate group of Compound I after completion of step 2. Kinetic and affinity analysis of Compound I, MLN4924, and their purified ubiquitin adducts suggest that both the rate of adduct formation and the affinity between the adduct and E1 contribute to the overall potency. Because all E1s are thought to use a similar mechanism to activate their cognate ubiquitin-like proteins, the substrate-assisted inhibition by adenosine sulfamate analogues represents a promising strategy to develop potent and selective E1 inhibitors that can modulate diverse biological pathways.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 383,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Assessing serotonin receptor mRNA editing frequency by a novel ultra high-throughput sequencing method. RNA editing is a post-transcriptional modification of pre-mRNA that results in increased diversity in transcriptomes and proteomes. It occurs in a wide variety of eukaryotic organisms and in some viruses. One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation. This phenomenon has been observed in numerous transcripts, including the mammalian 5-HT(2C) receptor, which can be edited at five distinct sites. Methods used to date to quantify 5-HT(2C) receptor editing are labor-intensive, expensive and provide limited information regarding the relative abundance of 5-HT(2C) receptor editing variants. Here, we present a novel, ultra high-throughput method to quantify 5-HT(2C) receptor editing, compare it to a more conventional method, and use it to assess the effect of a range of genetic and pharmacologic manipulations on 5-HT(2C) editing. We conclude that this new method is powerful and economical, and we provide evidence that alterations in 5-HT(2C) editing appear to be a result of regional changes in brain activity, rather than a mechanism to normalize 5-HT(2C) signaling.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 361,
                "text": "A-to-I"
            }
        },
        {
            "context": "The nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in brains of dementia with Lewy bodies. We immunohistochemically investigated the degeneration processes of the nigro-striatal and nigro-amygdaloid pathways and the relationship between the loss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia nigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and TH-positive axonal terminals in the putamen decreased with a specific pattern. The substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that were almost evenly distributed, while the putamen exhibited diffuse or granular alpha-synuclein-immunostaining. Most of the granular stains were positive for anti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were negative. These findings suggest that the axonal terminals in the putamen undergo abnormal alpha-synuclein accumulation, but may not always originate from LB-bearing neurons in the substantia nigra. The central amygdaloid nucleus contained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive dystrophic axonal terminals, the degree of which was greater for cases with granular staining in the putamen, and which was proportional to the number of alpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal terminals in the central amygdaloid nucleus may have originated from LB-bearing neurons in the substantia nigra. The results of the present study indicate that the nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in DLB, and suggest that the degeneration of the nigro-amygdaloid pathway more strongly reflects LB formation in dopaminergic neurons of the substantia nigra than that of the nigro-striatal pathway. In addition, they indicate that there is no direct relationship between the loss of dopaminergic neurons and LB formation in the substantia nigra.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 749,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Functional analysis of Rfx6 and mutant variants associated with neonatal diabetes. Mutations in rfx6 were recently associated with Mitchell-Riley syndrome, which involves neonatal diabetes, and other digestive system defects. To better define the function of Rfx6 in early endoderm development we cloned the Xenopus homologue. Expression of rfx6 begins early, showing broad expression throughout the anterior endoderm; at later stages rfx6 expression becomes restricted to the endocrine cells of the gut and pancreas. Morpholino knockdown of rfx6 caused a loss of pancreas marker expression, as well as other abnormalities. Co-injection of exogenous wild-type rfx6 rescued the morpholino phenotype in Xenopus tadpoles, whereas attempts to rescue the loss-of-function phenotype using mutant rfx6 based on Mitchell-Riley patients were unsuccessful. To better define the pleiotropic effects, we performed microarray analyses of gene expression in knockdown foregut tissue. In addition to pancreatic defects, the microarray analyses revealed downregulation of lung, stomach and heart markers and an upregulation of kidney markers. We verified these results using RT-PCR and in situ hybridization. Based on the different rfx6 expression patterns and our functional analyses, we propose that rfx6 has both early and late functions. In early development Rfx6 plays a broad role, being essential for development of most anterior endodermal organs. At later stages however, Rfx6 function is restricted to endocrine cells.",
            "question": "Which gene is associated with the Mitchell-Riley syndrome?",
            "answers": {
                "answer_start": 96,
                "text": "rfx6"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 606,
                "text": "xa"
            }
        },
        {
            "context": "Oral ixazomib maintenance therapy in multiple myeloma. Continuous therapy has proven to be an effective therapeutic strategy to improve the outcome of both young and elderly multiple myeloma patients. Remarkably, lenalidomide and bortezomib showed to play a crucial role in this setting due to their safety profile allowing long-term exposure. Ixazomib, the first oral proteasome inhibitor to be evaluated in multiple myeloma, exerts substantial anti-myeloma activity as a single agent and particularly in combination with immunomodulatory drugs and it may be an attractive option for maintenance therapy. Here we address the issue of maintenance therapy as part of a therapeutic approach of multiple myeloma patients focusing on the potential role of ixazomib.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 369,
                "text": "proteasome"
            }
        },
        {
            "context": "psygenet2r: a R/Bioconductor package for the analysis of psychiatric disease genes. Motivation: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. Results: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. Availability and implementation: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html). Contact: juanr.gonzalez@isglobal.org or laura.furlong@upf.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for the analysis of psychiatric disease genes?",
            "answers": {
                "answer_start": 0,
                "text": "psygenet2r"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 251,
                "text": "Xa"
            }
        },
        {
            "context": "The cellular and molecular mechanisms for neutropenia in Barth syndrome. Barth syndrome (BTHS), a rare, X-linked, recessive disease, is characterized by neutropenia and cardiomyopathy. BTHS is caused by loss-of-function mutations of the tafazzin (TAZ) gene. We developed a model of BTHS by transfecting human HL60 myeloid progenitor cells with TAZ-specific shRNAs. Results demonstrate a significant downregulation in TAZ expression, mimicking the effects of naturally occurring truncation mutations in TAZ. Flow cytometry analyses of cells with TAZ-specific, but not scrambled, shRNAs demonstrate nearly twofold increase in the proportion of annexin V-positive cells and significantly increased dissipation of mitochondrial membrane potential as determined by DIOC6 staining. Transfection of TAZ-specific shRNA had similar effects in U937 myeloid cells but not in lymphoid cell lines. Further studies in HL60 myeloid progenitor cells revealed aberrant release of cytochrome c from mitochondria and significantly elevated levels of activated caspase-3 in response to TAZ knockdown. Treatment with caspase-specific inhibitor zVAD-fmk resulted in substantially reduced apoptosis to near-normal levels. These data suggest that neutropenia in BTHS is attributable to increased dissipation of mitochondrial membrane potential, aberrant release of cytochrome c, activation of caspase-3, and accelerated apoptosis of myeloid progenitor cells, and that this defect can be partially restored in vitro by treatment with caspase-specific inhibitors.",
            "question": "Which gene is involved in the development of Barth syndrome?",
            "answers": {
                "answer_start": 237,
                "text": "tafazzin (TAZ) gene"
            }
        },
        {
            "context": "Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer's disease. Alzheimer's disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI's) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD. Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials. Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI's and NMDA receptor antagonists for the symptomatic treatment of AD.",
            "question": "What does intepirdine target?",
            "answers": {
                "answer_start": 1307,
                "text": "5-HT6"
            }
        },
        {
            "context": "Symptom-specific effects of fluoxetine in post-traumatic stress disorder. The selective serotonin reuptake inhibitors have become a first line treatment for post-traumatic stress disorder (PTSD). In a recent double-blind study in civilians, fluoxetine produced clinically and statistically significant effects on all general measures of PTSD. We examined the specific effects of fluoxetine versus placebo in the above mentioned study of PTSD clusters and individual symptoms. Individuals were included if they met criteria for PTSD according to the Structured Clinical Interview for DSM-III-R (SCID). Symptoms were assessed at sequential time points by the Structured Interview for PTSD (SIP), a clinician interview based assessment, and a self-report scale, the Davidson Trauma Scale (DTS). A total of 53 patients were included in the analysis. On the SIP and DTS, fluoxetine was found to produce statistically significant changes on all clusters. Significant effects for fluoxetine were noted on 10 items of the DTS, and 8 items of the SIP. The SIP and DTS had 6 items in common that were significant. Fluoxetine exerts a broad spectrum effect in reducing all the symptom clusters of PTSD in this sample. The symptoms of being physically upset at reminders of the trauma, avoiding thoughts of the trauma, having difficulty enjoying things, feeling distant/estranged, having a sense of foreshortened future, and impaired concentration, were the symptoms most responsive to the effects of treatment with fluoxetine on both scales.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 682,
                "text": "PTSD"
            }
        },
        {
            "context": "Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1877,
                "text": "factor Xa"
            }
        },
        {
            "context": "Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 kDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 234,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 186,
                "text": "teriflunomide"
            }
        },
        {
            "context": "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival. Cardiac contractility is regulated through the activity of various key Ca(2+)-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis. In the current study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide binding domain are required for its interaction with the C-terminal domain of HAX-1, containing amino acids 203-245. In transiently cotransfected human embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the ER, whereas HAX-1 selectively concentrated at mitochondria. On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2 abrogated the protective effects of HAX-1 on cell survival, after hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca(2+) stores.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 441,
                "text": "(HAX-1)"
            }
        },
        {
            "context": "Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks. Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 0,
                "text": "Telomerase"
            }
        },
        {
            "context": "Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 157,
                "text": "rabies"
            }
        },
        {
            "context": "Functional pulmonary atresia in a patient with neonatal Marfan syndrome caused by a c.3602G>A mutation in exon 29 of the FBN1 gene. Neonatal Marfan syndrome is a severe form of the syndrome mostly caused by de-novo mutations in the fibrillin-1 gene. We report a newborn with neonatal Marfan syndrome and functional pulmonary atresia who died from congestive heart failure on postnatal day 22 despite treatment. He had a mutation in exon 29 of the fibrillin-1 gene at position c.3602G>A. Functional pulmonary atresia may be a life-threatening cardiovascular manifestation of neonatal Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 121,
                "text": "FBN1"
            }
        },
        {
            "context": "Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 157,
                "text": "rabies"
            }
        },
        {
            "context": "Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Recent studies in the field of cancer stem cells have revealed that the alterations in key gene products involved in the epithelial-mesenchymal transition (EMT) program, altered metabolic pathways such as enhanced glycolysis, lipogenesis and/or autophagy and treatment resistance may occur in cancer stem/progenitor cells and their progenies during cancer progression. Particularly, the sustained activation of diverse developmental cascades such as hedgehog, epidermal growth factor receptor (EGFR), Wnt/β-catenin, Notch, transforming growth factor-β (TGF-β)/TGF-βR receptors and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) can play critical functions for high self-renewal potential, survival, invasion and metastases of cancer stem/progenitor cells and their progenies. It has also been observed that cancer cells may be reprogrammed to re-express different pluripotency-associated stem cell-like markers such as Myc, Oct-3/4, Nanog and Sox-2 along the EMT process and under stressful and hypoxic conditions. Moreover, the enhanced expression and/or activities of some drug resistance-associated molecules such as Bcl-2, Akt/molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), hypoxia-inducible factors (HIFs), macrophage inhibitory cytokine-1 (MIC-1) and ATP-binding cassette (ABC) multidrug transporters frequently occur in cancer cells during cancer progression and metastases. These molecular events may cooperate for the survival and acquisition of a more aggressive and migratory behavior by cancer stem/progenitor cells and their progenies during cancer transition to metastatic and recurrent disease states. Of therapeutic interest, these altered gene products may also be exploited as molecular biomarkers and therapeutic targets to develop novel multitargeted strategies for improving current cancer therapies and preventing disease relapse.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 1312,
                "text": "mTOR"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 371,
                "text": "CD38"
            }
        },
        {
            "context": "Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and p73. The small heat shock protein alphaB-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the alphaB-crystallin gene, we examined the alphaB-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced alphaB-crystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of alphaB-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an alphaB-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the alphaB-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. DeltaNp73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of alphaB-crystallin by p53. Moreover, ectopic expression of DeltaNp73alpha (but not other p73 isoforms) increased alphaB-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone alphaB-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1304,
                "text": "7"
            }
        },
        {
            "context": "Efficacy of anti-IL-1 treatment in Majeed syndrome. BACKGROUND AND OBJECTIVE: Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. METHODS: We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome. RESULTS: Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement. CONCLUSIONS: The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 301,
                "text": "LPIN2"
            }
        },
        {
            "context": "Targeting Intrinsic and Extrinsic Vulnerabilities for the Treatment of Multiple Myeloma. Multiple myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Over the past decade, MM therapy is significantly improved by the introduction of novel therapeutics such as immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (daratumumab and elotuzumab), histone deacetylase (HDAC) inhibitors (Panobinostat). The clinical success of these agents has clearly identified vulnerabilities intrinsic to the MM cell, as well as targets that emanate from the tumor microenvironment. Despite these significant improvements, MM remains incurable due to the development of drug resistance. This perspective will discuss more recent strategies which take advantage of multiple targets within the proteome recycling pathway, chromatin remodeling, and disruption of nuclear export. In addition, we will review the development of strategies designed to block opportunistic survival signaling that occurs between the MM cell and the tumor microenvironment including strategies for inhibiting myeloma-induced immune suppression. It has become clear that MM tumors continue to evolve on therapy leading to drug resistance. It will be important to understand the emerging drug resistant mechanisms and additional vulnerabilities that occur due to the development of clinical resistance. J. Cell. Biochem. 118: 15-25, 2017. © 2016 Wiley Periodicals, Inc.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 413,
                "text": "proteasome"
            }
        },
        {
            "context": "Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. AIMS: To evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12 weeks in patients with type 2 diabetes. METHODS: This dose-ranging, double-blind, placebo-controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to < 10%] to receive 1, 5, 10, 25, or 50 mg empagliflozin once daily (QD), or placebo, or open-label sitagliptin (100 mg QD), added to metformin for 12 weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo). RESULTS: Reductions in HbA1c of -0.09 to -0.56% were observed with empagliflozin after 12 weeks, versus an increase of 0.15% with placebo (baseline: 7.8-8.1%). Compared with placebo, empagliflozin doses from 5 to 50 mg resulted in reductions in fasting plasma glucose (-2 to -28 mg/dl vs. 5 mg/dl with placebo; p < 0.0001) and body weight (-2.3 to -2.9 kg vs. -1.2 kg; p < 0.01). Frequency of adverse events was generally similar with empagliflozin (29.6-48.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%). CONCLUSIONS: Once daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 72,
                "text": "SGLT2"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 0,
                "text": "INCA"
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 436,
                "text": "SLC9A6"
            }
        },
        {
            "context": "[Psychological Treatments for Borderline Personality Disorder: A Review of Cognitive-Behavioral Oriented Therapies]. INTRODUCTION: Borderline personality disorder is the most common personality disorder, with a global prevalence rate between 1.6% and 6%. It is characterized by affective disturbance and impulsivity, which lead to a high number of self-harm behaviors and great amount of health services use. International guidelines recommend psychotherapy as the primary treatment for borderline personality disorder. This paper reviews evidence about the effects and efficacy of cognitive-behavioral oriented psychological treatments for borderline personality disorder. MATERIAL AND METHODS: A literature review was conducted in Medline and PubMed databases, using the following keywords: borderline personality disorder, cognitive-behavioral psychotherapy and efficacy. RESULTS: Sixteen randomized clinical trials were evaluate in this review, which analyzed the effects of several cognitive-behavioral oriented psychotherapeutic interventions, namely dialectical behavioral therapy, cognitive behavioral therapy, schema-focused therapy and manual-assisted cognitive therapy. All above stated treatments showed clinical beneficial effects, by reducing borderline personality disorder core pathology and associated general psychopathology, as well as by reducing the severity and frequency of self-harm behaviors, and by improving the overall social, interpersonal and global adjustment. Dialectical behavioral therapy and schema-focused therapy also caused a soaring remission rate of diagnostic borderline personality disorder criteria of 57% and 94%, respectively. DISCUSSION: Although there were differences between the psychotherapeutic interventions analysed in this review, all showed clinical benefits in the treatment of borderline personality disorder. Dialectical behavioral therapy and schema-focused therapy presented the strongest scientific data documenting their efficacy, but both interventions are integrative cognitive-behavioral therapies which deviate from the traditional cognitive-behavioral model. CONCLUSION: In summary, the available studies support cognitive-behavioral psychological treatments as an efficacious intervention in borderline personality disorder. However, the existing scientific literature on this topic is still scarce and there is need for more studies, with higher methodological rigor, that should validate these results.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 1601,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Dominant alleles identify SET domain residues required for histone methyltransferase of Polycomb repressive complex 2. Polycomb gene silencing requires histone methyltransferase activity of Polycomb repressive complex 2 (PRC2), which methylates lysine 27 of histone H3. Information on how PRC2 works is limited by lack of structural data on the catalytic subunit, Enhancer of zeste (E(Z)), and the paucity of E(z) mutant alleles that alter its SET domain. Here we analyze missense alleles of Drosophila E(z), selected for molecular study because of their dominant genetic effects. Four missense alleles identify key E(Z) SET domain residues, and a fifth is located in the adjacent CXC domain. Analysis of mutant PRC2 complexes in vitro, and H3-K27 methylation in vivo, shows that each SET domain mutation disrupts PRC2 histone methyltransferase. Based on known SET domain structures, the mutations likely affect either the lysine-substrate binding pocket, the binding site for the adenosylmethionine methyl donor, or a critical tyrosine predicted to interact with the substrate lysine epsilon-amino group. In contrast, the CXC mutant retains catalytic activity, Lys-27 specificity, and trimethylation capacity. Deletion analysis also reveals a functional requirement for a conserved E(Z) domain N-terminal to CXC and SET. These results identify critical SET domain residues needed for PRC2 enzyme function, and they also emphasize functional inputs from outside the SET domain.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 444,
                "text": "SET domain"
            }
        },
        {
            "context": "Oligonucleotide n3'-->p5' phosphoramidates and thio-phoshoramidates as potential therapeutic agents. Nucleic acids analogues, i.e., oligonucleotide N3'-->P5' phosphoramidates and N3'-->P5' thio-phosphoramidates, containing 3'-amino-3'-deoxy nucleosides with various 2'-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, DeltaT(m), relative to their phosphodiester counterparts, reaches 2.2-4.0 degrees per modified nucleoside. 2'-OH- (RNA-like), 2'-O-Me-, and 2'-ribo-F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2'-deoxy- and 2'-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, T(m), of these triplexes exceeds T(m) values for the isosequential phosphodiester counterparts by up to 35 degrees . 2'-Deoxy-N3'-->P5' phosphoramidates adopt RNA-like C3'-endo or N-type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2'-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio-phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3'-->P5' thio-phosphoramidate conjugated to 5'-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent.",
            "question": "Which enzyme is targeted by the drug Imetelstat?",
            "answers": {
                "answer_start": 1926,
                "text": "human telomerase"
            }
        },
        {
            "context": "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 626,
                "text": "orexin"
            }
        },
        {
            "context": "A role for myosin II in mammalian mitochondrial fission. Mitochondria are dynamic organelles, undergoing both fission and fusion regularly in interphase cells. Mitochondrial fission is thought to be part of a quality-control mechanism whereby damaged mitochondrial components are segregated from healthy components in an individual mitochondrion, followed by mitochondrial fission and degradation of the damaged daughter mitochondrion. Fission also plays a role in apoptosis. Defects in mitochondrial dynamics can lead to neurodegenerative diseases such as Alzheimer's disease. Mitochondrial fission requires the dynamin GTPase Drp1, which assembles in a ring around the mitochondrion and appears to constrict both outer and inner mitochondrial membranes. However, mechanisms controlling Drp1 assembly on mammalian mitochondria are unclear. Recent results show that actin polymerization, driven by the endoplasmic reticulum-bound formin protein INF2, stimulates Drp1 assembly at fission sites. Here, we show that myosin II also plays a role in fission. Chemical inhibition by blebbistatin or small interfering RNA (siRNA)-mediated suppression of myosin IIA or myosin IIB causes an increase in mitochondrial length in both control cells and cells expressing constitutively active INF2. Active myosin II accumulates in puncta on mitochondria in an actin- and INF2-dependent manner. In addition, myosin II inhibition decreases Drp1 association with mitochondria. Based on these results, we propose a mechanistic model in which INF2-mediated actin polymerization leads to myosin II recruitment and constriction at the fission site, enhancing subsequent Drp1 accumulation and fission.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 578,
                "text": "Mitochondrial fission"
            }
        },
        {
            "context": "MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α. Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 618,
                "text": "miR-138"
            }
        },
        {
            "context": "Gene looping is conferred by activator-dependent interaction of transcription initiation and termination machineries. Gene looping juxtaposes the promoter and terminator regions of RNA polymerase II-transcribed genes in yeast and mammalian cells. Here we report an activator-dependent interaction of transcription initiation and termination factors during gene looping in budding yeast. Chromatin analysis revealed that MET16, INO1, and GAL1p-BUD3 are in a stable looped configuration during activated transcription. Looping was nearly abolished in the absence of transcription activators Met28, Ino2, and Gal4 of MET16, INO1, and GAL1p-BUD3 genes, respectively. The activator-independent increase in transcription was not accompanied by loop formation, thereby suggesting an essential role for activators in gene looping. The activators did not facilitate loop formation directly because they did not exhibit an interaction with the 3' end of the genes. Instead, activators physically interacted with the general transcription factor TFIIB when the genes were activated and in a looped configuration. TFIIB cross-linked to both the promoter and the terminator regions during the transcriptionally activated state of a gene. The presence of TFIIB on the terminator was dependent on the Rna15 component of CF1 3' end processing complex. Coimmunoprecipitation revealed a physical interaction of Rna15 with TFIIB. We propose that the activators facilitate gene looping through their interaction with TFIIB during transcriptional activation of genes.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1497,
                "text": "TFIIB"
            }
        },
        {
            "context": "Amino acid delta13C analysis of hair proteins and bone collagen using liquid chromatography/isotope ratio mass spectrometry: paleodietary implications from intra-individual comparisons. We report a novel method for the chromatographic separation and measurement of stable carbon isotope ratios (delta(13)C) of individual amino acids in hair proteins and bone collagen using the LC-IsoLink system, which interfaces liquid chromatography (LC) with isotope ratio mass spectrometry (IRMS). This paper provides baseline separation of 15 and 13 of the 18 amino acids in bone collagen and hair proteins, respectively. We also describe an approach to analysing small hair samples for compound-specific analysis of segmental hair sections. The LC/IRMS method is applied in a historical context by the delta(13)C analysis of hair proteins and bone collagen recovered from six individuals from Uummannaq in Greenland. The analysis of hair and bone amino acids from the same individual, compared for the first time in this study, is of importance in palaeodietary reconstruction. If hair proteins can be used as a proxy for bone collagen at the amino acid level, this validates compound-specific isotope studies using hair as a model for palaeodietary reconstruction. Our results suggest that a small offset observed in the bulk delta(13)C values of the hair and bone samples may be attributed to two factors: (i) amino acid compositional differences between hair and bone proteins, and (ii) differential turnover rates of the tissues and the amino acid pools contributing to their synthesis. This application proposes that hair may be a useful complementary or alternative source of compound-specific paleodietary information.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 55,
                "text": "collagen"
            }
        },
        {
            "context": "[The apoptosis-inducing activity of human selenoprotein P shorter isoform]. OBJECTIVE: Human selenoprotein P (HSelP) is unique protein that contains 10 selenocysteines encoded by 10 inframe UGA, which typically function as stop codon. The function of HSelP remains unclear, in part due to the inability to express it by gene recombinant technique. This study is to investigate expression and purification of recombinant HSelP in prokaryotic expression system, and its activity to induce apoptosis in vitro. METHODS: The shorter HSelP isoform was cloned. After the selenocysteine (SeCys) at 40th position from N terminus of the HSelP shorter isoform was mutated into cysteine by PCR, it was expressed in E. coli. The expressed product was purified with DEAE column and identified by Western blot. Subsequently, its function on induction of mitochondrial apoptotic activity was studied. RESULTS: The mutant HSelP shorter isoform expressed in prokaryotic system was purified by DEAE column to 90% homogeneity. The purified product, HSelP280m, induced the opening of mitochondrial permeability transition pore (PTP) and decreased the transmembrane potential in a dose-dependent manner. These events could be abolished by PTP specific inhibitors. CONCLUSION: HSelP280m can induce the opening of mitochondrial PTP, which provides a basis for investigating the structure and function of recombinant HSelP.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 93,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. NADPH oxidase (Nox) family enzymes are one of the main sources of cellular reactive oxygen species (ROS), which have been shown to function as second messenger molecules. To date, seven members of this family have been reported, including Nox1-5 and Duox1 and -2. With the exception of Nox2, the regulation of the Nox enzymes is still poorly understood. Nox1 is highly expressed in the colon, and it requires two cytosolic regulators, NoxO1 and NoxA1, as well as the binding of Rac1 GTPase, for its activity. In this study, we investigate the role of the tyrosine kinase c-Src in the regulation of ROS formation by Nox1. We show that c-Src induces Nox1-mediated ROS generation in the HT29 human colon carcinoma cell line through a Rac-dependent mechanism. Treatment of HT29 cells with the Src inhibitor PP2, expression of a kinase-inactive form of c-Src, and c-Src depletion by small interfering RNA (siRNA) reduce both ROS generation and the levels of active Rac1. This is associated with decreased Src-mediated phosphorylation and activation of the Rac1-guanine nucleotide exchange factor Vav2. Consistent with this, Vav2 siRNA that specifically reduces endogenous Vav2 protein is able to dramatically decrease Nox1-dependent ROS generation and abolish c-Src-induced Nox1 activity. Together, these results establish c-Src as an important regulator of Nox1 activity, and they may provide insight into the mechanisms of tumor formation in colon cancers.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 484,
                "text": "Nox1"
            }
        },
        {
            "context": "The tyrosinase gene in gorillas and the albinism of 'Snowflake'. The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla ('Snowflake'). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in 'Snowflake', indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 611,
                "text": "TYR"
            }
        },
        {
            "context": "c-Jun-mediated anticancer mechanisms of tylophorine. Tylophorine, a phenanthroindolizidine alkaloid, is the major medicinal constituent of herb Tylophora indica. Tylophorine treatment increased the accumulation of c-Jun protein, a component of activator protein 1 (AP1), in carcinoma cells. An in vitro kinase assay revealed that the resultant c-Jun phosphorylation was primarily mediated via activated c-Jun N-terminal protein kinase (JNK). Moreover, flow cytometry indicated that ectopically overexpressed c-Jun in conjunction with tylophorine significantly increased the number of carcinoma cells that were arrested at the G1 phase. The tylophorine-mediated downregulation of cyclin A2 protein levels is known to be involved in the primary G1 arrest. Chromatin immunoprecipitation and reporter assays revealed that tylophorine enhanced the c-Jun downregulation of the cyclin A2 promoter activity upon increased binding of c-Jun to the deregulation AP1 site and decreased binding to the upregulation activating transcription factor (ATF) site in the cyclin A2 promoter, thereby reducing cyclin A2 expression. Further, biochemical studies using pharmacological inhibitors and RNA silencing approaches demonstrated that tylophorine-mediated elevation of the c-Jun protein level occurs primarily via two discrete prolonged signaling pathways: (i) the NF-κB/PKCδ_(MKK4)_JNK cascade, which phosphorylates c-Jun and increases its stability by slowing its ubiquitination, and (ii) the PI3K_PDK1_PP2A_eEF2 cascade, which sustains eukaryotic elongation factor 2 (eEF2) activity and thus c-Jun protein translation. To the best of our knowledge, this report is the first to demonstrate the involvement of c-Jun in the anticancer activity of tylophorine and the release of c-Jun translation from a global translational blockade via the PI3K_PDK1_eEF2 signaling cascade.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 436,
                "text": "JNK"
            }
        },
        {
            "context": "Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. Mutations in the gene encoding fibrillin 1 (FBN1) cause Marfan syndrome (MFS), and related connective tissue disorders. The disease spectrum is wide and while many genotype-phenotype correlations have been reported, few have been consistent. In this study FBN1 was analyzed in 113 patients with MFS or Marfan-like features. Fifty-three mutations were identified in 52 individuals, 41 of which were novel. The mutations comprised 26 missense, 11 splice site, 7 frameshift, 6 nonsense, 1 in-frame deletion, and 2 whole exon deletions. In common with previous studies, genotype-phenotype analysis showed that a FBN1 mutation was more likely to be identified in patients fulfilling Ghent criteria (P = 0.005) and in those who had ectopia lentis (EL) (P < 0.0001). Other previously reported genotype-phenotype correlations were also considered and a new inverse association between a mutation in exons 59-65, and EL emerged (P = 0.002).",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 226,
                "text": "FBN1"
            }
        },
        {
            "context": "Post-translational modifications of p53 tumor suppressor: determinants of its functional targets. Tumor suppressor p53 functions as a \"guardian of the genome\" to prevent cells from transformation. p53 is constitutively ubiquitinated and degradated in unstressed conditions, thereby suppressing the expression. However, cellular stimuli enable p53 to escape from the negative regulation, and then stably expressed p53 transactivates its target genes to induce cell cycle arrest, DNA repair, or apoptosis. Promoter preference of target genes is determined by modification status of p53. Because p53 has two critical roles in the decision of cell fate, stopping cell cycle to repair damaged DNA or induction of apoptotic cell death in response to DNA damage, elucidation of switching mechanisms on p53 functions is of particular importance. Here we review recent evidence how several post-translational modifications of p53 including methylation, phosphorylation, acetylation, and ubiquitination, affect the functions of p53 in response to cellular stress.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 115,
                "text": "p53"
            }
        },
        {
            "context": "Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis. Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 203,
                "text": "α-Synuclein"
            }
        },
        {
            "context": "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. It comprises Ehlers-Danlos syndrome type I and Ehlers-Danlos syndrome type II, but it is now apparent that these form a continuum of clinical findings and differ only in phenotypic severity. It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively. However, because no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of patients with classic Ehlers-Danlos syndrome harboring a mutation in one of these genes. In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein. Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations have been observed. No treatment for the underlying defect is presently available for Ehlers-Danlos syndrome. However, a series of preventive guidelines are applicable.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 116,
                "text": "connective tissue"
            }
        },
        {
            "context": "Prospective comparison of the clinical impacts of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-susceptible MRSA. Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [>or=0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 microg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 166,
                "text": "MRSA"
            }
        },
        {
            "context": "Kell and XK immunohistochemistry in McLeod myopathy. The McLeod syndrome is an X-linked neuroacanthocytosis manifesting with myopathy and progressive chorea. It is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein of yet unknown function. In erythroid tissues, XK forms a functional complex with the Kell glycoprotein. Here, we present an immunohistochemical study in skeletal muscle of normal controls and a McLeod patient with a XK gene point mutation (C977T) using affinity-purified antibodies against XK and Kell proteins. Histological examination of the affected muscle revealed the typical pattern of McLeod myopathy including type 2 fiber atrophy. In control muscles, Kell immunohistochemistry stained sarcoplasmic membranes. XK immunohistochemistry resulted in a type 2 fiber-specific intracellular staining that was most probably confined to the sarcoplasmic reticulum. In contrast, there was only a weak background signal without a specific staining pattern for XK and Kell in the McLeod muscle. Our results demonstrate that the lack of physiological XK expression correlates to the type 2 fiber atrophy in McLeod myopathy, and suggest that the XK protein represents a crucial factor for the maintenance of normal muscle structure and function.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 553,
                "text": "XK"
            }
        },
        {
            "context": "Orteronel for the treatment of prostate cancer. Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Preclinical studies demonstrate that orteronel treatment suppresses androgen levels and causes shrinkage of androgen-dependent organs, such as the prostate gland. Early reports of clinical studies demonstrate that orteronel treatment leads to reduced prostate-specific antigen levels, a marker of prostate cancer tumor burden, and more complete suppression of androgen synthesis than conventional androgen deprivation therapies that act in the testes alone. Treatment with single-agent orteronel has been well tolerated with fatigue as the most common adverse event, while febrile neutropenia was the dose-limiting toxicity in a combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III clinical trial in patients with advanced-stage prostate cancer who had received prior docetaxel was unblinded as the overall survival primary end point was not achieved. However, additional Phase III orteronel trials are ongoing in men with earlier stages of prostate cancer.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 235,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Giant-cell tumor of bone: treatment options and role of denosumab. Giant-cell tumor of bone is a rare, locally aggressive tumor that typically occurs in the bones of skeletally mature young adults in their second to fourth decades. Traditionally, surgery has been the mainstay of therapy for this disease, but the disease can recur even with optimal procedures. Furthermore, it may occur in locations where a surgical approach would be morbid. The maturation of the understanding of the role of the receptor activator of nuclear factor-κB ligand (RANKL) in the pathophysiology of giant-cell tumor of bone has led to the use of denosumab, a monoclonal antibody against RANKL, in this disease. In 2013, the US Food and Drug Administration approved denosumab for use in patients with recurrent/unresectable/metastatic giant-cell tumor of bone or for patients in whom surgery would be morbid.",
            "question": "Which is the target of the drug Denosumab?",
            "answers": {
                "answer_start": 668,
                "text": "RANKL"
            }
        },
        {
            "context": "The biology of chronic myelogenous leukemia: implications for imatinib therapy. Chronic myelogenous leukemia (CML) results from the neoplastic transformation of primitive hematopoietic stem cells, and has been classified as a myeloproliferative disorder. The hallmark of CML is the presence of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2), which is known as the Philadelphia (Ph) chromosome. This translocation results in the formation of the bcr-abl fusion gene, which, in turn, is translated into a chimeric Bcr-Abl protein with deregulated tyrosine kinase activity. Constitutive Bcr-Abl expression has been shown to be necessary and sufficient for the transformed phenotype of CML cells. CML is unique among human cancers in that a single genetic defect, the Ph chromosome, is responsible for the transformed phenotype. Since this discovery more than 40 years ago, our understanding of the clinical course, therapy, and prognosis of patients with CML has changed significantly. These changes have culminated in the emergence of imatinib, the first rationally designed, molecularly targeted therapy for human malignancy. In this review, the authors describe the molecular biology of CML and the development of imatinib as a therapeutic agent for the treatment of CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 489,
                "text": "bcr-abl"
            }
        },
        {
            "context": "Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke: Design of the randomized Gore REDUCE Clinical Study. Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.",
            "question": "Treatment of which disease was studied in the Gore REDUCE Clinical Study?",
            "answers": {
                "answer_start": 523,
                "text": "patent foramen ovale"
            }
        },
        {
            "context": "Stepwise histone replacement by SWR1 requires dual activation with histone H2A.Z and canonical nucleosome. Histone variant H2A.Z-containing nucleosomes are incorporated at most eukaryotic promoters. This incorporation is mediated by the conserved SWR1 complex, which replaces histone H2A in canonical nucleosomes with H2A.Z in an ATP-dependent manner. Here, we show that promoter-proximal nucleosomes are highly heterogeneous for H2A.Z in Saccharomyces cerevisiae, with substantial representation of nucleosomes containing one, two, or zero H2A.Z molecules. SWR1-catalyzed H2A.Z replacement in vitro occurs in a stepwise and unidirectional fashion, one H2A.Z-H2B dimer at a time, producing heterotypic nucleosomes as intermediates and homotypic H2A.Z nucleosomes as end products. The ATPase activity of SWR1 is specifically stimulated by H2A-containing nucleosomes without ensuing histone H2A eviction. Remarkably, further addition of free H2A.Z-H2B dimer leads to hyperstimulation of ATPase activity, eviction of nucleosomal H2A-H2B, and deposition of H2A.Z-H2B. These results suggest that the combination of H2A-containing nucleosome and free H2A.Z-H2B dimer acting as both effector and substrate for SWR1 governs the specificity and outcome of the replacement reaction.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 247,
                "text": "SWR1"
            }
        },
        {
            "context": "Intracranial aneurysms in Marfan's syndrome: an autopsy study. OBJECTIVE: Marfan's syndrome is a heritable connective tissue disorder that has been associated with intracranial aneurysms. However, the prevalence of intracranial aneurysms in Marfan's syndrome is unknown and pathological studies of affected vessels have not been reported. We therefore examined the neuropathological findings in a group of patients with Marfan's syndrome. METHODS: We identified all patients with Marfan's syndrome in whom postmortem examination had been performed at the Mayo Clinic between 1969 and 1993. RESULTS: Autopsy included examination of the brain in seven patients with Marfan's syndrome (five men and two women with a mean age of 28 yr). Each of two patients had one or more intracranial aneurysms. The first patient, a 32-year-old man who died as a result of aortic dissection, was observed to have an incidental saccular supraclinoid carotid artery aneurysm (7 mm). Microscopic examination of the remainder of the cerebral arteries revealed duplication and fragmentation of the internal elastic lamina. The second patient, a 20-year-old man who died as a result of a subarachnoid hemorrhage, had ruptured saccular supraclinoid carotid artery (3 mm) and anterior cerebral artery (20 mm) aneurysms as well as unruptured fusiform middle cerebral artery (18 mm) and posterior cerebral artery (13 mm) aneurysms. Microscopic examination of the cerebral arteries revealed widespread changes consisting of intimal proliferation, medial degeneration, and fragmentation of the internal elastic lamina. CONCLUSION: These findings confirm an association between Marfan's syndrome and intracranial aneurysms. Microscopic involvement of cerebral arteries in Marfan's syndrome may be variable, even among those with intracranial aneurysms.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 107,
                "text": "connective tissue"
            }
        },
        {
            "context": "Diminished in vitro antibacterial activity of oxacillin against clinical isolates of borderline oxacillin-resistant Staphylococcus aureus. Since it is unknown whether β-lactam antimicrobial agents can be used effectively against borderline oxacillin-resistant Staphylococcus aureus (BORSA) with oxacillin MICs > 4 mg/L, the in vitro bactericidal activity and pharmacodynamic effect of oxacillin against clinical BORSA isolates was evaluated. Time-kill experiments with oxacillin were performed and the results compared with those obtained with vancomycin, daptomycin and linezolid against BORSA with oxacillin MICs > 4 mg/L and BORSA with oxacillin MICs < 2 mg/L. Furthermore, the effect of β-lactamase production and plasmid profile analysis were taken into account to clarify responses to oxacillin. Oxacillin killing activity was attenuated against BORSA compared with ATCC 29213 since the pharmacodynamic parameters revealed that the potency of oxacillin was markedly reduced (c. ten-fold) against BORSA with oxacillin MICs > 4 mg/L. pBORa53-like plasmid-containing BORSA with oxacillin MICs < 2 mg/L showed markedly more regrowth. In conclusion, oxacillin was non-effective in the eradication of either (i) BORSA with oxacillin MICs > 4 mg/L or (ii) β-lactamase-hyperproducing BORSA (MICs < 2 mg/L). Further investigation into β-lactam dosing strategies against different BORSA strains is warranted in order to avoid possible therapy failure.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 229,
                "text": "borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Preclinical and clinical development of an anti-kappa free light chain mAb for multiple myeloma. Monoclonal antibodies (mAb) have had tremendous success in treating a variety of cancers over the past twenty years. Yet despite their widespread clinical use, which includes treatments for haematological malignancies, there are still no approved mAb therapies for multiple myeloma (MM). This is likely to change within the next few years with a number of mAb therapies being assessed in late stage clinical trials, most notably, the anti-CS-1 mAb, elotuzumab, and the anti-CD38 mAb, daratumumab, which are currently being evaluated in Phase III clinical trials for MM. In this review, we will discuss the preclinical and clinical development of MDX-1097, a Phase II candidate which targets cell membrane-associated kappa immunoglobulin free light chains expressed on the surface of MM cells.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 571,
                "text": "CD38"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 1312,
                "text": "Malaria"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 947,
                "text": "TFIIS"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 315,
                "text": "RADAR"
            }
        },
        {
            "context": "Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. The methylation of lysine residues of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Here, we report two crystal structures of SET7/9, a histone methyltransferase (HMTase) that transfers methyl groups to Lys4 of histone H3, in complex with S-adenosyl-L-methionine (AdoMet) determined at 1.7 and 2.3 A resolution. The structures reveal an active site consisting of: (i) a binding pocket between the SET domain and a c-SET helix where an AdoMet molecule in an unusual conformation binds; (ii) a narrow substrate-specific channel that only unmethylated lysine residues can access; and (iii) a catalytic tyrosine residue. The methyl group of AdoMet is directed to the narrow channel where a substrate lysine enters from the opposite side. We demonstrate that SET7/9 can transfer two but not three methyl groups to unmodified Lys4 of H3 without substrate dissociation. The unusual features of the SET domain-containing HMTase discriminate between the un- and methylated lysine substrate, and the methylation sites for the histone H3 tail.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 1025,
                "text": "SET domain"
            }
        },
        {
            "context": "Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. Here we show that the membrane protease matriptase initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein cascade. Auto-activation of pro-inflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis. These results uncover a pathogenic matriptase-pro-kallikrein pathway that could operate in several human skin and inflammatory diseases.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 162,
                "text": "LEKTI"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model of multiple sclerosis (MS), is highly useful for studying inflammation, demyelination, and neurodegeneration in the central nervous system (CNS). EAE exhibits many similarities with MS, which is a chronic inflammatory disease affecting CNS white matter in humans. Various studies have indicated that EAE is a particularly useful animal model for understanding both the mechanisms of immune-mediated CNS pathology and also the progressive clinical course of MS. Demyelination and axonal dysfunction have previously been shown in MS and EAE but current evidences indicate that axonal damage and neuron death also occur, demonstrating that these diseases harbor a neurodegenerative component. Recent studies also have shown that the activation of calpain and caspase pathways contribute to the apoptotic death of oligodendrocytes and neurons, promoting the pathological events leading to neurological deficits. Apoptosis is involved in the disease-regulating as well as in the disease-promoting processes in EAE. This review discusses the major involvement of calpain and caspase pathways in causing demyelination and neurodegeneration in EAE animals.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 121,
                "text": "Experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "[Factors associated with achievement and durability of cytogenetic response in patients with chronic myeloid leukemia treated with imatinib]. BACKGROUND/AIM: Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia and become the standard of care for this disease. The aim of this study was evaluation and analysis of cytogenetic response in different intervals and risk groups as well as finding association between pre-treatment characteristics and later probability of achievement of major cytogenetic response. METHODS: We analyzed a total of 22 adult patients with newly diagnosed Philadelphia positive early chronic phase chronic myeloid leukemia treated at our institution from June 2006 to December 2009. RESULTS: The median follow-up time for patients during treatment with imatinib was 25.7 months (range, 12-42 months). A complete hematologic response was achieved in all of the analyzed patients within 6 months from the start of the treatment. The major cytogenetic response rate was 81.8%, and the complete cytogenetic response rate was 72.7%. The patients with low or moderate relative risk had the rate of complementary achieving major and complete cytogenetic response of 75-90%. A multivariate analysis identified the following independent prognostic factors for achieving major cytogenetic response: the absence of splenomegaly, white blood cell count less than 10 x 10(9)/L, the platelet count less than 450 x 10(9)/L, the presence of less than 5% of bone marrow blasts and basophils, the absence of blasts in peripheral blood, the presence of less than 7% of basophils in peripheral blood. CONCLUSION: Patients who early achieve complete and major cytogenetic response as well as those with low and moderate relative risk have a higher rate of achieving and maintaining complete cytogenetic response. There are also characteristics of patients before treatment that may indicate the treatment outcome.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 189,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. Kallikreins are a subgroup of serine proteases with diverse physiological functions. Recently, growing evidence indicates that many kallikrein genes are involved in malignancy. In rodents, kallikreins are encoded by a large multigene family, but in humans only three kallikreins were thought to exist. Based on the homology between the human and rodent kallikrein loci, we studied a 300 kb region of genomic sequences around the putative KLK1 gene locus on chromosome 19q13.3-q13.4. By using linear sequence information, restriction analysis, end sequencing, PCR and blotting techniques, as well as bioinformatic approaches, we were able to construct the first detailed map of the human kallikrein gene family. Comparative analysis of genes located in this area, provides strong evidence that the human kallikrein gene family locus on chromosome 19 is considerably larger than previously thought, containing at least fifteen genes. We have established, for the first time, the common structural features that apply to all members of the expanded kallikrein multigene family. Our map specifies the distance between genes to one base pair accuracy, the relative location, and the direction of transcription of all 15 genes. Determination of the true size of the kallikrein family in humans is important for our understanding of the contribution of the kallikreins to human biology and pathophysiology.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 1298,
                "text": "15"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1571,
                "text": "Xa"
            }
        },
        {
            "context": "Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats. Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 134,
                "text": "CYP17A1"
            }
        },
        {
            "context": "First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). Indication was based on the STI571 0109 study, in which imatinib favorably compared to historical treatments in patients failing prior therapies. The relevance of these results to currently newly diagnosed AP-CML patients remains unknown. We evaluated the benefit of imatinib in 42 newly diagnosed AP-CML patients. In all, 16 patients had hematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome (ACAs; HEM-AP), 16 solely had ACAs (ACA-AP) and 10 had hematological acceleration plus ACAs (HEM-AP + ACA). Major cytogenetic responses were achieved in 93.7% of HEM-AP patients, 75% of patients with ACA-AP (P=NS) and 40% of patients with HEM-AP + ACA (P=0.0053). The 24-month failure-free survival rate was 87.5% in HEM-AP patients, 43.8% in ACA-AP patients and 15% in HEM-AP + ACA patients (P=0.022). The 24-month estimate of progression-free survival was 100% in HEM-AP patients, 92.8% in ACA-AP patients and 58.3% in HEM-AP + ACA patients (P=0.0052). In conclusion, frontline imatinib allows favorable outcomes in HEM-AP and ACA-AP patients but appears insufficient for patients with HEM-AP + ACA. Broader-target and/or more potent BCR-ABL tyrosine kinase inhibitors alone or in combination may be considered in this setting.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 136,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 1419,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Links between granuloma annulare, necrobiosis lipoidica diabeticorum and childhood diabetes: a matter of time? Diabetes mellitus is associated with a range of dermatologic presentations, including granuloma annulare and necrobiosis lipoidica diabeticorum. Granuloma annulare occurs earlier than necrobiosis lipoidica diabeticorum and the association with diabetes mellitus is much weaker. We describe two children with diabetes who both developed granuloma annulare and later, necrobiosis lipoidica diabeticorum. We postulate that the early onset and transient nature of granuloma annulare, compared with the later onset and persistence of necrobiosis lipoidica diabeticorum, might account for the different apparent rates of association with diabetes mellitus.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 355,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Generation of Oxtr cDNA(HA)-Ires-Cre Mice for Gene Expression in an Oxytocin Receptor Specific Manner. The neurohypophysial hormone oxytocin (OXT) and its receptor (OXTR) have critical roles in the regulation of pro-social behaviors, including social recognition, pair bonding, parental behavior, and stress-related responses. Supporting this hypothesis, a portion of patients suffering from autism spectrum disorder have mutations, such as single nucleotide polymorphisms, or epigenetic modifications in their OXTR gene. We previously reported that OXTR-deficient mice exhibit pervasive social deficits, indicating the critical role of OXTR in social behaviors. In the present study, we generated Oxtr cDNA(HA)-Ires-Cre knock-in mice, expressing both OXTR and Cre recombinase under the control of the endogenous Oxtr promoter. Knock-in cassette of Oxtr cDNA(HA)-Ires-Cre consisted of Oxtr cDNA tagged with the hemagglutinin epitope at the 3' end (Oxtr cDNA(HA)), internal ribosomal entry site (Ires), and Cre. Cre was expressed in the uterus, mammary gland, kidney, and brain of Oxtr cDNA(HA)-Ires-Cre knock-in mice. Furthermore, the distribution of Cre in the brain was similar to that observed in Oxtr-Venus fluorescent protein expressing mice (Oxtr-Venus), another animal model previously generated by our group. Social behavior of Oxtr cDNA(HA)-Ires-Cre knock-in mice was similar to that of wild-type animals. We demonstrated that this construct is expressed in OXTR-expressing neurons specifically after an infection with the recombinant adeno-associated virus carrying the flip-excision switch vector. Using this system, we showed the transport of the wheat-germ agglutinin tracing molecule from the OXTR-expressing neurons to the innervated neurons in knock-in mice. This study might contribute to the monosynaptic analysis of neuronal circuits and to the optogenetic analysis of neurons expressing OXTR.",
            "question": "Which is the \"bonding hormone\"?",
            "answers": {
                "answer_start": 132,
                "text": "oxytocin"
            }
        },
        {
            "context": "Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α-synuclein. Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.",
            "question": "How many amino acids does davunetide consist of?",
            "answers": {
                "answer_start": 566,
                "text": "eight"
            }
        },
        {
            "context": "Focal cortical dysplasia in meningioangiomatosis. Meningioangiomatosis is a rare, benign, developmental, or hamartomatous lesion which may involve the leptomeninges and underlying brain parenchyma. Histologically, meningioangiomatosis is marked by a proliferation of blood vessels in the parenchyma, rimmed by collars of spindled meningothelial cells. There are anecdotal reports of an association of meningioangiomatosis with focal cortical dysplasia. We retrospectively analyzed the clinical, histopathologic, and treatment outcomes of 16 patients with a diagnosis of meningioangiomatosis, specifically investigating these cases for evidence of adjacent focal cortical dysplasia. Patients ranged in age from 1 to 34 years (median 18), 12 of whom had medically-intractable epilepsy as their presenting symptom. No patients in this study had a confirmed diagnosis of neurofibromatosis type II. Four patients (25%) were found to have fibrous meningiomas associated with the meningioangiomatosis. Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. Seven of the patients (44%) had no post-operative seizures, and were off anti-epileptic drugs, while 2 patients relapsed, and required pharmacologic treatment for seizure control. This study therefore presents evidence to support inclusion of meningioangiomatosis as a focal cortical dysplasia-associated entity, as suggested by the ILAE classification (type IIIc). As focal cortical dysplasia is a developmental malformation, its association with meningioangiomatosis supports a developmental etiology of sporadic meningioangiomatosis.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1118,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Riociguat (Adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 0,
                "text": "Riociguat"
            }
        },
        {
            "context": "Point mutations in the Rpb9-homologous domain of Rpc11 that impair transcription termination by RNA polymerase III. RNA polymerase III recognizes and pauses at its terminator, an oligo(dT) tract in non-template DNA, terminates 3' oligo(rU) synthesis within this sequence, and releases the RNA. The pol III subunit Rpc11p (C11) mediates RNA 3'-5' cleavage in the catalytic center of pol III during pausing. The amino and carboxyl regions of C11 are homologous to domains of the pol II subunit Rpb9p, and the pol II elongation and RNA cleavage factor, TFIIS, respectively. We isolated C11 mutants from Schizosaccharomyces pombe that cause pol III to readthrough terminators in vivo. Mutant RNA confirmed the presence of terminator readthrough transcripts. A predominant mutation site, F32, resides in the C11 Rpb9-like domain. Another mutagenic approach confirmed the F32 mutation and also isolated I34 and Y30 mutants. Modeling Y30, F32 and I34 of C11 in available cryoEM pol III structures predicts a hydrophobic patch that may interface with C53/37. Another termination mutant, Rpc2-T455I, appears to reside internally, near the RNA-DNA hybrid. We show that the Rpb9 and TFIIS homologous mutants of C11 reflect distinct activities, that differentially affect terminator recognition and RNA 3' cleavage. We propose that these C11 domains integrate action at the upper jaw and center of pol III during termination.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 550,
                "text": "TFIIS"
            }
        },
        {
            "context": "Antigenotoxic effects of p53 on spontaneous and ultraviolet light B--induced deletions in the epidermis of gpt delta transgenic mice. Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as \"the guardian of the genome.\" To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(+/+) mice. However, no increase of such large deletions was observed in irradiated p53(-/-) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 511,
                "text": "p53"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 363,
                "text": "stroke"
            }
        },
        {
            "context": "Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. PURPOSE: To compare tumor control rates after surgical resection or stereotactic radiosurgery for patients with small- to medium-size intracranial meningiomas. MATERIALS AND METHODS: Between 1990 and 1997, 198 adult meningioma patients treated at our center underwent either surgical resection (n = 136) or radiosurgery (n = 62) as primary management for benign meningiomas <35 mm in average diameter. Tumor recurrence or progression rates were calculated by the Kaplan-Meier method according to an independent radiographic review. The mean follow-up was 64 months. RESULTS: The tumor resections were Simpson Grade 1 in 57 (42%), Grade 2 in 57 (42%), and Grade 3-4 in 22 (16%). The mean margin and maximal radiation dose at radiosurgery was 17.7 Gy and 34.9 Gy, respectively. Tumor recurrence/progression was more frequent in the surgical resection group (12%) than in the radiosurgical group (2%; p = 0.04). No statistically significant difference was detected in the 3- and 7-year actuarial progression-free survival (PFS) rate between patients with Simpson Grade 1 resections (100% and 96%, respectively) and patients who underwent radiosurgery (100% and 95%, respectively; p = 0.94). Radiosurgery provided a higher PFS rate compared with patients with Simpson Grade 2 (3- and 7-year PFS rate, 91% and 82%, respectively; p <0.05) and Grade 3-4 (3- and 7-year PFS rate, 68% and 34%, respectively; p <0.001) resections. Subsequent tumor treatments were more common after surgical resection (15% vs. 3%, p = 0.02). Complications occurred in 10% of patients after radiosurgery compared with 22% of patients after surgical resection (p = 0.06). CONCLUSIONS: The PFS rate after radiosurgery was equivalent to that after resection of a Simpson Grade 1 tumor and was superior to Grade 2 and 3-4 resections in our study. If long-term follow-up confirms the high tumor control rate and low morbidity of radiosurgery, this technique will likely become the preferred treatment for most patients with small- to moderate-size meningiomas without symptomatic mass effect.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 129,
                "text": "meningioma"
            }
        },
        {
            "context": "Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene are associated with pituitary adenomas that usually occur as familial isolated pituitary adenomas (FIPA). Detailed pathological and tumor genetic data on AIP mutation-related pituitary adenomas are not sufficient. Non-identical twin females presented as adolescents to the emergency department with severe progressive headache caused by large pituitary macroadenomas require emergency neurosurgery; one patient had incipient pituitary apoplexy. Post-surgically, the patients were found to have silent somatotrope adenomas on pathological examination. Furthermore, the light microscopic, immunohistochemical, and electron microscopic studies demonstrated tumors of virtually identical characteristics. The adenomas were accompanied by multiple areas of pituitary hyperplasia, which stained positively for GH, indicating somatotrope hyperplasia. Genetic analyses of the FIPA kindred revealed a novel E216X mutation of the AIP gene, which was present in both the affected patients and the unaffected father. Molecular analysis of surgical specimens revealed loss of heterozygosity (LOH) in the adenoma but showed that LOH was not present in the hyperplastic pituitary tissue from either patient. AIP immunostaining confirmed normal staining in the hyperplastic tissue and decreased staining in the adenoma in the tumors from both patients. These results demonstrate that patients with AIP germline mutation can present with silent somatotrope pituitary adenomas. The finding of somatotrope hyperplasia unaccompanied by AIP LOH suggests that LOH at the AIP locus might be a late event in a potential progression from hyperplastic to adenomatous tissue.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 145,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "Transcriptional regulation by MAP kinases. Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 2055,
                "text": "c-Jun NH2-terminal kinase"
            }
        },
        {
            "context": "Predicting early mortality in acute exacerbation of chronic obstructive pulmonary disease using the CURB65 score. BACKGROUND AND OBJECTIVE: Hospitalization for exacerbation of COPD is associated with a high risk of mortality. A risk-prediction model using information easily obtained on admission could help to identify high-risk individuals. The CURB65 score was developed to predict mortality risk in community acquired pneumonia. A retrospective study found that this score was also associated with mortality in COPD exacerbations. We conducted a prospective study to assess the utility of the CURB65 score in acute COPD exacerbations. METHODS: Consecutive patients with physician diagnosed COPD exacerbations admitted to a public hospital during a 1-year period were studied prospectively. The CURB65 scores were calculated from information obtained at initial hospital presentation. CURB65 = one point each for Confusion, Urea > 7 mmol/L, Respiratory rate > 30/min, low Blood pressure, age > 65 years. RESULTS: 30-day mortality data were available for 249 of 252 patients. CURB65 scores on admission significantly predicted risk of death during the hospital admission and at 30 days. The 30-day mortality by score groups were: low risk (scores 0-1) 2.0% (2/98), moderate risk (score 2) 6.7% (6/90) and high risk (scores 3-5) 21.3% (13/61). CURB65 scores were not predictive of 1-year mortality. CONCLUSIONS: A simple 6-point score based on confusion, blood urea, respiratory rate, blood pressure and age can be used to stratify patients with COPD exacerbation into different management groups. The CURB65 score was as effective in predicting early mortality in our cohort of acute COPD exacerbations as it was in previous cohorts with community acquired pneumonia. Our findings suggest that CURB65 scores can help clinicians to assess patients with exacerbation of COPD.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 422,
                "text": "pneumonia"
            }
        },
        {
            "context": "RAPIDR: an analysis package for non-invasive prenatal testing of aneuploidy. UNLABELLED: Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package) is an easy-to-use open-source R package that implements several published NIPT analysis methods. The input to RAPIDR is a set of sequence alignment files in the BAM format, and the outputs are calls for aneuploidy, including trisomies 13, 18, 21 and monosomy X as well as fetal sex. RAPIDR has been extensively tested with a large sample set as part of the RAPID project in the UK. The package contains quality control steps to make it robust for use in the clinical setting. AVAILABILITY AND IMPLEMENTATION: RAPIDR is implemented in R and can be freely downloaded via CRAN from here: http://cran.r-project.org/web/packages/RAPIDR/index.html. CONTACT: kitty.lo@ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package has been developed for analyzing Non-invasive prenatal testing (NIPT) data?",
            "answers": {
                "answer_start": 219,
                "text": "RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package)"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1336,
                "text": "coilin"
            }
        },
        {
            "context": "Comparative FISH mapping of the ancestral fusion point of human chromosome 2. It is known that human chromosome 2 originated from the fusion of two ancestral primate chromosomes. This has been confirmed by chromosome banding and fluorescence in-situ hybridization (FISH) with human chromosome-2-specific DNA libraries. In this study, the order of 38 cosmid clones derived from the human chromosome region 2q12-q14 was exactly determined by high-resolution FISH in human chromosome 2 and its homologous chromosomes in chimpanzees (Pan trogrodydes, 2n=48) and cynomolgus monkeys (Macacafascicularis, 2n = 42). This region includes the telomere-to-telomere fusion point of two ancestral ape-type chromosomes. As a result of comparative mapping, human chromosome region 2q12-q14 was found to correspond to the short arms of chimpanzee chromosomes 12 and 13 and cynomolgus monkey chromosomes 9 and 15. It is noted that no difference was detected in the relative order of the cosmid clones between human and chimpanzee chromosomes. This suggests that two ancestral ape-type chromosomes fused tandemly at telomeres to form human chromosome 2, and the genomic organization of this region is thought to be considerably conserved. In the cynomolgus monkey, however, the order of clones in each homologue was inverted. In addition to cosmid mapping, two chromosome-2-specific yeast artificial chromosome (YAC) clones containing the fusion point were identified by FISH.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 101,
                "text": "chromosome 2"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 411,
                "text": "tyrosinase"
            }
        },
        {
            "context": "The ring plus project: safety and acceptability of vaginal rings that protect women from unintended pregnancy. BACKGROUND: Research is ongoing to develop multipurpose vaginal rings to be used continuously for contraception and to prevent Human Immunodeficiency Virus (HIV) infection. Contraceptive vaginal rings (CVRs) are available in a number of countries and are most of the time used intermittently i.e. three weeks out of a 4-week cycle. Efficacy trials with a dapivirine-containing vaginal ring for HIV prevention are ongoing and plans to develop multi-purpose vaginal rings for prevention of both HIV and pregnancy have been elaborated. In contrast with the CVRs, multi-purpose vaginal rings will have to be used continuously. Women who continuously use a CVR will no longer have menses. Furthermore, some safety aspects of CVR use have never been studied in-depth in the past, such as the impact of the vaginal ring on the vaginal microbiota, biofilm formation and induction of inflammation. We studied acceptability and these novel aspects of safety in Rwandan women. Although significant progress has been made over the past decade, Rwanda still has a high unmet need for contraception (with 47% unplanned births) and a generalized HIV epidemic, and CVRs are not yet available. METHODS: We will conduct an open label, single centre, randomized controlled trial. A total of 120 HIV-negative women will be randomized to intermittent CVR use (to allow menstruation) or continuous CVR use. Women will be followed for a maximum of 14 weeks. In parallel, we will conduct a qualitative study using in-depth interview and focus group discussion methodology. DISCUSSION: In addition to evaluating the safety and acceptability of intermittent and continuous CVR use in Rwandan women, we hope that our findings will inform the development of future multipurpose vaginal rings, will prepare Rwandan study populations for future clinical trials of multipurpose vaginal rings, and will pave the way for introduction of CVRs on African markets. TRIAL REGISTRATION: Clinicaltrials.gov NCT01796613 . Registered 14 February 2013.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 505,
                "text": "HIV"
            }
        },
        {
            "context": "A cascade of genes related to Waardenburg syndrome. On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 181,
                "text": "MITF"
            }
        },
        {
            "context": "Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 746,
                "text": "NF1"
            }
        },
        {
            "context": "Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 (FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 238,
                "text": "FBN1"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 209,
                "text": "7"
            }
        },
        {
            "context": "Oridonin in combination with imatinib exerts synergetic anti-leukemia effect in Ph+ acute lymphoblastic leukemia cells in vitro by inhibiting activation of LYN/mTOR signaling pathway. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by constitutively activated BCR-ABL and SRC family tyrosine kinases.They account for the activations of multiple growth-signaling pathways, including Raf/MEK/ERK, Akt/mTOR and STAT5 pathways. The BCR-ABL tyrosine kinase inhibitor imatinib is the standard treatment for Ph+ leukemia and plays efficacious role in CML. However, imatinib has few inhibitory effects on SRC tyrosine kinase with response rate of Ph+ ALL lower and relapse more frequent and quicker compared with CML. Previous studies showed that oridonin inhibits proliferation and induces apoptosis in many tumor cells. However, the anticancer activity and mechanism of oridonin in Ph+ ALL is unknown. To investigate the anticancer activity of oridonin, we examined its role in constitutively activated Akt/mTOR, Raf/MEK/ERK, STAT5 and SRC pathway, mRNA level of bcr/abl gene, cell viability and apoptosis in Ph+ ALL SUP-B15 cells. Furthermore, we detected synergetic effect of oridonin plus imatinib. Our results showed that oridonin inhibiting activations of LYN (one of SRC family kinases) and ABL and their downstream Akt/mTOR, Raf/MEK/ERK and STAT5 pathways, downregulated Bcl-2 but upregulated Bax protein and then induced apoptosis in Ph+ ALL cells. Oridonin plus imatinib exerted synergetic effects by overcoming imatinib defect of upregulating Akt/mTOR and LYN signaling. Additionally, we examined the effect of oridonin on the signaling pathways in the primary specimens from Ph+ ALL patients. Our data showed that oridonin remarkably suppressed activations of Akt/mTOR, Raf/MEK and STAT5 pathway in these primary specimens and oridonin with imatinib exerted synergetic suppressive effects on mTOR, STAT5 and LYN signaling in one imatinib resistant patient specimen. Additional evaluation of oridonin as a potential therapeutic agent for Ph+ ALL seems warranted.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 297,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 195,
                "text": "MITF"
            }
        },
        {
            "context": "PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation. A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 390,
                "text": "PD-L1"
            }
        },
        {
            "context": "Association of restless legs syndrome variants in Korean patients with restless legs syndrome. STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS. DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci. MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters. CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 255,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "ESET histone methyltransferase is essential to hypertrophic differentiation of growth plate chondrocytes and formation of epiphyseal plates. The ESET (also called SETDB1) protein contains an N-terminal tudor domain that mediates protein-protein interactions and a C-terminal SET domain that catalyzes methylation of histone H3 at lysine 9. We report here that ESET protein is transiently upregulated in prehypertrophic chondrocytes in newborn mice. To investigate the in vivo effects of ESET on chondrocyte differentiation, we generated conditional knockout mice to specifically eliminate the catalytic SET domain of ESET protein only in mesenchymal cells. Such deletion of the ESET gene caused acceleration of chondrocyte hypertrophy in both embryos and young animals, depleting chondrocytes that are otherwise available to form epiphyseal plates for endochondral bone growth. ESET-deficient mice are thus characterized by defective long bone growth and trabecular bone formation. To understand the underlying mechanism for ESET regulation of chondrocytes, we carried out co-expression experiments and found that ESET associates with histone deacetylase 4 to bind and inhibit the activity of Runx2, a hypertrophy-promoting transcription factor. Repression of Runx2-mediated gene transactivation by ESET is dependent on its H3-K9 methyltransferase activity as well as its associated histone deacetylase activity. In addition, knockout of ESET is associated with repression of Indian hedgehog gene in pre- and early hypertrophic chondrocytes. Together, these results provide clear evidence that ESET controls hypertrophic differentiation of growth plate chondrocytes and endochondral ossification during embryogenesis and postnatal development.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 275,
                "text": "SET domain"
            }
        },
        {
            "context": "Analysis of amino acid 13C abundance from human and faunal bone collagen using liquid chromatography/isotope ratio mass spectrometry. The scope of compound-specific stable isotope analysis has recently been increased with the development of the LC IsoLink which interfaces high-performance liquid chromatography (HPLC) and isotope ratio mass spectrometry (IRMS) to provide online LC/IRMS. This enables isotopic measurement of non-volatile compounds previously not amenable to compound-specific analysis or requiring substantial modification for gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS), which results in reduced precision. Amino acids are an example of such compounds. We present a new chromatographic method for the HPLC separation of underivatized amino acids using an acidic, aqueous mobile phase in conjunction with a mixed-mode stationary phase that can be interfaced with the LC IsoLink for compound-specific delta13C analysis. The method utilizes a reversed-phase Primesep-A column with embedded, ionizable, functional groups providing the capability for ion-exchange and hydrophobic interactions. Baseline separation of 15 amino acids and their carbon isotope values are reported with an average standard deviation of 0.18 per thousand (n = 6). In addition delta13C values of 18 amino acids are determined from modern protein and archaeological bone collagen hydrolysates, demonstrating the potential of this method for compound-specific applications in a number of fields including metabolic, ecological and palaeodietary studies.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 64,
                "text": "collagen"
            }
        },
        {
            "context": "K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association. K201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial. It is believed to stabilize the closed state of the RyR2 (cardiac ryanodine receptor) by increasing its affinity for the FKBP12.6 (12.6 kDa FK506 binding protein) [Wehrens, Lehnart, Reiken, Deng, Vest, Cervantes, Coromilas, Landry and Marks (2004) Science 304, 292-296]. In the present study, we investigated the effect of K201 on spontaneous Ca2+ release induced by Ca2+ overload in rat ventricular myocytes and in HEK-293 cells (human embryonic kidney cells) expressing RyR2 and the role of FKBP12.6 in the action of K201. We found that K201 abolished spontaneous Ca2+ release in cardiac myocytes in a concentration-dependent manner. Treating ventricular myocytes with FK506 to dissociate FKBP12.6 from RyR2 did not affect the suppression of spontaneous Ca2+ release by K201. Similarly, K201 was able to suppress spontaneous Ca2+ release in FK506-treated HEK-293 cells co-expressing RyR2 and FKBP12.6. Furthermore, K201 suppressed spontaneous Ca2+ release in HEK-293 cells expressing RyR2 alone and in cells co-expressing RyR2 and FKBP12.6 with the same potency. In addition, K201 inhibited [3H]ryanodine binding to RyR2-wt (wild-type) and an RyR2 mutant linked to ventricular tachycardia and sudden death, N4104K, in the absence of FKBP12.6. These observations demonstrate that FKBP12.6 is not involved in the inhibitory action of K201 on spontaneous Ca2+ release. Our results also suggest that suppression of spontaneous Ca2+ release and the activity of RyR2 contributes, at least in part, to the anti-arrhythmic properties of K201.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 139,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Viroids: petite RNA pathogens with distinguished talents. Viroids are small, circular, single-stranded RNA molecules that cause several infectious plant diseases. Viroids do not encode any pathogen-specific peptides but nonetheless, the subviral pathogens replicate autonomously and spread in the plant by recruiting host proteins via functional motifs encoded in their RNA genome. During the past couple of years, considerable progress has been made towards comprehending how viroids interact with their hosts. Here, we summarize recent findings on the structure-function relationships of viroids, their strategies and mechanisms of replication and trafficking, and the identification and characterization of interacting host proteins. We also describe the impact of the RNA silencing machinery of plants on viroid RNAs and how this has started to influence our models of viroid replication and pathogenicity.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 0,
                "text": "Viroids"
            }
        },
        {
            "context": "Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos. The Dishevelled protein mediates several diverse biological processes. Intriguingly, within the same tissues where Xenopus Dishevelled (Xdsh) controls cell fate via canonical Wnt signaling, it also controls cell polarity via the vertebrate planar cell polarity (PCP) cascade [1, 2, 3, 4, 5, 6, 7, 8 and 9]. The relationship between subcellular localization of Dishevelled and its signaling activities remains unclear; conflicting results have been reported depending upon the organism and cell types examined [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20]. We have approached this issue by developing new reagents to sequester wild-type Dishevelled protein either at the cell membrane or away from the cell membrane. Removal of Dishevelled from the cell membrane disrupts convergent extension by preventing Rho/Rac activation and mediolateral cell polarization. By manipulating the subcellular localization of K-->M (dsh1), we show that this mutation inhibits Dishevelled activation of Rac, regardless of its subcellular localization. These data demonstrate that membrane localization of Dishevelled is a prerequisite for vertebrate PCP signaling. However, both membrane-targeted and cytoplasm-targeted Dishevelled can potently activate canonical Wnt signaling, suggesting that local concentration of Dishevelled protein, but not its spatial localization, is central to canonical Wnt signaling. These results suggest that in vertebrate embryos, subcellular localization is insufficient to account for the pathway specificity of Dishevelled in the canonical Wnt versus PCP signaling cascades.",
            "question": "Which signaling pathway is activating the dishevelled proteins?",
            "answers": {
                "answer_start": 274,
                "text": "Wnt signaling"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1214,
                "text": "CD38"
            }
        },
        {
            "context": "Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis in mammals. Mutations at a single N-glycosylation sequon of tyrosinase have been reported to be responsible for oculocutaneous albinism type IA in humans, characterized by inactive tyrosinase and the total absence of pigmentation. To probe the role that each N-glycosylation site plays in the synthesis of biologically active tyrosinase, we analyzed the calnexin mediated folding of tyrosinase N-glycosylation mutants. We have determined that four of the six potential N-glycosylation sites, including that associated with albinism, are occupied. Analysis of the folding pathway and activity of 15 tyrosinase mutants lacking one or more of the occupied N-glycosylation sites shows that glycans at any two N-glycosylation sites are sufficient to interact with calnexin and give partial activity, but a specific pair of sites (Asn(86) and Asn(371)) is required for full activity. The mutants with less than two N-glycosylation sites do not interact with calnexin and show a complete absence of enzyme activity. Copper analysis of selected mutants suggests that the observed partial activity is due to two populations with differential copper content. By correlating the degree of folding with the activity of tyrosinase, we propose a local folding mechanism for tyrosinase that can explain the mechanism of inactivation of tyrosinase N-glycosylation mutants found in certain pigmentation disorders.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 370,
                "text": "tyr"
            }
        },
        {
            "context": "Discovering viroids--a personal perspective. During 1970 and 1971, I discovered that a devastating disease of potato plants is not caused by a virus, as had been assumed, but by a new type of subviral pathogen, the viroid. Viroids are so small--one fiftieth of the size of the smallest viruses--that many scientists initially doubted their existence. We now know that viroids cause many damaging diseases of crop plants. Fortunately, new methods that are based on the unique properties of viroids now promise effective control.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 223,
                "text": "Viroids"
            }
        },
        {
            "context": "In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 1150,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Two regions within the amino-terminal half of APOBEC3G cooperate to determine cytoplasmic localization. APOBEC3G limits the replication of human immunodeficiency virus type 1, other retroviruses, and retrotransposons. It localizes predominantly to the cytoplasm of cells, which is consistent with a model wherein cytosolic APOBEC3G packages into assembling virions, where it exerts its antiviral effect by deaminating viral cDNA cytosines during reverse transcription. To define the domains of APOBEC3G that determine cytoplasmic localization, comparisons were made with APOBEC3B, which is predominantly nuclear. APOBEC3G/APOBEC3B chimeric proteins mapped a primary subcellular localization determinant to a region within the first 60 residues of each protein. A panel of 25 APOBEC3G mutants, each with a residue replaced by the corresponding amino acid of APOBEC3B, revealed that several positions within this region were particularly important, with Y19D showing the largest effect. The mislocalization phenotype of these mutants was only apparent in the context of the amino-terminal half of APOBEC3G and not the full-length protein, suggesting the existence of an additional localization determinant. Indeed, a panel of five single amino acid substitutions within the region from amino acids 113 to 128 had little effect by themselves but, in combination with Y19D, two substitutions-F126S and W127A-caused full-length APOBEC3G to redistribute throughout the cell. The critical localization-determining residues were predicted to cluster on a common solvent-exposed surface, suggesting a model in which these two regions of APOBEC3G combine to mediate an intermolecular interaction that controls subcellular localization.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 603,
                "text": " nuclear"
            }
        },
        {
            "context": "Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 49,
                "text": "Rabies"
            }
        },
        {
            "context": "Antigenotoxic effects of p53 on spontaneous and ultraviolet light B--induced deletions in the epidermis of gpt delta transgenic mice. Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as \"the guardian of the genome.\" To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(+/+) mice. However, no increase of such large deletions was observed in irradiated p53(-/-) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 250,
                "text": "p53"
            }
        },
        {
            "context": "Pharmacokinetics, Safety, and Tolerability of Glecaprevir and Pibrentasvir in Healthy White, Chinese, and Japanese Adult Subjects. Glecaprevir and pibrentasvir are direct-acting antiviral agents being developed as combination therapy for the treatment of chronic hepatitis C virus infection. The aim of the present studies was to assess the effect of race and ethnicity (white, Han Chinese, Japanese) on the pharmacokinetics and safety of multiple oral doses of glecaprevir and pibrentasvir given alone and in combination. Two multiple-dose, single-center, phase 1 studies were conducted in healthy adult male and female subjects (n = 170) of respective Asian and white race/ethnicity. Glecaprevir (100, 200, 300, or 700 mg once daily) and pibrentasvir (80, 120, or 160 mg once daily) were administered alone for 7 days followed by the combination of both direct-acting antiviral agents for another 7 days. Intensive blood sampling was performed, and pharmacokinetic parameters were estimated by noncompartmental analyses. ANOVA was employed to evaluate for differences of steady-state glecaprevir and pibrentasvir exposures between Asian (Japanese or Han Chinese) and white subjects. Glecaprevir and pibrentasvir exposures in Han Chinese and Japanese were similar to those in whites across dose levels. The nonlinear dose-exposure relationships for glecaprevir and pibrentasvir were similar across Japanese, Han Chinese, and white subjects, and the safety profiles of the agents were comparable across these groups. The results of these studies demonstrate that race/ethnicity has no clinically meaningful impact on direct-acting antiviral agent exposures, safety, or tolerability of the glecaprevir and pibrentasvir combination. This is supported in part by the large global registration program of the pangenotypic, coformulated fixed-dose glecaprevir/pibrentasvir regimen and allows for inclusion of diverse ethnic populations.",
            "question": "Glecaprevir and Pibrentasvir are used for tratment of which disease?",
            "answers": {
                "answer_start": 263,
                "text": "hepatitis C virus infection"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 2843,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Human Rabies: a 2016 Update. Rabies is a zoonotic disease that is usually transmitted to humans by animal bites. Dogs are the most important vector worldwide. There are encephalitic and paralytic forms of the disease. There are differences in the clinical features of the disease acquired from dogs and bats. Neuroimaging is non-specific. Confirmatory diagnostic laboratory tests for rabies include detection of neutralizing anti-rabies virus antibodies in serum or cerebrospinal fluid and rabies virus antigen or RNA in tissues or fluids. Rabies is preventable after recognized exposures with wound cleansing and administration of rabies vaccine and rabies immune globulin. Rabies is virtually always fatal after clinical disease develops, and there have only been rare survivors. The Milwaukee protocol, which includes therapeutic coma, has been shown to be ineffective and should no longer be used. The development of novel therapeutic approaches may depend on a better understanding of basic mechanisms underlying the disease.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 675,
                "text": "Rabies"
            }
        },
        {
            "context": "Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine. Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r > 0.99. The assay demonstrated accuracy > 80% and precision < 20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 427,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Discovery of an antibody for pan-ebolavirus therapy. During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. However, due to the antigenic differences among the five ebolavirus species, the current therapeutic monoclonal antibodies are only effective against viruses of the species Zaire ebolavirus. Although this particular species has indeed caused the majority of human infections in Central and, recently, West Africa, other ebolavirus species (e.g., Sudan ebolavirus and Bundibugyo ebolavirus) have also repeatedly caused outbreaks in Central Africa and thus should not be neglected in the development of countermeasures against ebolaviruses. Here we report the generation of an ebolavirus glycoprotein-specific monoclonal antibody that effectively inhibits cellular entry of representative isolates of all known ebolavirus species in vitro and show its protective efficacy in mouse models of ebolavirus infections. This novel neutralizing monoclonal antibody targets a highly conserved internal fusion loop in the glycoprotein molecule and prevents membrane fusion of the viral envelope with cellular membranes. The discovery of this highly cross-neutralizing antibody provides a promising option for broad-acting ebolavirus antibody therapy and will accelerate the design of improved vaccines that can selectively elicit cross-neutralizing antibodies against multiple species of ebolaviruses.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 83,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 664,
                "text": "5-HT2A"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "A randomized trial of intraarterial treatment for acute ischemic stroke. BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 1948,
                "text": "acute ischemic stroke"
            }
        },
        {
            "context": "Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy. The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 729,
                "text": "Cardiotoxicity"
            }
        },
        {
            "context": "Delamanid for multidrug-resistant pulmonary tuberculosis. BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 44,
                "text": "tuberculosis"
            }
        },
        {
            "context": "A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 1008,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Ancient duplicated conserved noncoding elements in vertebrates: a genomic and functional analysis. Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Although most of these elements share little sequence identity to each other, a small number are remarkably similar and appear to be the product of duplication events. Here, we searched for duplicated conserved noncoding elements in the human genome, using comparisons with Fugu to select putative cis-regulatory sequences. We identified 124 families of duplicated elements, each containing between two and five members, that are highly conserved within and between vertebrate genomes. In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family, thus removing much of the ambiguity in identifying associated genes. We find that duplicate elements have the potential to up-regulate reporter gene expression in a tissue-specific manner and that expression domains often overlap, but are not necessarily identical, between family members. Over two thirds of the families are conserved in duplicate in fish and appear to predate the large-scale duplication events thought to have occurred at the origin of vertebrates. We propose a model whereby gene duplication and the evolution of cis-regulatory elements can be considered in the context of increased morphological diversity and the emergence of the modern vertebrate body plan.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 1028,
                "text": "development"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 424,
                "text": "CD38"
            }
        },
        {
            "context": "Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.",
            "question": "Which properties of the mRNA does N6-methyladenosine (m6A) affect?",
            "answers": {
                "answer_start": 744,
                "text": "mRNA stability"
            }
        },
        {
            "context": "Onyx 18 embolisation of dural arteriovenous fistula via arterial and venous pathways: preliminary experience and evaluation of the short-term outcomes. OBJECTIVE: This paper mainly focuses on our preliminary experience and short-term outcome evaluation of embolisation of non-cavernous dural arteriovenous fistulas (ncsDAVFs) and cavernous sinus dural arteriovenous fistulas (csDAVFs) using Onyx 18 (ev3, Plymouth, MN), and in combination with coils, via arterial and venous approaches, respectively. METHODS: Between August 2008 and March 2010, 21 DAVFs (11 ncsDAVFs and 10 csDAVFs; age range: 28-68 years; 12 females and 9 males) were undertaken. Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs. Onyx 18 was used in 11 ncsDAVFs (10 via single feeder and 1 via 2 feeders). Onyx 18 or in combination with coils was used in 10 csDAVFs (9 via the inferior petrosal sinus and 1 via the superior ophthalmic vein). RESULTS: Total occlusion in immediate angiography was achieved in 18 cases (85.7%; 10 ncsDAVFs and 8 csDAVFs), and near-total occlusion in 1 ncsDAVF and 2 csDAVFs. Onyx 18 was migrated into normal vasculature in two ncsDAVFs without any sequelae. One csDAVF had VI cranial nerve palsy post-operatively, which completely recovered 2 weeks post-embolisation. Follow-up angiography at 3-12 months showed complete occlusion in 20 cases (95.2%; 10 ncsDAVFs and 10 csDAVFs). One ncsDAVF (4.8%) recurred after 3 months and was successfully re-embolised. CONCLUSION: Preliminary results achieved after embolising 11 ncsDAVFs and 10 csDAVFs using Onyx 18 and in combination with coils via arterial and venous pathways, respectively, appeared to be safe, feasible and effective, as 95.2% of cases were totally occluded without any clinical sequelae.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 755,
                "text": "DAVF"
            }
        },
        {
            "context": "Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924. Cullin-RING ubiquitin ligases (CRLs) are responsible for the ubiquitination of many cellular proteins, thereby targeting them for proteasomal degradation. In most cases the substrates of the CRLs have not been identified, although many of those that are known have cancer relevance. MLN4924, an investigational small molecule that is a potent and selective inhibitor of the Nedd8-activating enzyme (NAE), is currently being explored in Phase I clinical trials. Inhibition of Nedd8-activating enzyme by MLN4924 prevents the conjugation of cullin proteins with NEDD8, resulting in inactivation of the entire family of CRLs. We have performed stable isotope labeling with amino acids in cell culture analysis of A375 melanoma cells treated with MLN4924 to identify new CRL substrates, confidently identifying and quantitating 5122-6012 proteins per time point. Proteins such as MLX, EID1, KLF5, ORC6L, MAGEA6, MORF4L2, MRFAP1, MORF4L1, and TAX1BP1 are rapidly stabilized by MLN4924, suggesting that they are novel CRL substrates. Proteins up-regulated at later times were also identified and siRNA against their corresponding genes were used to evaluate their influence on MLN4924-induced cell death. Thirty-eight proteins were identified as being particularly important for the cytotoxicity of MLN4924. Strikingly, these proteins had roles in cell cycle, DNA damage repair, and ubiquitin transfer. Therefore, the combination of RNAi with stable isotope labeling with amino acids in cell culture provides a paradigm for understanding the mechanism of action of novel agents affecting the ubiquitin proteasome system and a path to identifying mechanistic biomarkers.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 597,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 287,
                "text": "FBN1"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 601,
                "text": "Hsp90"
            }
        },
        {
            "context": "Endoplasmic reticulum calcium pumps and cancer. Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as \"house-keeping\" functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA-dependent calcium transport is the only calcium uptake mechanism in this organelle, and therefore the regulation of SERCA function by the cell constitutes a key mechanism to adjust calcium homeostasis in the endoplasmic reticulum depending on the cell type and its state of differentiation. The direct pharmacological modulation of SERCA activity affects cell differentiation and survival. SERCA expression levels can undergo significant changes during cell differentiation or tumorigenesis, leading to modified endoplasmic reticulum calcium storage. In several cell types such as cells of hematopoietic origin or various epithelial cells, two SERCA genes (SERCA2 and SERCA3) are simultaneously expressed. Expression levels of SERCA3, a lower calcium affinity calcium pump are highly variable. In several cell systems SERCA3 expression is selectively induced during differentiation, whereas during tumorigenesis and blastic transformation SERCA3 expression is decreased. These observations point at the existence of a cross-talk, via the regulation of SERCA3 levels, between endoplasmic reticulum calcium homeostasis and the control of cell differentiation, and show that endoplasmic reticulum calcium homeostasis itself can undergo remodeling during differentiation. The investigation of the anomalies of endoplasmic reticulum differentiation in tumor and leukemia cells may be useful for a better understanding of the contribution of calcium signaling to the establishment of malignant phenotypes.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 374,
                "text": "SERCA"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 596,
                "text": "xa"
            }
        },
        {
            "context": "[Screening of FBN1 gene mutations in a family with Marfan syndrome]. OBJECTIVE: To identify FBN1 gene mutations in a Chinese family with Marfan syndrome. METHODS: Four affected and two unaffected individuals in the family were recruited after informed consent. Five ml blood samples were drawn from each family member and genomic DNA was extracted. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of FBN1 gene. Polyphen program was used to predict the functional and structural changes of the mutant protein. RESULTS: We found all four affected individuals carried FBN1gene mutations, c.2261A > G (p.Y754C), in exon18 by sequence analysis, while two unaffected family members and 100 normal controls did not have this mutation. A PSIC score of 2.6 was acquired by Polyphen program analysis. CONCLUSION: Our study supports that FBN1 gene mutation, c.2261A > G (p.Y754C), is the underlying molecular pathogenesis of this family with Marfan syndrome. This mutation is identified for the first time in Chinese population.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 14,
                "text": "FBN1"
            }
        },
        {
            "context": "Genetic mapping of \"Lubag\" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome. \"Lubag\" is an X-linked disorder causing dystonia and parkinsonism that has only been described in families from the Philippines, principally from the island of Panay. We have established linkage between the disease phenotype \"lubag\" and DNA markers which span the Xp11.22-Xq21.3 region by using a large Filipino family with 8 affected men in three generations. These DNA markers define an interval of about 20 centimorgans in the pericentromeric region of the X chromosome as the most likely site of the disease locus XDPD (X-linked dystonia-parkinsonism). XDPD has a maximum multipoint log likelihood ratio score (Zmax) of about 4.6 over the interval from Xq12 to Xq21.31 (DXS159-DXYS1X). The co-occurrence of dystonia and parkinsonism in lubag and in other known disorders suggests there may be a common pathogenetic mechanism. Identification of the genetic defect in this family may provide an important clue toward understanding the pathogenesis and pathophysiology of both dystonia and parkinsonism.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 28,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "A Study to Determine if Addition of Palatal Petechiae to Centor Criteria Adds More Significance to Clinical Diagnosis of Acute Strep Pharyngitis in Children. Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 564,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Mepolizumab treatment in patients with severe eosinophilic asthma. BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 628,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L.) 11. Molecular cloning and expression of alfalfa isoflavone reductase, a key enzyme of isoflavonoid phytoalexin biosynthesis. The major phytoalexin in alfalfa is the isoflavonoid (-)-medicarpin (or 6aR, 11aR)-medicarpin. Isoflavone reductase (IFR), the penultimate enzyme in medicarpin biosynthesis, is responsible for introducing one of two chiral centers in (-)-medicarpin. We have isolated a 1.18 kb alfalfa cDNA (pIFRalf1) which, when expressed in Escherichia coli, converts 2'-hydroxyformononetin stereospecifically to (3R)-vestitone, as would be predicted for IFR from alfalfa. The calculated molecular weight of the polypeptide (35,400) derived from the 954 bp open reading frame compares favorably to estimated Mrs determined for IFR proteins purified from other legumes. The transcript (1.4 kb) is highly induced in elicited alfalfa cell cultures. The kinetics of induction are consistent with the appearance of IFR activity, the accumulation of medicarpin, and the observed induction of other enzymes in the pathway. Low levels of IFR transcripts were found in healthy plant parts (roots and nodules) which accumulate low levels of a medicarpin glucoside. IFR appears to be encoded by a single gene in alfalfa. The cloning of IFR opens up the possibility of genetic manipulation of phytoalexin biosynthesis in alfalfa by altering isoflavonoid stereochemistry.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 257,
                "text": "medicarpin"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 432,
                "text": "CD38"
            }
        },
        {
            "context": "Flumazenil's reversal of myoclonic-like movements associated with midazolam in term newborns. Sedation is an important aspect of care for critically ill newborns. Proper sedation reduces stress during procedures such as mechanical ventilation. Midazolam, a short-acting benzodiazepine, is widely administered as a sedative in newborn intensive care units but is not without side effects. Three term newborns developed myoclonic-like abnormal movements after receiving midazolam. In one, flumazenil controlled the abnormal movements. Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose. Flumazenil may be considered in cases of abnormal movements associated with midazolam. However, further studies are needed to provide guidelines for the administration of this drug in newborns.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 533,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Involvement of cardiomyocyte apoptosis in myocardial injury of hereditary epileptic rats. Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax). Catecholamine level was detected by HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were up-regulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondria-initiated and the mitogen-activated protein kinase pathways.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 912,
                "text": "JNK"
            }
        },
        {
            "context": "RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation. RAP80, a nuclear protein with two functional ubiquitin-interaction motifs (UIMs) at its N-terminus, plays a critical role in the regulation of estrogen receptor alpha and DNA damage response signaling. A yeast two-hybrid screen identified the SUMO-conjugating enzyme UBC9 as a protein interacting with RAP80. The interaction of RAP80 with UBC9 was confirmed by co-immunoprecipitation and GST pull-down analyses. The region between aa 122-204 was critical for the interaction of RAP80 with UBC9. In addition, we demonstrate that RAP80 is a target for SUMO-1 modification in intact cells. Expression of UBC9 enhanced RAP80 mono-sumoylation and also induced multi-sumoylation of RAP80. In addition to SUMO-1, RAP80 was efficiently conjugated to SUMO-3 but was only a weak substrate for SUMO-2 conjugation. These findings suggest that sumoylation plays a role in the regulation of RAP80 functions.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 25,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1348,
                "text": "CD38"
            }
        },
        {
            "context": "Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1708,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks. Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 464,
                "text": "telomerase"
            }
        },
        {
            "context": "Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73gamma in lung cancer. The p73 gene possesses an extrinsic P1 promoter and an intrinsic P2 promoter, resulting in TAp73 and DeltaNup73 isoforms, respectively. The ultimate effect of p73 in oncogenesis is thought to depend on the apoptotic TA to antiapoptotic DeltaN isoforms' ratio. This study was aimed at identifying novel transcription factors that affect TA isoform synthesis. With the use of bioinformatics tools, in vitro binding assays, and chromatin immunoprecipitation analysis, a region extending -233 to -204 bp upstream of the transcription start site of the human p73 P1 promoter, containing conserved Sp1-binding sites, was characterized. Treatment of cells with Sp1 RNAi and Sp1 inhibitor functionally suppress TAp73 expression, indicating positive regulation of P1 by the Sp1 protein. Notably Sp1 inhibition or knockdown also reduces DeltaNup73 protein levels. Therefore, Sp1 directly regulates TAp73 transcription and affects DeltaNup73 levels in lung cancer. TAp73gamma was shown to be the only TA isoform overexpressed in several lung cancer cell lines and in 26 non-small cell lung cancers, consistent with Sp1 overexpression, thereby questioning the apoptotic role of this specific p73 isoform in lung cancer.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 113,
                "text": "7"
            }
        },
        {
            "context": "A novel frameshift mutation in the McLeod syndrome gene in a Japanese family. We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome. A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis. The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK. This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408. We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 474,
                "text": "XK"
            }
        },
        {
            "context": "Atrial fibrillation. Atrial fibrillation is the most common arrhythmia affecting patients today. Disease prevalence is increasing at an alarming rate worldwide, and is associated with often catastrophic and costly consequences, including heart failure, syncope, dementia, and stroke. Therapies including anticoagulants, anti-arrhythmic medications, devices, and non-pharmacologic procedures in the last 30 years have improved patients' functionality with the disease. Nonetheless, it remains imperative that further research into AF epidemiology, genetics, detection, and treatments continues to push forward rapidly as the worldwide population ages dramatically over the next 20 years.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 71,
                "text": "af"
            }
        },
        {
            "context": "Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. CONTEXT: The molecular pathogenesis of primary hyperparathyroidism is still largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene has a major role in the pathogenesis of familial isolated pituitary adenoma. OBJECTIVE: We evaluated the involvement of the AIP gene in sporadic parathyroid adenomas. PATIENTS AND DESIGN: We performed direct sequencing and multiplex ligation-dependent probe amplification analyses of the AIP gene in a large series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP locus was studied, and aryl hydrocarbon receptor interacting protein immunostaining was also performed. In addition, alterations in the MEN1 gene were studied. RESULTS: A somatic AIP mutation, substitution of arginine with glutamine at codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline in both cases despite the nonfamilial presentation. Heterozygous AIP large deletions were detected in 29 cases including 1 of the 2 mutated tumors, confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at the MEN1 locus, which often shared LOH at the AIP locus, was found in one third of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 patient. CONCLUSIONS: The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 206,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "Postdural puncture headache. Postdural puncture headache (PDPH) has been a problem for patients, following dural puncture, since August Bier reported the first case in 1898. His paper discussed the pathophysiology of low-pressure headache resulting from leakage of cerebrospinal fluid (CSF) from the subarachnoid to the epidural space. Clinical and laboratory research over the last 30 years has shown that use of small-gauge needles, particularly of the pencil-point design, is associated with a lower risk of PDPH than traditional cutting point needle tips (Quincke-point needle). A careful history can rule out other causes of headache. A postural component of headache is the sine qua non of PDPH. In high-risk patients , for example, age < 50 years, postpartum, large-gauge needle puncture, epidural blood patch should be performed within 24-48 h of dural puncture. The optimum volume of blood has been shown to be 12-20 mL for adult patients. Complications of AEBP are rare.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 796,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 152,
                "text": "xa"
            }
        },
        {
            "context": "Relevant Cytokines in the Management of Community-Acquired Pneumonia. Community-acquired pneumonia (CAP) is the leading cause of infectious death in the world. Immune dysregulation during acute lung infection plays a role in lung injury and the systemic inflammatory response. Cytokines seem to be major players in severe lung infection cases. Here, we present a review of published papers in the last 3 years regarding this topic. The cytokine response during pneumonia is different in bacterial vs viral infections; some of these cytokines correlate with clinical severity scales such as CURB65 or SOFA. Treatment focused in the cytokine environment is an interesting area that could impact the prognosis of CAP. Some of the agents that have been studied as co-adjuvant therapy are corticosteroids, macrolides, and linezolid, but anyone of those have shown a clear or proven efficacy or have been recommended as a part of the standard of care for CAP. More studies designed to define the role of immunomodulatory agents, such as co-adjuvant therapy in pneumonia, are needed.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 461,
                "text": "pneumonia"
            }
        },
        {
            "context": "Dissecting the genetic basis of myoclonic-astatic epilepsy. Herman Doose first described the generalized childhood epilepsy syndrome of myoclonic astatic epilepsy (MAE) in 1970, attributing a genetic cause from this first description. However, although the International League Against Epilepsy (ILAE) defined criteria for MAE in 1989, the diagnostic boundaries of the syndrome continue to be debated. Moreover, 40 years since Doose's first description of MAE, although a genetic predisposition is acknowledged and many studies have demonstrated familial aggregation of seizures within MAE families, the actual genetic determinants of MAE still remain unknown. Although initially thought to be within the same spectrum as severe myoclonic epilepsy of infancy, the exclusion of SCN1A mutations in non-generalized epilepsy with febrile seizures plus (GEFS+) MAE cases has confirmed the genetic distinction of MAE. In this critical review, we shall trace the historical evolution of concepts around MAE and its distinction from Lennox-Gastaut syndrome, review the described phenotypic features of MAE from updated studies that will allow its distinction from other overlap epilepsy syndromes, review the evidence of genetic influences and clues for genetic heterogeneity, and discuss strategies that may be helpful in elucidating the etiology of MAE in light of current genetic techniques.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 136,
                "text": "myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review. Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 664,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabon. BACKGROUND: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion--based formulation (AS02) and a formulation based on liposomes (AS01). METHODS & PRINCIPAL FINDINGS: In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01(E) or RTS,S/AS02(D), on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02(D)/AS01(E)) of 0.88 (95% CI: 0.68-1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated. CONCLUSIONS: RTS,S/AS01(E) proved similarly as well tolerated and immunogenic as RTS,S/AS02(D), completing an essential step in the age de-escalation process within the RTS,S clinical development plan. TRIAL REGISTRATION: ClinicalTrials.gov. NCT00307021.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 93,
                "text": "malaria"
            }
        },
        {
            "context": "Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.",
            "question": "Does dasatinib promote or inhibit T-cell proliferation?",
            "answers": {
                "answer_start": 557,
                "text": "inhibits"
            }
        },
        {
            "context": "Early discharge of patients with presumed opioid overdose: development of a clinical prediction rule. OBJECTIVE: To develop a clinical prediction rule to identify patients who can be safely discharged one hour after the administration of naloxone for presumed opioid overdose. METHODS: Patients who received naloxone for known or presumed opioid overdose were formally evaluated one hour later for multiple potential predictor variables. Patients were classified into two groups: those with adverse events within 24 hours and those without. Using classification and regression tree methodology, a decision rule was developed to predict safe discharge. RESULTS: Clinical findings from 573 patients allowed us to develop a clinical prediction rule with a sensitivity of 99% (95% CI = 96% to 100%) and a specificity of 40% (95% CI = 36% to 45%). Patients with presumed opioid overdose can be safely discharged one hour after naloxone administration if they: 1) can mobilize as usual; 2) have oxygen saturation on room air of >92%; 3) have a respiratory rate >10 breaths/min and <20 breaths/min; 4) have a temperature of >35.0 degrees C and <37.5 degrees C; 5) have a heart rate >50 beats/min and <100 beats/min; and 6) have a Glasgow Coma Scale score of 15. CONCLUSIONS: This prediction rule for safe early discharge of patients with presumed opioid overdose performs well in this derivation set but requires validation followed by confirmation of safe implementation.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 922,
                "text": "naloxone"
            }
        },
        {
            "context": "Specificity and function of archaeal DNA replication initiator proteins. Chromosomes with multiple DNA replication origins are a hallmark of Eukaryotes and some Archaea. All eukaryal nuclear replication origins are defined by the origin recognition complex (ORC) that recruits the replicative helicase MCM(2-7) via Cdc6 and Cdt1. We find that the three origins in the single chromosome of the archaeon Sulfolobus islandicus are specified by distinct initiation factors. While two origins are dependent on archaeal homologs of eukaryal Orc1 and Cdc6, the third origin is instead reliant on an archaeal Cdt1 homolog. We exploit the nonessential nature of the orc1-1 gene to investigate the role of ATP binding and hydrolysis in initiator function in vivo and in vitro. We find that the ATP-bound form of Orc1-1 is proficient for replication and implicates hydrolysis of ATP in downregulation of origin activity. Finally, we reveal that ATP and DNA binding by Orc1-1 remodels the protein's structure rather than that of the DNA template.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 90,
                "text": "multiple"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 969,
                "text": "LARVA"
            }
        },
        {
            "context": "Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 486,
                "text": "xa"
            }
        },
        {
            "context": "Spontaneous resolution of invasive cerebral aspergillosis following partial resection in a medically untreated infant. Invasive craniocerebral aspergillosis, often encountered in an immunocompromised setting, is almost uniformly fatal despite radical surgical and medical management, and is frequently a necropsy finding. The authors report a unique, self-resolving clinical course of this aggressive infection in a 10-month-old infant. The infant was brought to the emergency services in altered sensorium with a 1-week history of left-sided hemiparesis, excessive irritability, and vomiting. An MRI study of the brain revealed multiple, heterogeneously enhancing lesions in the right cerebral hemisphere with mass effect. The largest lesion in the frontotemporal cortical and subcortical regions was decompressed on an emergent basis. Histopathological findings were suggestive of invasive aspergillosis, although there was no evidence of the infection in the lungs or paranasal sinuses. Computed tomography-guided aspiration of the remaining lesions and follow-up antifungal therapy were recommended. The parents, however, requested discharge without further treatment. The child was seen at a follow-up visit 3 years later without having received any antifungal treatment. Imaging showed resolution of the infection and features of Dyke-Davidoff-Masson syndrome (cerebral hemiatrophy). This report of invasive cerebral aspergillosis resolving without medical therapy is the first of its kind. Its clinicoradiological aspects are discussed in light of previously reported cases.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 1367,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristics of the BD GeneOhm MRSA assay, the Xpert MRSA assay, and broth-enriched culture in an area with a low prevalence of MRSA infections. Universal surveillance upon patient admission is important in reducing the transmission of methicillin-resistant Staphylococcus aureus (MRSA) and associated disease in hospitals. High costs for the health care system in conjunction with MRSA have promoted the development of rapid screening methods to detect MRSA carriers. This study compared two real-time PCR methods, the BD GeneOhm MRSA assay (BDGO) and the Xpert MRSA assay, with broth-enriched culture to define their performance characteristics and rapidity in an area with low MRSA prevalence. In total, 414 swabs from the nose and 389 swabs from the groin from 425 patients were tested. Of those 425 patients, 378 had swabs from both the nose and groin in parallel. Two hundred thirty-one and 194 patients were randomly assigned to the BDGO group and the Xpert MRSA group, respectively. In general, sensitivity, specificity, and negative predictive value (NPV) were high for the BDGO (100%, 98.5%, and 100%, respectively) and the Xpert MRSA (100%, 98.2%, and 100%, respectively), irrespective of whether or not nasal and inguinal specimens were considered alone or combined. In contrast, the positive predictive value (PPV) was lower: before the resolution of discrepant results, the PPVs for nasal and inguinal specimens alone and combined were 87.5%, 86.7%, and 82.4% for the BDGO and 91.7%, 66.7%, and 92.9% for the Xpert MRSA, respectively. After the resolution of discrepant results, PPVs were 93.8%, 93.3% and 94.1% for the BDGO and 91.7%, 88.9% and 92.9% for the Xpert MRSA, respectively. With the BDGO, 4 of 16 carriers were each identified by nasal or inguinal swabs alone, whereas in the Xpert MRSA group, 4 of 13 carriers were exclusively identified by nasal swabs and 2 of 13 were identified by inguinal swabs alone. Both PCR methods showed no significant difference in the number of discrepant results (odds ratio, 0.70 [P = 0.789]), but specimens from wounds and other body sites (axilla, vagina, and throat) produced discrepancies more often than nasal and groin specimens (odds ratios, 4.724 [P = 0.058] and 12.163 [P < 0.001], respectively). The facts that no false-negative PCR results were detected and increased PPVs were found after the resolution of discrepant results point to PCR as the actual gold standard. Since both sensitivity and NPV were exceptionally high for PCR, backup cultures may, therefore, be unnecessary in an area with low prevalence and with a preemptive isolation strategy but may still be useful for PCR-positive specimens because of the lower PPV for both methods and the possibility of susceptibility testing. The median time for analysis, including extraction, hands-on time, and actual PCR was 2 h 20 min for the Xpert MRSA versus 5 h 40 min for the BDGO. Concerning reporting time, including administration and specimen collection, the Xpert MRSA was faster than the BDGO (7 h 50 min versus 17 h).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 245,
                "text": "MRSA"
            }
        },
        {
            "context": "Immunodetection of human double homeobox 4. Double homeobox 4 (DUX4) is a candidate disease gene for facioscapulohumeral dystrophy (FSHD), one of the most common muscular dystrophies characterized by progressive skeletal muscle degeneration. Despite great strides in understanding precise genetics of FSHD, the molecular pathophysiology of the disease remains unclear. One of the major limitations has been the availability of appropriate molecular tools to study DUX4 protein. In the present study, we report the development of five new monoclonal antibodies targeted against the N- and C-termini of human DUX4, and characterize their reactivity using Western blot and immunofluorescence staining. Additionally, we show that expression of the canonical full coding DUX4 induces cell death in human primary muscle cells, whereas the expression of a shorter splice form of DUX4 results in no such toxicity. Immunostaining with these new antibodies reveals a differential effect of two DUX4 isoforms on human muscle cells. These antibodies will provide an excellent tool for investigating the role of DUX4 in FSHD pathogenesis.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 101,
                "text": "facioscapulohumeral dystrophy"
            }
        },
        {
            "context": "SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 188,
                "text": "NCX"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 69,
                "text": "orexin"
            }
        },
        {
            "context": "[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 541,
                "text": "xa"
            }
        },
        {
            "context": "Analysis of deletions in three McLeod patients: exclusion of the XS locus from the Xp21.1-Xp21.2 region. The McLeod syndrome is a rare X-linked recessive disorder characterized by blood group, neuromuscular and haematopoietic abnormalities. It is caused by XK gene defects and may include large deletions in the Xp21 region. Analysis of three unrelated McLeod patients for the presence of the XK, DMD, CYBB, ETX1, RPGR and OTC loci, as well as for the DXS709 marker, revealed deletions from the 39th exon of DMD to the ETX1 locus (patient Be), from the XK to RPGR loci (patient Bi) and from the XK to CYBB loci (patient Lh). All three patients normally expressed the Lutheran (Lu) red cell antigens, thus excluding the interval between the RPGR and DMD genes as site of the XS locus, previously mapped to the Xp21.2-Xq21.1 region and thought to regulate the expression of the LU blood group gene on chromosome 19.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 257,
                "text": "XK"
            }
        },
        {
            "context": "Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 101,
                "text": "Thyroid transcription factor 1"
            }
        },
        {
            "context": "MicroRNA genes are transcribed by RNA polymerase II. MicroRNAs (miRNAs) constitute a large family of noncoding RNAs that function as guide molecules in diverse gene silencing pathways. Current efforts are focused on the regulatory function of miRNAs, while little is known about how these unusual genes themselves are regulated. Here we present the first direct evidence that miRNA genes are transcribed by RNA polymerase II (pol II). The primary miRNA transcripts (pri-miRNAs) contain cap structures as well as poly(A) tails, which are the unique properties of class II gene transcripts. The treatment of human cells with alpha-amanitin decreased the level of pri-miRNAs at a concentration that selectively inhibits pol II activity. Furthermore, chromatin immunoprecipitation analyses show that pol II is physically associated with a miRNA promoter. We also describe, for the first time, the detailed structure of a miRNA gene by determining the promoter and the terminator of mir-23a approximately 27a approximately 24-2. These data indicate that pol II is the main, if not the only, RNA polymerase for miRNA gene transcription. Our study offers a basis for understanding the structure and regulation of miRNA genes.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 34,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Mutational analysis of the U12-dependent branch site consensus sequence. Highly conserved sequences at the 5' splice site and branch site of U12-dependent introns are important determinants for splicing by U12-dependent spliceosomes. This study investigates the in vivo splicing phenotypes of mutations in the branch site consensus sequence of the U12-dependent intron F from a human NOL1 (P120) minigene. Intron F contains a fully consensus branch site sequence (UUCCUUAAC). Mutations at each position were analyzed for their effects on U12-dependent splicing in vivo. Mutations at most positions resulted in a significant reduction of correct U12-dependent splicing. Defects observed included increased unspliced RNA levels, the activation of cryptic U2-dependent 5' and 3' splice sites, and the activation of cryptic U12-dependent branch/3' splice sites. A strong correlation was observed between the predicted thermodynamic stability of the branch site: U12 snRNA interaction and correct U12-dependent splicing. The lack of a polypyrimidine tract between the branch site and 3' splice site of U12-dependent introns and the observed reliance on base-pairing interactions for correct U12-dependent splicing emphasize the importance of RNA/RNA interactions during U12-dependent intron recognition and proper splice site selection.",
            "question": "Which is the branch site consensus sequence in U12-dependent introns?",
            "answers": {
                "answer_start": 464,
                "text": "UUCCUUAAC"
            }
        },
        {
            "context": "Structural ramification for acetyl-lysine recognition by the bromodomain of human BRG1 protein, a central ATPase of the SWI/SNF remodeling complex. Bromodomains represent an extensive family of evolutionarily conserved domains that are found in many chromatin-associated proteins such as histone acetyltransferases (HAT) and subunits of ATP-dependent chromatin-remodeling complexes. These domains are associated with acetylated lysine residues that bind both in vivo and in vitro; for example, they bind to the N-acetylated lysines of the histone tail of nucleosomes. In this report, we determined the structure of the bromodomain from human brahma-related gene 1 (BRG1) protein, a subunit of an ATP-dependent switching/sucrose nonfermenting (SWI/SNF) remodeling complex, and have also characterized its in vitro interaction with N-acetylated lysine peptides from histones. In addition to a typical all-alpha-helical fold that was observed in the bromodomains, we observed for the first time a small beta-sheet in the ZA loop region of the BRG1 protein. The BRG1 bromodomain exhibited binding, albeit weak, to acetylated peptides that were derived from histones H3 and H4. We have compared the acetyl-lysine binding sites of BRG1 bromodomain with the yGCN5 (general control of amino acid biosynthesis). By modeling the acetylated-lysine peptide into the BRG1 bromodomain structure, we were able to explain the weak binding of acetylated-lysine peptides to this bromodomain.",
            "question": "What is the structural fold of bromodomain proteins?",
            "answers": {
                "answer_start": 899,
                "text": "all-alpha-helical fold"
            }
        },
        {
            "context": "Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 882,
                "text": "HIV"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1751,
                "text": "telomerase"
            }
        },
        {
            "context": "Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.",
            "question": "What is the role of eteplirsen in DMD patients?",
            "answers": {
                "answer_start": 325,
                "text": "skipping of dystrophin exon 51"
            }
        },
        {
            "context": "The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.",
            "question": "How is OCT3 associated with serotonin?",
            "answers": {
                "answer_start": 367,
                "text": "serotonin clearance"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 303,
                "text": "XK"
            }
        },
        {
            "context": "Fine mapping of the McLeod locus (XK) to a 150-380-kb region in Xp21. McLeod syndrome, characterized by acanthocytosis and the absence of a red-blood-cell Kell antigen (Kx), is a multisystem disorder involving a late-onset myopathy, splenomegaly, and neurological defects. The locus for this syndrome has been mapped, by deletion analysis, to a region between the loci for Duchenne muscular dystrophy (DMD) and chronic granulomatous disease (CGD). In this study, we describe a new marker, 3BH/R 0.3 (DXS 709), isolated by cloning the deletion breakpoint of a DMD patient. A long-range restriction map of Xp21, encompassing the gene loci for McLeod and CGD, was constructed, and multiple CpG islands were found clustered in a 700-kb region. Using the new marker, we have limited the McLeod syndrome critical region to 150-380-kb. Within this interval, two CpG-rich islands which may represent candidate sites for the McLeod gene were identified.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 34,
                "text": "XK"
            }
        },
        {
            "context": "A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz's disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 271,
                "text": "IgG4"
            }
        },
        {
            "context": "Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 618,
                "text": "ad"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 405,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Future options for ALK-positive non-small cell lung cancer. Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of 'targetable' genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in ALK-rearranged (-positive) disease. Crizotinib was the first ALK-TKI to undergo clinical development in ALK-positive advanced NSCLC, in which it has been shown to greatly outperform the best available chemotherapy regimen in either second- or first-line setting. More recently, the novel second-generation ALK-TKI ceritinib has been shown to be highly active in either crizotinib-pretreated or -naïve population. Nevertheless, as mechanisms of resistance to crizotinib and ALK-TKIs in general are being progressively elucidated, the treatment landscape of ALK-positive NSCLC is expected to evolve rapidly. In the present review we will briefly discuss the current knowledge of ALK-positive advanced non-small cell lung cancer. Also, we will touch upon new developments on drugs/combination regimens aimed at inhibiting the ALK-TK, in an attempt to delineate how treatment of ALK-positive disease may change in the next future.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 455,
                "text": "cancer"
            }
        },
        {
            "context": "N terminus of Swr1 binds to histone H2AZ and provides a platform for subunit assembly in the chromatin remodeling complex. Variant histone H2AZ-containing nucleosomes are involved in the regulation of gene expression. In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Previous work defined the role of seven SWR1 subunits (Swr1 ATPase, Swc2, Swc3, Arp6, Swc5, Yaf9, and Swc6) in maintaining complex integrity and H2AZ histone replacement activity. Here we examined the function of three additional SWR1 subunits, bromodomain containing Bdf1, actin-related protein Arp4 and Swc7, by analyzing affinity-purified mutant SWR1 complexes. We observed that depletion of Arp4 (arp4-td) substantially impaired the association of Bdf1, Yaf9, and Swc4. In contrast, loss of either Bdf1 or Swc7 had minimal effects on overall complex integrity. Furthermore, the basic H2AZ histone replacement activity of SWR1 in vitro required Arp4, but not Bdf1 or Swc7. Thus, three out of fourteen SWR1 subunits, Bdf1, Swc7, and previously noted Swc3, appear to have roles auxiliary to the basic histone replacement activity. The N-terminal region of the Swr1 ATPase subunit is necessary and sufficient to direct association of Bdf1 and Swc7, as well as Arp4, Act1, Yaf9 and Swc4. This same region contains an additional H2AZ-H2B specific binding site, distinct from the previously identified Swc2 subunit. These findings suggest that one SWR1 enzyme might be capable of binding two H2AZ-H2B dimers, and provide further insight on the hierarchy and interdependency of molecular interactions within the SWR1 complex.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 320,
                "text": "SWR1"
            }
        },
        {
            "context": "Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 52,
                "text": "MITF"
            }
        },
        {
            "context": "Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 291,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. BACKGROUND: Monoclonal antibodies (MoAbs) are increasingly integrated in the standard of care. The notion that therapeutic MoAbs can interfere with clinical laboratory tests is an emerging concern that requires immediate recognition and the development of appropriate solutions. Here, we describe that treatment of multiple myeloma patients with daratumumab, a novel anti-CD38 MoAb, resulted in false-positive indirect antiglobulin tests (IATs) for all patients for 2 to 6 months after infusion. This precluded the correct identification of irregular blood group antibodies for patients requiring blood transfusion. STUDY DESIGN AND METHODS: The IAT was performed using three- and 11-donor-cell panels. Interference of daratumumab and three other anti-CD38 MoAbs was studied using fresh-frozen plasma spiked with different MoAb concentrations. Additionally it was tested whether two potentially neutralizing agents, anti-idiotype antibody and recombinant soluble CD38 (sCD38) extracellular domain, were able to inhibit the interference. RESULTS: The CD38 MoAbs caused agglutination in the IAT in a dose-dependent manner. Addition of an excess of anti-idiotype antibodies or sCD38 protein to the test abrogated CD38 MoAb interference and successfully restored irregular antibody screening and identification. DISCUSSION: CD38 MoAb therapy causes false-positive results in the IAT. The reliability of the test could be restored by adding a neutralizing agent against the CD38 MoAb to the patient's plasma. This study emphasizes that during drug development, targeted therapeutics should be investigated for potential interference with laboratory tests. Clinical laboratories should be informed when patients receive MoAb treatments and matched laboratory tests to prevent interference should be employed.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 856,
                "text": "CD38"
            }
        },
        {
            "context": "Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. PURPOSE: To determine the reproducibility of measurements of brain 5-HT2A receptors with an [18F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects reproducibility and the required sample size. METHODS: For assessment of the variability, six subjects were investigated with [18F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [18F]altanserin PET studies in 84 healthy subjects. Regions of interest were automatically delineated on co-registered MR and PET images. RESULTS: In cortical brain regions with a high density of 5-HT2A receptors, the outcome parameter (binding potential, BP1) showed high reproducibility, with a median difference between the two group measurements of 6% (range 5-12%), whereas in regions with a low receptor density, BP1 reproducibility was lower, with a median difference of 17% (range 11-39%). Partial volume correction reduced the variability in the sample considerably. The sample size required to detect a 20% difference in brain regions with high receptor density is approximately 27, whereas for low receptor binding regions the required sample size is substantially higher. CONCLUSION: This study demonstrates that [18F]altanserin PET with a bolus/infusion design has very low variability, particularly in larger brain regions with high 5-HT2A receptor density. Moreover, partial volume correction considerably reduces the sample size required to detect regional changes between groups.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 201,
                "text": "5-HT2A"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 134,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Comparison of the Xpert methicillin-resistant Staphylococcus aureus (MRSA) assay, BD GeneOhm MRSA assay, and culture for detection of nasal and cutaneous groin colonization by MRSA. Detection of methicillin (meticillin)-resistant Staphylococcus aureus colonization was assessed using combined nose and groin swabs in two commercial PCR assays (the Xpert MRSA assay and the BD GeneOhm MRSA assay). Compared to routine culture, both had similar sensitivities (87.0% versus 84.8%, respectively) and specificities (93.8% versus 92.7%, respectively). Combined PCR assays provide a rapid and more-complete assessment of colonization at a cost similar to that of single-site analysis.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 93,
                "text": "MRSA"
            }
        },
        {
            "context": "Regulation of NF-κB by ubiquitination and degradation of the IκBs. The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3, β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have been worked out, the development of β-TrCP inhibitors might be a feasible therapeutic approach for NF-κB-associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β-TrCP in vivo.",
            "question": "Which is the E3 ubiquitin ligase which ubiquitinates IkB leading to its proteasomal degradation?",
            "answers": {
                "answer_start": 799,
                "text": "SCF(β-TrCP)"
            }
        },
        {
            "context": "Clinical features and management issues in Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 219,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "The NEDD8-activating enzyme inhibitor, MLN4924, cooperates with TRAIL to augment apoptosis through facilitating c-FLIP degradation in head and neck cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective cytokine with potential anticancer activity and is currently under clinical testing. Head and neck squamous cell carcinoma (HNSCC), like other cancer types, exhibits varied sensitivity to TRAIL. MLN4924 is a newly developed investigational small molecule inhibitor of NEDD8-activating enzyme with potent anticancer activity. This study reveals a novel function of MLN4924 in synergizing with TRAIL to induce apoptosis in HNSCC cells. MLN4924 alone effectively inhibited the growth of HNSCC cells and induced apoptosis. When combined with TRAIL, synergistic effects on decreasing the survival and inducing apoptosis of HNSCC cells occurred. MLN4924 decreased c-FLIP levels without modulating death receptor 4 and death receptor 5 expression. Enforced expression of c-FLIP substantially attenuated MLN4924/TRAIL-induced apoptosis. Thus c-FLIP reduction plays an important role in mediating MLN4924/TRAIL-induced apoptosis. Moreover, MLN4924 decreased c-FLIP stability, increased c-FLIP ubiquitination, and facilitated c-FLIP degradation, suggesting that MLN4924 decreases c-FLIP levels through promoting its degradation. MLN4924 activated c-jun-NH(2)-kinase (JNK) signaling, evidenced by increased levels of phospho-c-Jun in MLN4924-treated cells. Chemical inhibition of JNK activation not only prevented MLN4924-induced c-FLIP reduction, but also inhibited MLN4924/TRAIL-induced apoptosis, suggesting that JNK activation mediates c-FLIP downregulation and subsequent enhancement of TRAIL-induced apoptosis by MLN4924. Because knockdown of NEDD8 failed to activate JNK signaling and downregulate c-FLIP, it is likely that MLN4924 reduces c-FLIP levels and enhances TRAIL-induced apoptosis independent of NEDD8 inhibition.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 4,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "LHCII is an antenna of both photosystems after long-term acclimation. LHCII, the most abundant membrane protein on earth, is the major light-harvesting complex of plants. It is generally accepted that LHCII is associated with Photosystem II and only as a short-term response to overexcitation of PSII a subset moves to Photosystem I, triggered by its phosphorylation (state1 to state2 transition). However, here we show that in most natural light conditions LHCII serves as an antenna of both Photosystem I and Photosystem II and it is quantitatively demonstrated that this is required to achieve excitation balance between the two photosystems. This allows for acclimation to different light intensities simply by regulating the expression of LHCII genes only. It is demonstrated that indeed the amount of LHCII that is bound to both photosystems decreases when growth light intensity increases and vice versa. Finally, time-resolved fluorescence measurements on the photosynthetic thylakoid membranes show that LHCII is even a more efficient light harvester when associated with Photosystem I than with Photosystem II.",
            "question": "Which is the most abundant membrane protein on Earth?",
            "answers": {
                "answer_start": 70,
                "text": "LHCII"
            }
        },
        {
            "context": "c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 761,
                "text": "JNK"
            }
        },
        {
            "context": "Active site substitutions delineate distinct classes of eubacterial flap endonuclease. FENs (flap endonucleases) play essential roles in DNA replication, pivotally in the resolution of Okazaki fragments. In eubacteria, DNA PolI (polymerase I) contains a flap processing domain, the N-terminal 5'-->3' exonuclease. We present evidence of paralogous FEN-encoding genes present in many eubacteria. Two distinct classes of these independent FEN-encoding genes exist with four groups of eubacteria, being identified based on the number and type of FEN gene encoded. The respective proteins possess distinct motifs hallmarking their differentiation. Crucially, based on primary sequence and predicted secondary structural motifs, we reveal key differences at their active sites. These results are supported by biochemical characterization of two family members--ExoIX (exonuclease IX) from Escherichia coli and SaFEN (Staphylococcus aureus FEN). These proteins displayed marked differences in their ability to process a range of branched and linear DNA structures. On bifurcated substrates, SaFEN exhibited similar substrate specificity to previously characterized FENs. In quantitative exonuclease assays, SaFEN maintained a comparable activity with that reported for PolI. However, ExoIX showed no observable enzymatic activity. A threaded model is presented for SaFEN, demonstrating the probable interaction of this newly identified class of FEN with divalent metal ions and a branched DNA substrate. The results from the present study provide an intriguing model for the cellular role of these FEN sub-classes and illustrate the evolutionary importance of processing aberrant DNA, which has led to their maintenance alongside DNA PolI in many eubacteria.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 137,
                "text": "DNA replication"
            }
        },
        {
            "context": "Identification and functional analysis of a novel CaSR mutation in a family with familial hypocalciuric hypercalcemia. The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays an essential role in maintaining calcium homeostasis. In the present study, we analyzed the CaSR gene in a Korean family with familial hypocalciuric hypercalcemia (FHH). Genetic studies were performed by direct sequence analysis of the CaSR gene in genomic DNA obtained from peripheral leukocytes. A novel heterozygous G to T substitution at nucleotide position 1711 in exon 6, resulting in the G571W mutation, was identified in the CaSR gene in a 26-year-old female with asymptomatic hypercalcemia, a low calcium/creatinine clearance ratio, and normal intact parathyroid hormone. To study CaSR expression, the mutation was introduced by site-directed mutagenesis into a wild-type (WT) CaSR-expressing pCR3.1 vector, and COS-7 cells were transfected with either the WT or mutant CaSR-containing vector. Transfected cells loaded with Fura-2/AM, a fluorescent indicator of Ca, were assessed for CaSR function by the change in intracellular calcium [as measured by the 340 nm/380 nm fluorescence intensity ratio (F340/F380)] made in response to challenge with extracellular Ca. Both WT and G571W cells had equivalent amounts of CaSR protein in the cell membrane. However, after challenge with extracellular Ca, cells transfected with G571W CaSR responded with a lower F340/F380 ratio than those transfected with WT CaSR and showed decreased sensitivity to extracellular Ca concentrations. The G571W mutation had therefore impaired the CaSR function. In conclusion, we identified a novel loss-of-function mutation, G571W, in the CaSR gene in a Korean family with FHH.",
            "question": "What is the function of calcium-sensing receptor (CaSR)?",
            "answers": {
                "answer_start": 119,
                "text": "The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays an essential role in maintaining calcium homeostasis."
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 10,
                "text": "tyr"
            }
        },
        {
            "context": "Efficacy of anti-interleukin-5 therapy with mepolizumab in patients with asthma: a meta-analysis of randomized placebo-controlled trials. BACKGROUND: Interleukin (IL)-5 is believed to be a key cytokine in eosinophil inflammatory infiltration in asthma. Previous clinical trials have evaluated the efficacy and safety of mepolizumab, a monoclonal antibody against IL-5, in patients with asthma. However, most of these studies were small, the conclusions were inconsistent, and the precise effects are therefore debatable. METHODS: A meta-analysis of randomized placebo-controlled trials was conducted to evaluate the effect of intravenous infusion of mepolizumab on clinical outcomes in patients with asthma. Trials were searched in PubMed, Embase, Web of Science, Cochrane CENTRAL, Scopus, reviews, and reference lists of relevant articles. The outcome variables analyzed included eosinophil counts in blood and sputum, airways outcome measures, exacerbations, asthma control, and quality of life scores. RESULTS: Seven studies met final inclusion criteria (total n = 1131). From the pooled analyses, mepolizumab significantly reduced eosinophils in blood (MD -0.29×10(9)/L, 95% CI -0.44 to -0.14×10(9)/L, P = 0.0001) and sputum (MD -6.05%, 95% CI -9.34 to -2.77%, P = 0.0003). Mepolizumab was also associated with significantly decreased exacerbation risk than placebo (OR 0.30, 95%CI 0.13 to 0.67, P = 0.004), and with a significant improvement in the scores on the Asthma Quality of Life Questionnaire (AQLQ) (MD 0.26, 95% CI 0.03 to 0.49, P = 0.03) in patients with eosinophilic asthma. There were no statistical differences between the groups with respect to FEV1, PEF, or histamine PC20 (all P>0.05), and a non-significant trend for improvement in scores on the Juniper Asthma Control Questionnaire (JACQ) (MD -0.21, 95% CI -0.43 to 0.01, P = 0.06) in the mepolizumab group was observed. CONCLUSIONS: Mepolizumab reduces the risk of exacerbations and improves quality of life in patients with eosinophilic asthma, but no significant improvement in lung function outcomes was observed. Further research is required to establish the possible role of anti-IL-5 as a therapy for asthma.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 17,
                "text": "interleukin-5"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 736,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades heme to iron, carbon monoxide (CO), and biliverdin, the latter two of which are thought to mediate the anti-inflammatory and antioxidant actions of HO-1. Bach1 is a transcriptional repressor of the HO-1 gene (Hmox-1). Previous reports have demonstrated that the genetic ablation of Bach1 engenders an increased HO-1 expression and a marked reduction in the degree of oxidative tissue damage in vivo. However, the function of Bach1 in spinal cord injury is still not understood. In the present study, we examined whether Bach1 deficiency increases HO-1 expression and reduces neural tissue damage in a spinal cord injury model using Bach1 knock-out (KO) mice and wild-type (WT) mice. The expression of HO-1 protein in the spinal cord was significantly higher in the Bach1 KO mice than in the WT mice before and after injury. The KO mice also had significantly higher Basso mouse scale scores for locomotor function and larger areas of spared white matter than the WT mice at 6 weeks after injury. Neuronal loss and apoptotic cell death in the injured spinal cord was significantly reduced in the KO mice in comparison to the WT mice. These results suggest that Bach1 deficiency engenders a constitutively higher expression of HO-1 and a dramatic increase in cytoprotection against spinal cord injury.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 400,
                "text": "repressor"
            }
        },
        {
            "context": "Comment on \"A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme\". Watanabe et al (Reports, 12 April 2013, p. 195) study the yeast SWR1/SWR-C complex responsible for depositing the histone variant H2A.Z by replacing nucleosomal H2A with H2A.Z. They report that reversal of H2A.Z replacement is mediated by SWR1 and related INO80 on an H2A.Z nucleosome carrying H3K56Q. Using multiple assays and reaction conditions, we find no evidence of such reversal of H2A.Z exchange.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 340,
                "text": "SWR1"
            }
        },
        {
            "context": "Monitoring minimal residual disease and controlling drug resistance in chronic myeloid leukaemia patients in treatment with imatinib as a guide to clinical management. Imatinib mesylate, binding to the inactive conformation of Bcr-Abl tyrosine kinase and suppressing the Ph chromosome positive clone, has revolutionized the treatment of chronic myeloid leukaemia (CML) patients. Given the high rates of clinical and cytogenetic remission achieved, the molecular monitoring of BCR-ABL transcript levels by RT-qPCR has become always more important to assess minimal residual disease. Recently, recommendations for harmonizing current methodologies for detecting and measuring BCR-ABL transcripts in CML patients have been suggested. Studies of imatinib-treated patients have determined that the BCR-ABL levels measured early in therapy may predict durable cytogenetic remission and in turn prolonged progression free-survival or acquisition of resistance. The major mechanism of imatinib resistance is clonal expansion of leukaemia cells with mutations in the Bcr-Abl fusion tyrosine kinase. The early reduction of such mutations may allow timely treatment intervention to prevent or overcome resistance. We review current trends in the management of chronic myeloid leukaemia patients undergoing treatment with tyrosine kinase inhibitors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 227,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Calpain cleavage regulates the protein stability of p73. The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 710,
                "text": "7"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1056,
                "text": "xa"
            }
        },
        {
            "context": "A transcription-independent role for TFIIB in gene looping. Recent studies demonstrated the existence of gene loops that juxtapose the promoter and terminator regions of genes with exceptionally long ORFs in yeast. Here we report that looping is not idiosyncratic to long genes but occurs between the distal ends of genes with ORFs as short as 1 kb. Moreover, looping is dependent upon the general transcription factor TFIIB: the E62K (glutamic acid 62 --> lysine) form of TFIIB adversely affects looping at every gene tested, including BLM10, SAC3, GAL10, SEN1, and HEM3. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP. We propose a model suggesting that TFIIB binds RNAP II at the terminator, which in turn associates with the promoter scaffold.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 573,
                "text": "TFIIB"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 489,
                "text": "xa"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 406,
                "text": "Stroke"
            }
        },
        {
            "context": "Dax1 associates with Esrrb and regulates its function in embryonic stem cells. Self-renewal capacity and pluripotency, which are controlled by the Oct3/4-centered transcriptional regulatory network, are major characteristics of embryonic stem (ES) cells. Nuclear hormone receptor Dax1 is one of the crucial factors in the network. Here, we identified an orphan nuclear receptor, Esrrb (estrogen-related receptor beta), as a Dax1-interacting protein. Interaction of Dax1 and Esrrb was mediated through LXXLL motifs of Dax1 and the activation- and ligand-binding domains of Esrrb. Furthermore, Esrrb enhanced the promoter activity of the Dax1 gene via direct binding to Esrrb-binding site 1 (ERRE1, where \"ERRE\" represents \"Esrrb-responsive element\") of the promoter. Expression of Dax1 was suppressed followed by Oct3/4 repression; however, overexpression of Esrrb maintained expression of Dax1 even in the absence of Oct3/4, indicating that Dax1 is a direct downstream target of Esrrb and that Esrrb can regulate Dax1 expression in an Oct3/4-independent manner. We also found that the transcriptional activity of Esrrb was repressed by Dax1. Furthermore, we revealed that Oct3/4, Dax1, and Esrrb have a competitive inhibition capacity for each complex. These data, together with previous findings, suggest that Dax1 functions as a negative regulator of Esrrb and Oct3/4, and these molecules form a regulatory loop for controlling the pluripotency and self-renewal capacity of ES cells.",
            "question": "What is the link between Dax1 and Esrrb?",
            "answers": {
                "answer_start": 0,
                "text": "Dax1 associates with Esrrb and regulates its function in embryonic stem cells."
            }
        },
        {
            "context": "[Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis]. Dermatitis herpetiformis is an autoimmune blistering disease that appears as a cutaneous manifestation of gluten intolerance. It is one of a group of disorders that have gluten sensitivity in common, including celiac disease and gluten ataxia. Patients with dermatitis herpetiformis present with a pruritic papulovesicular rash on extensor surfaces and on the buttocks. Immunological studies demonstrate the presence of specific immunoglobulin (Ig) A anti-endomysial and anti-transglutaminase antibodies. The finding of granular deposits of IgA along the dermal-epidermal junction is pathognomonic of dermatitis herpetiformis. Treatment of dermatitis herpetiformis is based on a life-long, strict gluten-free diet, which improves all clinical aspects of gluten sensitivity, and dapsone, a drug that is only effective for the skin manifestations.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 83,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. DESIGN: A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. SETTING: An 800-bed, teaching, university-affiliated hospital. PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant \"waking\" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 687,
                "text": "flumazenil"
            }
        },
        {
            "context": "CROI 2016: Hot Spots in HIV Infection and Advances in HIV Prevention. The 2016 Conference on Retroviruses and Opportunistic Infections (CROI) highlighted hot spots in HIV infection. Men who have sex with men (MSM), transgender populations, people who inject drugs, fisherfolk, migrants, adolescents, and older adults are heavily impacted in a number of regions. Stigma contributes to risk behaviors and HIV acquisition across populations. HIV testing is a crucial first step in the HIV care continuum, and several large community-based surveys are underway in Africa to increase HIV testing, linkage to care, and uptake of antiretroviral treatment. Advances in preexposure prophylaxis (PrEP) featured prominently at CROI 2016. Two large efficacy trials of a vaginal ring containing the investigational drug dapivirine demonstrated efficacy and safety in preventing HIV infections in women in Africa. Data on the safety of long-acting injectable PrEP and several investigational PrEP drugs and formulations were also presented. Knowledge and use of PrEP among MSM in the United States appears to be increasing, and high uptake was seen among black MSM when provided as part of a culturally tailored support program. The use of broadly neutralizing antibodies for HIV prevention is a novel and promising approach to be evaluated in efficacy trials.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 865,
                "text": "HIV"
            }
        },
        {
            "context": "Evaluation of some physical and chemical treatments for inactivating microsporidian spores isolated from fish. Microsporidia are a large diverse group of intracellular parasites now considered as fungi. They are particularly prevalent in fish and are recognized as important opportunistic parasites in humans. Although the mode of transmission of microsporidia has not been fully clarified, the consumption and manipulation of infected fish may be a risk factor for humans. Comparative analysis of rDNA sequence revealed that the microsporidians used in the present study had 99-100% identity with anglerfish microsporidians of the genus Spraguea and very low identity with microsporidians that infect humans. Microsporidian spores were exposed to different physical and chemical treatments: freezing at -20°C for 24-78 h, heating at 60°C for 5-15 min, microwaving at 700 W, 2.45 GHz for 15-60s, and treatment with ethanol at concentrations of between 1 and 70% for 15 min. The viability of the spores after each treatment was evaluated by two methods: a) haemocytometer counts, measuring the extrusion of the polar filament in control and treated spores, and b) a fluorometric method, testing the membrane integrity by propidium iodide exclusion. The results of both methods were concordant. Spores were inactivated by freezing at -20°C for more than 48 h, by heating to 60°C for 10 min and by microwaving at 750 W, for 20s. Exposure to 70% ethanol for 15 min also inactivated microsporidian spores. The results suggest that both freezing and heating are effective treatments for destroying microsporidian spores in European white anglerfish, and that 70% ethanol could be used by fish processors to disinfect their hands and the utensils used in processing fish. The fluorometric method can be used as an alternative to haemocytometer counts in disinfection studies aimed at establishing strategies for inactivating and reducing the viability and the potential infectivity of microsporidians present in fish or in the environment.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 196,
                "text": "fungi"
            }
        },
        {
            "context": "Enhancer Sharing Promotes Neighborhoods of Transcriptional Regulation Across Eukaryotes. Enhancers physically interact with transcriptional promoters, looping over distances that can span multiple regulatory elements. Given that enhancer-promoter (EP) interactions generally occur via common protein complexes, it is unclear whether EP pairing is predominantly deterministic or proximity guided. Here, we present cross-organismic evidence suggesting that most EP pairs are compatible, largely determined by physical proximity rather than specific interactions. By reanalyzing transcriptome datasets, we find that the transcription of gene neighbors is correlated over distances that scale with genome size. We experimentally show that nonspecific EP interactions can explain such correlation, and that EP distance acts as a scaling factor for the transcriptional influence of an enhancer. We propose that enhancer sharing is commonplace among eukaryotes, and that EP distance is an important layer of information in gene regulation.",
            "question": "Which effects create neighborhoods of transcriptional regulation in eukaryotes?",
            "answers": {
                "answer_start": 905,
                "text": "enhancer sharing"
            }
        },
        {
            "context": "GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.",
            "question": "Which receptor does GDF15 bind?",
            "answers": {
                "answer_start": 367,
                "text": "GDNF family receptor α-like (GFRAL)"
            }
        },
        {
            "context": "Kinetic manifestation of processivity during multiple methylations catalyzed by SET domain protein methyltransferases. Processive versus distributive methyl group transfer was assessed for pea Rubisco large subunit methyltransferase, a SET domain protein lysine methyltransferase catalyzing the formation of trimethyllysine-14 in the large subunit of Rubisco. Catalytically competent complexes between an immobilized form of des(methyl) Rubisco and Rubisco large subunit methyltransferase were used to demonstrate enzyme release that was co-incident with and dependent on formation of trimethyllysine. Catalytic rate constants determined for formation of trimethyllysine were considerably lower ( approximately 10-fold) than rate constants determined for total radiolabel incorporation from [3H-methyl]-S-adenosylmethionine. Double-reciprocal velocity plots under catalytic conditions favoring monomethyllysine indicated a random or ordered reaction mechanism, while conditions favoring trimethyllysine suggested a hybrid ping-pong mechanism. These results were compared with double-reciprocal velocity plots and product analyses obtained for HsSET7/9 (a monomethyltransferase) and SpCLR4 (a dimethyltransferase) and suggest a predictive ability of double-reciprocal velocity plots for single versus multiple methyl group transfers by SET domain protein lysine methyltransferases. A model is proposed for SET domain protein lysine methyltransferases in which initial binding of polypeptide substrate and S-adenosylmethionine is random, with polypeptide binding followed by deprotonation of the epsilon-amine of the target lysyl residue and subsequent methylation. Following methyl group transfer, S-adenosylhomocysteine and monomethylated polypeptide dissociate from monomethyltransferases, but di- and trimethyltransferases begin a successive and catalytically obligatory deprotonation of enzyme-bound methylated lysyl intermediates, which along with binding and release of S-adenosylmethionine and S-adenosylhomocysteine is manifested as a hybrid ping-pong-like reaction mechanism.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 80,
                "text": "SET domain"
            }
        },
        {
            "context": "Novel details of calsequestrin gel conformation in situ. Calsequestrin (CASQ) is the major component of the sarcoplasmic reticulum (SR) lumen in skeletal and cardiac muscles. This calcium-binding protein localizes to the junctional SR (jSR) cisternae, where it is responsible for the storage of large amounts of Ca(2+), whereas it is usually absent, at least in its polymerized form, in the free SR. The retention of CASQ inside the jSR is due partly to its association with other jSR proteins, such as junctin and triadin, and partly to its ability to polymerize, in a high Ca(2+) environment, into an intricate gel that holds the protein in place. In this work, we shed some light on the still poorly described in situ structure of polymerized CASQ using detailed EM images from thin sections, with and without tilting, and from deep-etched rotary-shadowed replicas. The latter directly illustrate the fundamental network nature of polymerized CASQ, revealing repeated nodal points connecting short segments of the linear polymer.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 57,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. OBJECTIVE: Evaluate efficacy and safety of tanezumab, a humanized monoclonal antibody against nerve growth factor, in neuropathic pain. DESIGN: Two randomized controlled trials. SUBJECTS: Patients with pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN). METHODS: In the DPN study, patients received subcutaneous tanezumab 20 mg or placebo on Day 1 and Week 8. Evaluations included change from baseline in average DPN pain (primary endpoint), Patient's Global Assessment of DPN, and safety (including neuropathy assessments). Due to a partial clinical hold limiting enrollment and treatment duration, the prespecified landmark analysis was modified post hoc from Week 16 to Week 8. In the PHN study, patients received intravenous tanezumab 50 μg/kg, tanezumab 200 μg/kg, or placebo on Day 1. Evaluations included change from baseline in average daily pain (primary endpoint), Brief Pain Inventory-short form, Patient's Global Assessment of pain from PHN, and safety. RESULTS: Mean DPN pain reduction from baseline to Week 8 was greater with tanezumab vs placebo (P = 0.009); differences in Patient's Global Assessment of DPN were not significant (P > 0.05). Neither tanezumab dose resulted in significant differences vs placebo in efficacy in PHN (P > 0.05), although tanezumab 200 μg/kg provided some benefit. Neuropathy assessments showed no meaningful changes. CONCLUSIONS: Tanezumab provided effective pain reduction in DPN. In PHN, only the highest tanezumab dose reduced pain; treatment differences were not significant. No new safety concerns were observed despite preexisting neuropathy.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 183,
                "text": "nerve growth factor"
            }
        },
        {
            "context": "The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. The molecular target of rapamycin (mTOR), which is a member of the phosphoinositide 3-kinase related kinase (PIKK) family and a central modulator of cell growth, is a prime strategic target for anti-cancer therapeutic development. mTOR plays a critical role in transducing proliferative signals mediated through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, principally by activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of key mRNAs of proteins required for G(1) to S phase traverse. By targeting mTOR, the immunsuppressant and antiproliferative agent rapamycin (RAP) inhibits signals required for cell cycle progression, cell growth, and proliferation. RAP, a complex macrolide and highly potent fungicide, immunosuppressant, and anti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP gains function by binding to the immunophilin FK506 binding protein 12 (FKBP12) and the resultant complex inhibits the activity of mTOR. Since mTOR activates both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest. RAP also prevents cyclin-dependent kinase (cdk) activation, inhibits retinoblastoma protein ((p)Rb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficienciy of active cdk4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of RAP at the G(1)/S phase transition. Both RAP and several RAP analogs with more favorable pharmaceutical properties have demonstrated prominent growth inhibitory effects against a broad range of human cancers in both preclinical and early clinical evaluations. This review will summarize the principal mechanisms of action of RAP and RAP derivatives and their potential utility of these agents as anti-cancer therapeutics. The preliminary results of early clinical evaluations with RAP analogs and the unique developmental challenges that lie ahead will also be discussed.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 116,
                "text": "mTOR"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1475,
                "text": "XK"
            }
        },
        {
            "context": "Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys. Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses > 3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2252,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 182,
                "text": "XK"
            }
        },
        {
            "context": "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival. Cardiac contractility is regulated through the activity of various key Ca(2+)-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis. In the current study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide binding domain are required for its interaction with the C-terminal domain of HAX-1, containing amino acids 203-245. In transiently cotransfected human embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the ER, whereas HAX-1 selectively concentrated at mitochondria. On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2 abrogated the protective effects of HAX-1 on cell survival, after hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca(2+) stores.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 301,
                "text": "phospholamban"
            }
        },
        {
            "context": "Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria. Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 32,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Pharmaceutical approval update. Duavee, an oral contraceptive; riociguat (Adempas) for two types of pulmonary hypertension; and macitentan (Opsumit) for pulmonary arterial hypertension.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 63,
                "text": "riociguat"
            }
        },
        {
            "context": "Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant. Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis.",
            "question": "Which amino acid residue appears mutated in most of the cases reported with  cadasil syndrome?",
            "answers": {
                "answer_start": 205,
                "text": "cysteine"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 305,
                "text": "MethPed"
            }
        },
        {
            "context": "DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation. Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 349,
                "text": "FSHD"
            }
        },
        {
            "context": "Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative disorder of childhood, is caused by mutations in a recently identified gene ( CLN3 ) localized to chromosome 16p11.2-12.1. To elucidate the biosynthesis and localization of the CLN3 protein, we expressed CLN3 cDNA in COS-1 and HeLa cell lines. In vitro translation, immunoprecipitation and Western blotting analyses detected an approximately 43 kDa polypeptide. Pulse-chase experiments indicated that the CLN3 protein is synthesized as an N -glycosylated single-chain polypeptide, which was not detected in growth medium. Confocal immunofluorescence microscopy revealed that the CLN3 protein is localized to the lysosomal compartment. These results provide evidence that Batten disease can be classified as a member of lysosomal diseases.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 106,
                "text": "juvenile-onset neuronal ceroid lipofuscinosis"
            }
        },
        {
            "context": "Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 53,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "From animal models to human disease: a genetic approach for personalized medicine in ALS. Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 121,
                "text": "ALS"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 969,
                "text": "libFLASM"
            }
        },
        {
            "context": "Xce haplotypes show modified methylation in a region of the active X chromosome lying 3' to Xist. During early mammalian embryogenesis, one of the two X chromosomes in somatic cells of the female becomes inactivated through a process that is thought to depend on a unique initiator region, the X-chromosome inactivation center (Xic). The recently characterized Xist sequence (X-inactive-specific transcript) is thought to be a possible candidate for Xic. In mice a further genetic element, the X chromosome-controlling element (Xce), is also known to influence the choice of which of the two X chromosomes is inactivated. We report that a region of the mouse X chromosome lying 15 kb distal to Xist contains several sites that show hypermethylation specifically associated with the active X chromosome. Analysis of this region in various Xce strains has revealed a correlation between the strength of the Xce allele carried and the methylation status of this region. We propose that such a region could be involved in the initial stages of the inactivation process and in particular in the choice of which of the two X chromosomes present in a female cell will be inactivated.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 361,
                "text": "Xist"
            }
        },
        {
            "context": "Selective estrogen receptor modulators: an update on recent clinical findings. Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 103,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 704,
                "text": "CD38"
            }
        },
        {
            "context": "Saccharomyces cerevisiae lacking Btn1p modulate vacuolar ATPase activity to regulate pH imbalance in the vacuole. The vacuolar H(+)-ATPase (V-ATPase) along with ion channels and transporters maintains vacuolar pH. V-ATPase ATP hydrolysis is coupled with proton transport and establishes an electrochemical gradient between the cytosol and vacuolar lumen for coupled transport of metabolites. Btn1p, the yeast homolog to human CLN3 that is defective in Batten disease, localizes to the vacuole. We previously reported that Btn1p is required for vacuolar pH maintenance and ATP-dependent vacuolar arginine transport. We report that extracellular pH alters both V-ATPase activity and proton transport into the vacuole of wild-type Saccharomyces cerevisiae. V-ATPase activity is modulated through the assembly and disassembly of the V(0) and V(1) V-ATPase subunits located in the vacuolar membrane and on the cytosolic side of the vacuolar membrane, respectively. V-ATPase assembly is increased in yeast cells grown in high extracellular pH. In addition, at elevated extracellular pH, S. cerevisiae lacking BTN1 (btn1-Delta), have decreased V-ATPase activity while proton transport into the vacuole remains similar to that for wild type. Thus, coupling of V-ATPase activity and proton transport in btn1-Delta is altered. We show that down-regulation of V-ATPase activity compensates the vacuolar pH imbalance for btn1-Delta at early growth phases. We therefore propose that Btn1p is required for tight regulation of vacuolar pH to maintain the vacuolar luminal content and optimal activity of this organelle and that disruption in Btn1p function leads to a modulation of V-ATPase activity to maintain cellular pH homeostasis and vacuolar luminal content.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 452,
                "text": "Batten disease"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 53,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Oxantel disrupts polymicrobial biofilm development of periodontal pathogens. Bacterial pathogens commonly associated with chronic periodontitis are the spirochete Treponema denticola and the Gram-negative, proteolytic species Porphyromonas gingivalis and Tannerella forsythia. These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation. Here, we demonstrate that oxantel inhibited P. gingivalis Frd activity with a 50% inhibitory concentration (IC50) of 2.2 μM and planktonic growth of T. forsythia with a MIC of 295 μM, but it had no effect on the growth of T. denticola. Oxantel treatment caused the downregulation of six P. gingivalis gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that P. gingivalis may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of P. gingivalis, T. forsythia, and T. denticola in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of T. denticola on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of P. gingivalis-infected mice reduced bone loss to the same level as the uninfected control.",
            "question": "Oxantel is used for periodontitis treatment. How does it work?",
            "answers": {
                "answer_start": 0,
                "text": "Oxantel disrupts polymicrobial biofilm"
            }
        },
        {
            "context": "Treatment of chronic myeloid leukemia with imatinib mesylate. Philadelphia (Ph) chromosome is the cytogenetic hallmark of chronic myeloid leukemia (CML). The translocation forms a chimeric gene, bcr-abl, which generates BCR-ABL. This fusion protein constitutively activate ABL tyrosine kinase and causes CML. Imatinib mesylate is a selective tyrosine kinase inhibitor on ABL, c-Kit and PGDF-receptor, and functions through competitive inhibition at the ATP-binding site of the enzyme, which leads to growth arrest or apoptosis in cells that express BCR-ABL. Imatinib has revolutionized the management of patients with CML, and at a dose of 400 mg daily has become the current standard therapy for newly diagnosed patients with CML even when they have HLA-matched family donors. Although imatinib therapy has only a 5-year history, it is hoped that CML will be cured with this drug and with forthcoming second-generation tyrosine kinase inhibitors as well as by allogeneic stem cell transplantation in patients who have become resistant to these drugs.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 220,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Simple synthesis of endophenazine G and other phenazines and their evaluation as anti-methicillin-resistant Staphylococcus aureus agents. Community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) has become a severe health concern because of its treatment difficulties. Herein, we report the synthesis and biological evaluation of two phenazine natural products and a series of phenazines that show promising activities against MRSA with MIC values in the low micromolar range. Basic studies revealed that these compounds are bacteriostatic agents. The most active compound also displayed promising IC50 values against HaCat cells. Finally, a QSAR model was developed to understand the key structural features of the molecules.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 207,
                "text": "MRSA"
            }
        },
        {
            "context": "S phase-dependent interaction with DNMT1 dictates the role of UHRF1 but not UHRF2 in DNA methylation maintenance. Recent studies demonstrate that UHRF1 is required for DNA methylation maintenance by targeting DNMT1 to DNA replication foci, presumably through its unique hemi-methylated DNA-binding activity and interaction with DNMT1. UHRF2, another member of the UHRF family proteins, is highly similar to UHRF1 in both sequence and structure, raising questions about its role in DNA methylation. In this study, we demonstrate that, like UHRF1, UHRF2 also binds preferentially to methylated histone H3 lysine 9 (H3K9) through its conserved tudor domain and hemi-methylated DNA through the SET and Ring associated domain. Like UHRF1, UHRF2 is enriched in pericentric heterochromatin. The heterochromatin localization depends to large extent on its methylated H3K9-binding activity and to less extent on its methylated DNA-binding activity. Coimmunoprecipitation experiments demonstrate that both UHRF1 and UHRF2 interact with DNMT1, DNMT3a, DNMT3b and G9a. Despite all these conserved functions, we find that UHRF2 is not able to rescue the DNA methylation defect in Uhrf1 null mouse embryonic stem cells. This can be attributed to the inability for UHRF2 to recruit DNMT1 to replication foci during S phase of the cell cycle. Indeed, we find that while UHRF1 interacts with DNMT1 in an S phase-dependent manner in cells, UHRF2 does not. Thus, our study demonstrates that UHRF2 and UHRF1 are not functionally redundant in DNA methylation maintenance and reveals the cell-cycle-dependent interaction between UHRF1 and DNMT1 as a key regulatory mechanism targeting DNMT1 for DNA methylation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 328,
                "text": "DNMT1"
            }
        },
        {
            "context": "Serum sclerostin: relation with mortality and impact of hemodiafiltration. Background: The glycoprotein sclerostin (Scl; 22 kDa), which is involved in bone metabolism, may play a role in vascular calcification in haemodialysis (HD) patients. In the present study, we investigated the relation between serum Scl (sScl) and mortality. The effects of dialysis modality and the magnitude of the convection volume in haemodiafiltration (HDF) on sScl were also investigated. Methods: In a subset of patients from the CONTRAST study, a randomized controlled trial comparing HDF with HD, sScl was measured at baseline and at intervals of 6, 12, 24 and 36 months. Patients were divided into quartiles, according to their baseline sScl. The relation between time-varying sScl and mortality with a 4-year follow-up period was investigated using crude and adjusted Cox regression models. Linear mixed models were used for longitudinal measurements of sScl. Results: The mean (±standard deviation) age of 396 test subjects was 63.6 (±13.9 years), 61.6% were male and the median follow-up was 2.9 years. Subjects with the highest sScl had a lower mortality risk than those with the lowest concentrations [adjusted hazard ratio 0.51 (95% confidence interval, CI, 0.31-0.86, P = 0.01)]. Stratified models showed a stable sScl in patients treated with HD (Δ +2.9 pmol/L/year, 95% CI -0.5 to +6.3, P = 0.09) and a decreasing concentration in those treated with HDF (Δ -4.5 pmol/L/year, 95% CI -8.0 to -0.9, P = 0.02). The relative change in the latter group was related to the magnitude of the convection volume. Conclusions: (i) A high sScl is associated with a lower mortality risk in patients with end-stage kidney disease; (ii) treatment with HDF causes sScl to fall; and (iii) the relative decline in patients treated with HDF is dependent on the magnitude of the convection volume.",
            "question": "Sclerostin regulates what process?",
            "answers": {
                "answer_start": 151,
                "text": "bone metabolism"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 821,
                "text": "xa"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 739,
                "text": "xa"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1125,
                "text": "dabigatran"
            }
        },
        {
            "context": "Adherence and Acceptability of a Multidrug Vaginal Ring for HIV Prevention in a Phase I Study in the United States. We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 287,
                "text": "HIV"
            }
        },
        {
            "context": "Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation. Cardiolipin is a mitochondrion-specific phospholipid that stabilizes the assembly of respiratory chain complexes, favoring full-yield operation. It also mediates key steps in apoptosis. In Barth syndrome, an X chromosome-linked cardiomyopathy caused by tafazzin mutations, cardiolipins display acyl chain modifications and are present at abnormally low concentrations, whereas monolysocardiolipin accumulates. Using immortalized lymphoblasts from Barth syndrome patients, we showed that the production of abnormal cardiolipin led to mitochondrial alterations. Indeed, the lack of normal cardiolipin led to changes in electron transport chain stability, resulting in cellular defects. We found a destabilization of the supercomplex (respirasome) I+III2+IVn but also decreased amounts of individual complexes I and IV and supercomplexes I+III and III+IV. No changes were observed in the amounts of individual complex III and complex II. We also found decreased levels of complex V. This complex is not part of the supercomplex suggesting that cardiolipin is required not only for the association/stabilization of the complexes into supercomplexes but also for the modulation of the amount of individual respiratory chain complexes. However, these alterations were compensated by an increase in mitochondrial mass, as demonstrated by electron microscopy and measurements of citrate synthase activity. We suggest that this compensatory increase in mitochondrial content prevents a decrease in mitochondrial respiration and ATP synthesis in the cells. We also show, by extensive flow cytometry analysis, that the type II apoptosis pathway was blocked at the mitochondrial level and that the mitochondria of patients with Barth syndrome cannot bind active caspase-8. Signal transduction is thus blocked before any mitochondrial event can occur. Remarkably, basal levels of superoxide anion production were slightly higher in patients' cells than in control cells as previously evidenced via an increased protein carbonylation in the taz1Δ mutant in the yeast. This may be deleterious to cells in the long term. The consequences of mitochondrial dysfunction and alterations to apoptosis signal transduction are considered in light of the potential for the development of future treatments.",
            "question": "Which gene is involved in the development of Barth syndrome?",
            "answers": {
                "answer_start": 143,
                "text": "tafazzin (TAZ) gene"
            }
        },
        {
            "context": "Molecular and trophic mechanisms of pituitary tumourigenesis. BACKGROUND: The paradox of pituitary tumours is that persistent growth is so atypical. By definition, all pituitary microadenomas regain complete trophic stability after an initial period of deregulated growth. Unlike tumours in many other organ systems, concern about significant growth of macroadenoma remnants after debulking is minimal. Despite reports of a relatively high prevalence of aneuploidy and clonal skewing in these tumours, prolonged efforts to implicate classical proto-oncogene activation and tumour suppressor mutations have been of limited success. No histological or molecular markers reliably predict behaviour. To date, the number of molecular genetic factors unequivocally linked to pituitary tumours can be counted on the fingers of one hand: (1) GNAS1 activation in acromegaly; (2) the MENIN and p27Kip1 (CDKN1B) mutations associated with multiple endocrine neoplasia type 1; (3) mutations of PRKA1RA with loss of 17q22-24 in Carney complex, and (4) aryl hydrocarbon receptor interacting protein gene mutations in 15% of familial isolated pituitary adenomas and 50% of familial isolated acromegaly. Together, these account for only a small proportion (<5%) of sporadic pituitary macroadenomas. CONCLUSION: In most instances, we still do not know what causes quantitative aberrations in trophic behaviour.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 1038,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.",
            "question": "Which type of GTPases is required for amino acid-dependent activation of mTORC1?",
            "answers": {
                "answer_start": 193,
                "text": "Heterodimeric Rag GTPases"
            }
        },
        {
            "context": "Delayed L-DOPA-induced hyperalgesia. Previously we reported on L-DOPA's antinociceptive effect on substance P-induced nociceptive behaviors in mice [Shimizu T, Iwata S, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of L-DOPA. Pain 2004;110;246-9.]. Since significant hyperalgesia was noted following antinociception, our study was designed to investigate the mechanism of this hyperalgesia. Nociceptive behaviors were enhanced 2 h after L-DOPA administration. L-DOPA induced hyperalgesia occurred after conversion to dopamine because co-administration of benserazide, a DOPA decarboxylase inhibitor, completely abolished the L-DOPA-induced hyperalgesia. The D2 receptor agonist, quinpirole, depressed these behaviors entirely, while the D1 antagonist, SCH23390, inhibited the enhancement of these behaviors by L-DOPA. The D2 receptor antagonist, sulpiride, which induced hyperalgesia of the substance P-induced behaviors in naive mice, did not have any effects on L-DOPA-induced hyperalgesia. Spinal cord dopamine content increased rapidly after L-DOPA administration, exhibiting levels 100 times greater than baseline, and then returned to control after 1 h. These results suggested that the dopaminergic inhibitory system for pain sensation was temporarily impaired by excess amounts of exogenous dopamine that were derived from L-DOPA and both D1 and D2 receptors were involved in L-DOPA-induced hyperalgesia.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 483,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. Heme controls expression of genes involved in the synthesis of globins and heme. The mammalian transcription factor Bach1 functions as a repressor of the Maf recognition element (MARE) by forming antagonizing hetero-oligomers with the small Maf family proteins. We show here that heme binds specifically to Bach1 and regulates its DNA-binding activity. Deletion studies demonstrated that a heme-binding region of Bach1 is confined within its C-terminal region that possesses four dipeptide cysteine-proline (CP) motifs. Mutations in all of the CP motifs of Bach1 abolished its interaction with heme. The DNA-binding activity of Bach1 as a MafK hetero-oligomer was markedly inhibited by heme in gel mobility shift assays. The repressor activity of Bach1 was lost upon addition of hemin in transfected cells. These results suggest that increased levels of heme inactivate the repressor Bach1, resulting in induction of a host of genes with MARES:",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 94,
                "text": "repressor"
            }
        },
        {
            "context": "Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 457,
                "text": "CD38"
            }
        },
        {
            "context": "Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. BACKGROUND: The \"long/short\"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.",
            "question": "What disease is mirtazapine predominantly used for?",
            "answers": {
                "answer_start": 916,
                "text": "major depression"
            }
        },
        {
            "context": "Sleepiness, fatigue, and risk of obstructive sleep apnea using the STOP-BANG questionnaire in multiple sclerosis: a pilot study. PURPOSE: This study aims: (1) to identify patients with multiple sclerosis (MS) who are at high risk for obstructive sleep apnea (OSA) by utilizing the STOP-BANG questionnaire and (2) to evaluate the relationship between OSA risk as determined by the STOP-BANG questionnaire and self-reported sleepiness and fatigue using the Epworth Sleepiness Scale (ESS) and the Fatigue Severity Scale (FSS), respectively. METHODS: A total of 120 consecutive patients presenting to the UC Davis Neurology MS Clinic were invited to participate in an anonymous survey. The exclusion criteria were: age <18 years, indefinite MS diagnosis, or incomplete survey. RESULTS: There were 103 subjects included in our study: 42% of subjects (n = 43) met the criteria for high-risk OSA, 69% of subjects (n = 71) screened high for fatigue (FSS > 4), but only 24 subjects (23%) screened high for excessive daytime sleepiness (ESS > 10). In males, 44% of the variation in ESS scores and 63% in FSS scores were explained by the STOP-BANG components. However, only 17% of the variation in ESS scores and 15% of the variation in FSS scores was explained by the STOP-BANG components in females. CONCLUSIONS: Over 40% of MS patients were identified as high risk for OSA based on the STOP-BANG questionnaire. The STOP-BANG questionnaire offers clinicians an efficient and objective tool for improving detection of OSA risk in MS patients.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 234,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 113,
                "text": "FBN1"
            }
        },
        {
            "context": "Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate gene expression, genome imprinting, and X-chromosome inactivation. We report on the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex containing a central hemimethylated CpG site. The methyl group of methylcytosine is positioned within a shallow hydrophobic concave surface, whereas the cytosine on the target strand is looped out and covalently anchored within the catalytic pocket. The DNA is distorted at the hemimethylated CpG step, with side chains from catalytic and recognition loops inserting through both grooves to fill an intercalation-type cavity associated with a dual base flip-out on partner strands. Structural and biochemical data establish how a combination of active and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated maintenance DNA methylation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 86,
                "text": "DNMT1"
            }
        },
        {
            "context": "Multiple evolutionary origins of the fungus causing Panama disease of banana: concordant evidence from nuclear and mitochondrial gene genealogies. Panama disease of banana, caused by the fungus Fusarium oxysporum f. sp. cubense, is a serious constraint both to the commercial production of banana and cultivation for subsistence agriculture. Previous work has indicated that F. oxysporum f. sp. cubense consists of several clonal lineages that may be genetically distant. In this study we tested whether lineages of the Panama disease pathogen have a monophyletic origin by comparing DNA sequences of nuclear and mitochondrial genes. DNA sequences were obtained for translation elongation factor 1alpha and the mitochondrial small subunit ribosomal RNA genes for F. oxysporum strains from banana, pathogenic strains from other hosts and putatively nonpathogenic isolates of F. oxysporum. Cladograms for the two genes were highly concordant and a partition-homogeneity test indicated the two datasets could be combined. The tree inferred from the combined dataset resolved five lineages corresponding to \"F. oxysporum f. sp. cubense\" with a large dichotomy between two taxa represented by strains most commonly isolated from bananas with Panama disease. The results also demonstrate that the latter two taxa have significantly different chromosome numbers. F. oxysporum isolates collected as nonpathogenic or pathogenic to other hosts that have very similar or identical elongation factor 1alpha and mitochondrial small subunit genotypes as banana pathogens were shown to cause little or no disease on banana. Taken together, these results indicate Panama disease of banana is caused by fungi with independent evolutionary origins.",
            "question": "What is the causative agent of the \"Panama disease\" affecting bananas?",
            "answers": {
                "answer_start": 194,
                "text": "Fusarium oxysporum f. sp. cubense"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 152,
                "text": "orexin"
            }
        },
        {
            "context": "Combined Pharmacologic Therapy in Postmenopausal Osteoporosis. Antiresorptive agents for treating postmenopausal osteoporosis include selective estrogen receptor modulator (SERM), bisphosphonates and denoumab. Teriparatide is the only Food and Drug Administration-approved anabolic agent. Synergistic effects of combining teriparatide with an antiresorptive agent have been proposed and studied. This article reviews the trial designs and the outcomes of combination therapies. Results of the combination therapy for teriparatide and bisphosphonates were mixed; while small increases of bone density were observed in the combination therapy of teriparatide and estrogen/SERM and that of teriparatide and denosumab. Those clinical studies were limited by small sample sizes and lack of fracture outcomes.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 134,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Proteasome inhibitors. Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 826,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "[Molecular mechanism of tissue-specific actions of SERM]. Selective estrogen receptor modulator (SERM) is designated as synthetic ligands for estrogen receptors (ERs), exhibiting tissue-specific agonisitic/antagonisitic activities. Among SERM, raloxifen is a most clinically successful as an anti-oseteoporotic agent. Such tissue-specific actions of SERM are presumed to mediate through unusual structure alteration of liganded ERs coupled with co-regulator recruitments.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 58,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Heterogeneity of genomes: measures and values. Genomic homogeneity is investigated for a broad base of DNA sequences in terms of dinucleotide relative abundance distances (abbreviated delta-distances) and of oligonucleotide compositional extremes. It is shown that delta-distances between different genomic sequences in the same species are low, only about 2 or 3 times the distance found in random DNA, and are generally smaller than the between-species delta-distances. Extremes in short oligonucleotides include underrepresentation of TpA and overrepresentation of GpC in most temperate bacteriophage sequences; underrepresentation of CTAG in most eubacterial genomes; underrepresentation of GATC in most bacteriophage; CpG suppression in vertebrates, in all animal mitochondrial genomes, and in many thermophilic bacterial sequences; and overrepresentation of GpG/CpC in all animal mitochondrial sets and chloroplast genomes. Interpretations center on DNA structures (dinucleotide stacking energies, DNA curvature and superhelicity, nucleosome organization), context-dependent mutational events, methylation effects, and processes of replication and repair.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 455,
                "text": "delta-distance"
            }
        },
        {
            "context": "Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait. We report a case of fulminant liver failure resulting in emergent liver transplantation following 3 weeks of nausea, vomiting, and malaise from Jamaican Vomiting Sickness. Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks. It is characterized by acute gastrointestinal illness and hypoglycemia. In severe cases, central nervous system depression can occur. In previous studies, histologic sections taken from patients with Jamaican Vomiting Sickness have shown hepatotoxicity similar to that seen in Reye syndrome and/or acetaminophen toxicity. We highlight macroscopic and microscopic changes in the liver secondary to hepatoxicity of Ackee fruit versus those caused by a previously unknown sickle cell trait. We discuss the clinical variables and the synergistic hepatotoxic effect of Ackee fruit and ischemic injury from sickled red blood cells, causing massive hepatic necrosis in this patient.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 348,
                "text": "Ackee fruit"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. AIMS: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). RESULTS: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0 -∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. CONCLUSIONS: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 218,
                "text": "SGLT2"
            }
        },
        {
            "context": "[Pharmacologic treatment of sarcoidosis]. Sarcoidosis is still a mysterious disease since we don't know exactly what is the cause. Interestingly some patients get cured without any treatment. There is still a controversy about the indications of treatment in sarcoidosis. This article is an update on pharmacologic treatment in sarcoidosis. Corticosteroids are still the first-line treatment, but alternative therapy with anti-TNF agents, like pentoxifylline, thalidomide and anti-TNF monoclonal antibodies become more interesting, especially in refractory sarcoidosis.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 341,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "Myoclonic astatic epilepsy (Doose syndrome) - a lamotrigine responsive epilepsy? PURPOSE: Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients. PATIENTS AND METHODS: In an exploratory, retrospective study, 10 pharmacoresistant MAE patients were included who had been admitted to the Northern German Epilepsy Center between 07/2007 and 12/2010 and had been treated with LTG. Documentation was performed with the electronic seizure diary Epivista. A total observation period of 32 weeks was defined: 8-week 'pre LTG treatment phase' (before starting with LTG), 16-week 'titration phase' (starting with very low LTG doses), 8-week 'follow-up phase'. Seizure frequency, medication and adverse events were extracted from the electronic diary and evaluated in each particular patient. The individual reduction of seizure frequency per day was defined as primary outcome variable. Additionally, a dose-effect-relationship was analyzed for each patient. RESULTS: Six out of ten patients were seizure free during the follow-up phase. Statistical analysis indicated a significant seizure reduction in seven patients at follow-up compared to the pre LTG treatment phase. Seizure frequency did not significantly decrease in two patients and increased in one patient. A significant relationship between seizure frequency per day and LTG dosage during titration and follow-up phase could be demonstrated in nine patients. Group statistics using the exact Wilcoxon test revealed a significant reduction in seizure frequency (p = 0.049, two-sided). CONCLUSION: Our data provide evidence that adjunctive LTG is an eligible therapeutic option for the treatment of pharmacoresistant MAE and encourage further prospective studies to verify this observation.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 90,
                "text": "Myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Reversal of Newer Direct Oral Anticoagulant Drugs (DOACs). Anticoagulation therapy is indicated for management of various clinical conditions to prevent adverse events and introduction of direct oral anticoagulants (DOACs) has ushered in a new era in anticoagulation therapy. Major advantages of DOACS include fewer drug interactions and that they do not need periodic monitoring. Several patients who were not on anticoagulation before due to older age, polypharmacy/drug interaction concerns, and logistics of periodic monitoring are now on anticoagulation with DOACs. Despite their many advantages, a challenge while prescribing DOACs is very limited availability of specific reversal agents and lack of understanding or guidance about the treatment strategy in case of major life threatening bleeding or need for urgent surgery. So far only one reversal agent has been approved by the Food and Drug Administration (FDA), idarucizumab for one of the DOACs i.e., dabigatran. Several other reversal agents are under final phases of development such as andexanet alfa and PER977 (ciraparantag) and will help in developing specific strategies for reversal of these agents. In this article, we review current strategies to manage bleeding with DOACs and provide guidance to clinicians of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 965,
                "text": "dabigatran"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 369,
                "text": "INCA"
            }
        },
        {
            "context": "Rethinking how DNA methylation patterns are maintained. DNA methylation patterns are set up early in mammalian development and are then copied during the division of somatic cells. A long-established model for the maintenance of these patterns explains some, but not all, of the data that are now available. We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 470,
                "text": "DNMT1"
            }
        },
        {
            "context": "Temperature-dependent sensitivity enhancement of solid-state NMR spectra of alpha-synuclein fibrils. The protein alpha-synuclein (AS) is the primary fibrillar component of Lewy bodies, the pathological hallmark of Parkinson's disease. Wild-type human AS and the three mutant forms linked to Parkinson's disease (A53T, A30P, and E46K) all form fibrils through a nucleation-dependent pathway; however, the biophysical details of these fibrillation events are not yet well understood. Atomic-level structural insight is required in order to elucidate the potential role of AS fibrils in Parkinson's disease. Here we show that low temperature acquisition of magic-angle spinning NMR spectra of wild type AS fibrils-greatly enhances spectral sensitivity, enabling the detection of a substantially larger number of spin systems. At 0 +/- 3 degrees C sample temperature, cross polarization (CP) experiments yield weak signals. Lower temperature spectra (-40 +/- 3 degrees C) demonstrated several times greater signal intensity, an effect further amplified in 3D 15N-13C-13C experiments, which are required to perform backbone assignments on this sample. Thus 3D experiments enabled assignments of most amino acids in the rigid part of the fibril (approximately residues 64 to 94), as well as tentative site-specific assignments for T22, V26, A27, Y39, G41, S42, H50, V52, A53, T54, V55, V63, A107, I112, and S129. Most of these signals were not observed in 2D or 3D spectra at 0 +/- 3 degrees C. Spectra acquired at low temperatures therefore permitted more complete chemical shift assignments. Observation of the majority of residues in AS fibrils represents an important step towards solving the 3D structure.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 113,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors. DNA methylation at promoter CpG islands (CGI) is an epigenetic modification associated with inappropriate gene silencing in multiple tumor types. In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20. Sustained knockdown induced reexpression of the fully methylated and normally imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite restriction analysis (COBRA) revealed that reexpression of Nnat was associated with partial CGI demethylation, which was also observed at the H19 differentially methylated region. Subsequent genome-wide microarray analysis identified 91 genes that were significantly differentially expressed in Dnmt1 knockdown cells (10% false discovery rate). The analysis showed that genes associated with the induction of apoptosis, signal transduction, and developmental processes were significantly overrepresented in this list (P < 0.05). Following validation by reverse transcription-PCR and detection of inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and S100A10) were analyzed in primary human pituitary tumors, each displaying significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For two of these genes, NNAT and S100A10, decreased expression was associated with increased promoter CGI methylation. Induced expression of Nnat in stable transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is the first report of array-based \"epigenetic unmasking\" in combination with Dnmt1 knockdown and reveals the potential of this strategy toward identifying genes silenced by epigenetic mechanisms across species boundaries.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 446,
                "text": "Dnmt1"
            }
        },
        {
            "context": "In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first 'outside to in' signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of interleukin 17 (IL-17) and interferon γ production and proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA animal model using SCID mice implanted with synovium and cartilage from patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice and also reduced synovial inflammation and invasion into the implanted cartilage. A phase 2 double-blind study using tofacitinib was carried out in Japanese patients with active RA and inadequate response to methotrexate (MTX). A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1612,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Calcineurin signaling has been implicated in a broad spectrum of developmental processes in a variety of organ systems. Calcineurin is a calmodulin-dependent, calcium-activated protein phosphatase composed of catalytic and regulatory subunits. The serine/threonine-specific phosphatase functions within a signal transduction pathway that regulates gene expression and biological responses in many developmentally important cell types. Calcineurin signaling was first defined in T lymphocytes as a regulator of nuclear factor of activated T cells (NFAT) transcription factor nuclear translocation and activation. Recent studies have demonstrated the vital nature of calcium/calcineurin/NFAT signaling in cardiovascular and skeletal muscle development in vertebrates. Inhibition, mutation, or forced expression of calcineurin pathway genes result in defects or alterations in cardiomyocyte maturation, heart valve formation, vascular development, skeletal muscle differentiation and fiber-type switching, and cardiac and skeletal muscle hypertrophy. Conserved calcineurin genes are found in invertebrates such as Drosophila and Caenorhabditis elegans, and genetic studies have demonstrated specific myogenic functions for the phosphatase in their development. The ability to investigate calcineurin signaling pathways in vertebrates and model genetic organisms provides a great potential to more fully comprehend the functions of calcineurin and its interacting genes in heart, blood vessel, and muscle development.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 93,
                "text": "Calcineurin"
            }
        },
        {
            "context": "The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 482,
                "text": "ecallantide"
            }
        },
        {
            "context": "Aerial dispersal of meticillin-resistant Staphylococcus aureus in hospital rooms by infected or colonised patients. The aim of this study was to assess to what extent patients with meticillin-resistant Staphylococcus aureus (MRSA) at respiratory sites shed viable MRSA into the air of hospital rooms. We also evaluated whether the distance from the patient could influence the level of contamination. Air sampling was performed directly onto MRSA-selective agar in 24 hospital rooms containing patients with MRSA colonization or infection of the respiratory tract. Samplings were performed in duplicate at 0.5, 1 and 2-3 m from the patients' heads. Clinical and environmental isolates were compared using antimicrobial resistance patterns and pulsed-field gel electrophoresis. MRSA strains were isolated from 21 out of 24 rooms, in quantities varying from between 1 and 78 cfu/m3. In each of the 21 rooms, at least one of the environmental isolates was identical to a clinical isolate from the patient in that room. There was no significant difference in MRSA counts between the distance from the patient's head and the sampler. This study demonstrates that most patients with MRSA infection or colonisation of the respiratory tract shed viable MRSA into the air of their room. The results emphasise the need to study MRSA in air in more detail in order to improve infection control recommendations.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 264,
                "text": "MRSA"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2778,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Effect of hydroxyurea and normal plasma on DNA synthesis in lymphocytes from Fanconi anemia patients. Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited. Deoxyribonucleotides are needed in both semiconservative and repair DNA synthesis. To investigate the involvement of deoxyribonucleotide pools in the inhibition of DNA synthesis in FA, we evaluated the effect on FA lymphocytes of hydroxyurea (HU), an inhibitor of ribonucleotide reductase which is known to alter the intracellular levels of deoxyribonucleotides. To achieve this goal, lymphocyte cultures of 4 FA patients and 4 normal individuals were used. Cultures were treated with HU and/or mitomycin C and normal human plasma. All cultures were processed to detect the number of DNA synthesizing nuclei by autoradiography. Scoring of 2000 nuclei for each kind of culture every 6 h in the last 24 h of incubation showed that, in long incubation periods, DNA synthesis in FA is largely inhibited by HU and this hypersensitivity may be partially decreased by addition of normal human plasma. It is known that recovery from damage induced by HU involves several enzymes such as flavin oxido-reductase, superoxide dismutase and catalase which are involved in the production or scavenging of O2 radicals; FA cells are deficient in the detoxification of oxygen and this could explain the response of FA cells to HU.",
            "question": "What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?",
            "answers": {
                "answer_start": 102,
                "text": "Fanconi anemia"
            }
        },
        {
            "context": "Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 194,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 370,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "[Puffy hand syndrome]. Puffy hand syndrome is an unrecognized complication of intravenous drug abuse. This painless syndrome appears during or after a long period of drug addiction. It involves the hands and sometimes the forearms, and may cause functional, aesthetic and social disturbances when the hand volume is important. Physiopathological mechanisms of the puffy hand syndrome are unclear and include venous and lymphatic insufficiencies, infectious complications and direct toxicity of injected drugs and their adulterants. Low-stretch bandage and elastic garment, usually used in lymphedema treatment, are proposed to treat the puffy hand syndrome.",
            "question": "What causes \"Puffy hand syndrome\"?",
            "answers": {
                "answer_start": 78,
                "text": "intravenous drug abuse"
            }
        },
        {
            "context": "Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 814,
                "text": "orally"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. AIMS: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). RESULTS: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0 -∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. CONCLUSIONS: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 218,
                "text": "SGLT2"
            }
        },
        {
            "context": "Evaluation of the Recognition of Stroke in the Emergency Room (ROSIER) scale in Chinese patients in Hong Kong. BACKGROUND AND PURPOSE: The objective of this study was to determine the performance of the Recognition Of Stroke In the Emergency Room (ROSIER) scale in risk-stratifying Chinese patients with suspected stroke in Hong Kong. METHODS: This was a prospective cohort study in an urban academic emergency department (ED) over a 7-month period. Patients over 18 years of age with suspected stroke were recruited between June 2011 and December 2011. ROSIER scale assessment was performed in the ED triage area. Logistic regression analysis was used to estimate the impacts of diagnostic variables, including ROSIER scale, past history and ED characteristics. FINDINGS: 715 suspected stroke patients were recruited for assessment, of whom 371 (52%) had acute cerebrovascular disease (302 ischaemic strokes, 24 transient ischaemic attacks (TIA), 45 intracerebral haemorrhages), and 344 (48%) had other illnesses i.e. stroke mimics. Common stroke mimics were spinal neuropathy, dementia, labyrinthitis and sepsis. The suggested cut-off score of>0 for the ROSIER scale for stroke diagnosis gave a sensitivity of 87% (95%CI 83-90), a specificity of 41% (95%CI 36-47), a positive predictive value of 62% (95%CI 57-66), and a negative predictive value of 75% (95%CI 68-81), and the AUC was 0.723. The overall accuracy at cut off>0 was 65% i.e. (323+141)/715. INTERPRETATION: The ROSIER scale was not as effective at differentiating acute stroke from stroke mimics in Chinese patients in Hong Kong as it was in the original studies, primarily due to a much lower specificity. If the ROSIER scale is to be clinically useful in Chinese suspected stroke patients, it requires further refinement.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 1740,
                "text": "stroke"
            }
        },
        {
            "context": "emMAW: computing minimal absent words in external memory. Motivation: The biological significance of minimal absent words has been investigated in genomes of organisms from all domains of life. For instance, three minimal absent words of the human genome were found in Ebola virus genomes. There exists an O(n) -time and O(n) -space algorithm for computing all minimal absent words of a sequence of length n on a fixed-sized alphabet based on suffix arrays. A standard implementation of this algorithm, when applied to a large sequence of length n , requires more than 20 n  bytes of RAM. Such memory requirements are a significant hurdle to the computation of minimal absent words in large datasets. Results: We present emMAW, the first external-memory algorithm for computing minimal absent words. A free open-source implementation of our algorithm is made available. This allows for computation of minimal absent words on far bigger data sets than was previously possible. Our implementation requires less than 3 h on a standard workstation to process the full human genome when as little as 1 GB of RAM is made available. We stress that our implementation, despite making use of external memory, is fast; indeed, even on relatively smaller datasets when enough RAM is available to hold all necessary data structures, it is less than two times slower than state-of-the-art internal-memory implementations. Availability and implementation: https://github.com/solonas13/maw (free software under the terms of the GNU GPL). Contact: alice.heliou@lix.polytechnique.fr or solon.pissis@kcl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm is available for computing minimal absent words using external memory?",
            "answers": {
                "answer_start": 0,
                "text": "emMAW"
            }
        },
        {
            "context": "Anesthesia for deep brain stimulation in a patient with X-linked dystonia-parkinsonism/Lubag disease. Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men. This disease is characterized by dystonia dominating the first 10-15 years of the disorder, which is associated with or replaced by parkinsonian features in later years of life. A 49-year-old man with Lubag disease underwent general anesthesia for deep brain stimulation (DBS) surgery. Anesthesia was maintained mainly with propofol, remifentanil, rocuronium bromide, and sevoflurane. During magnetic resonance imaging, the patient was anesthetized with midazolam, fentanyl, and rocuronium bromide. The surgery was completed safely using these anesthetic agents. After DBS, some symptoms including involuntary movement improved within 10 days.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 129,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Specificity of Dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain. The maintenance methylation of hemimethylated CpG sites by the DNA methyltransferase Dnmt1 is the molecular basis of the inheritance of DNA methylation patterns. Based on structural data and kinetics obtained with a truncated form of Dnmt1, an autoinhibition model for the specificity of Dnmt1 was proposed in which unmethylated DNA binds to Dnmt1's CXXC domain, which prevents its methylation. We have prepared CXXC domain variants that lost DNA binding. Corresponding full-length Dnmt1 variants did not display a reduction in specificity, indicating that the autoinhibition model does not apply in full-length Dnmt1. Furthermore, we show that the Dnmt1 M1235S variant, which carries an exchange in the catalytic domain of the enzyme, has a marked reduction in specificity, indicating that the recognition of the hemimethylated state of target sites resides within the catalytic domain.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 183,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 369,
                "text": "SMA"
            }
        },
        {
            "context": "The developmental potentials of the caudalmost part of the neural crest are restricted to melanocytes and glia. The avian spinal cord is characterized by an absence of motor nerves and sensory nerves and ganglia at its caudalmost part. Since peripheral sensory neurons derive from neural crest cells, three basic mechanisms could account for this feature: (i) the caudalmost neural tube does not generate any neural crest cells; (ii) neural crest cells originating from the caudal part of the neural tube cannot give rise to dorsal root ganglia or (iii) the caudal environment is not permissive for the formation of dorsal root ganglia. To solve this problem, we have first studied the pattern of expression of ventral (HNF3beta) and dorsal (slug) marker genes in the caudal region of the neural tube; in a second approach, we have recorded the emergence of neural crest cells using the HNK1 monoclonal antibody; and finally, we have analyzed the developmental potentials of neural crest cells arising from the caudalmost part of the neural tube in avian embryo in in vitro culture and by means of heterotopic transplantations in vivo. We show here that neural crest cells arising from the neural tube located at the level of somites 47-53 can differentiate both in vitro and in vivo into melanocytes and Schwann cells but not into neurons. Furthermore, the neural tube located caudally to the last pair of somites (i.e. the 53rd pair) does not give rise to neural crest cells in any of the situations tested. The specific anatomical aspect of the avian spinal cord can thus be accounted for by limited developmental potentials of neural crest cells arising from the most caudal part of the neural tube.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 1154,
                "text": "neural crest cells"
            }
        },
        {
            "context": "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.",
            "question": "Which syndrome is associated with mutant DVL1?",
            "answers": {
                "answer_start": 86,
                "text": "Robinow syndrome"
            }
        },
        {
            "context": "Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective. Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 336,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Targeting experimental autoimmune encephalomyelitis lesions to a predetermined axonal tract system allows for refined behavioral testing in an animal model of multiple sclerosis. In multiple sclerosis (MS) the structural damage to axons determines the persistent clinical deficit patients acquire during the course of the disease. It is therefore important to test therapeutic strategies that can prevent or reverse this structural damage. The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in the central nervous system, which leads to a clinical deficit that cannot be directly attributed to a defined tract system. For this reason we have developed a localized EAE model, in which large inflammatory lesions are targeted to the dorsal columns of the spinal cord, an area including the corticospinal tract. These lesions show the pathological hallmarks of MS plaques and lead to reproducible and pronounced deficits in hindlimb locomotion. Because of the anatomical specificity of this technique we can now use highly sensitive behavioral tests that assess the functional integrity of specific axonal tracts. We show that these tests are predictive of the site and extent of a given lesion and are more sensitive for assessing the clinical course than the scales commonly used for disseminated EAE models. We believe that this targeted EAE model will become a helpful new tool for the evaluation of therapeutic approaches for MS that attempt to protect axons or support their repair.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 477,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade. X chromosome inactivation begins when a novel chromosomal RNA (cRNA) from the imprinted mouse Xist or human XIST locus coats or \"paints\" one X chromosome in cis and initiates a cascade of chromosome remodeling events. Molecular cytological studies have proven invaluable for understanding the distinctive cellular behavior of this singular RNA involved in chromosome structure and regulation. While the detailed mechanism of XIST/Xist (X-inactivation Specific Transcript) RNA function remains largely unknown, recent advances provide new insights into the complex cellular factors which impact the RNA's localization to the chromosome, as well as the early events of chromosome remodeling that follow painting by Xist RNA. Because chromatin changes can be directly visualized on a silenced chromosome, X chromosome inactivation provides an advantageous model to investigate genome-wide heterochromatin formation and maintenance, with wide-ranging implications for normal cells and disease.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 222,
                "text": "XIST"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 398,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and DNA repair through a mechanism related to homologous recombination. Recent studies show overlap between Fanconi anemia (FA) proteins and those involved in DNA repair mediated by homologous recombination (HR). However, the mechanism by which FA proteins affect HR is unclear. FA proteins (FancA/C/E/F/G/L) form a multiprotein complex, which is responsible for DNA damage-induced FancD2 monoubiquitination, a key event for cellular resistance to DNA damage. Here, we show that FANCD2-disrupted DT40 chicken B-cell line is defective in HR-mediated DNA double-strand break (DSB) repair, as well as gene conversion at the immunoglobulin light-chain locus, an event also mediated by HR. Gene conversions occurring in mutant cells were associated with decreased nontemplated mutations. In contrast to these defects, we also found increased spontaneous sister chromatid exchange (SCE) and intact Rad51 foci formation after DNA damage. Thus, we propose that FancD2 promotes a subpathway of HR that normally mediates gene conversion by a mechanism that avoids crossing over and hence SCEs.",
            "question": "What is the presumed key event in Fanconi anemia pathogenesis?",
            "answers": {
                "answer_start": 452,
                "text": "FancD2 monoubiquitination"
            }
        },
        {
            "context": "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in > 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 10,
                "text": "CD38"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 441,
                "text": "CO2"
            }
        },
        {
            "context": "Treatment of patients with the hypereosinophilic syndrome with mepolizumab. BACKGROUND: The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity. METHODS: We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks. RESULTS: The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6 months). CONCLUSIONS: Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov].).",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 559,
                "text": "interleukin-5"
            }
        },
        {
            "context": "DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation. Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 477,
                "text": "FSHD"
            }
        },
        {
            "context": "The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31 degrees C than at 37 degrees C, and their degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 272,
                "text": "TYR"
            }
        },
        {
            "context": "In-silico analysis of kallikrein gene expression in pancreatic and colon cancers. Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer. We utilized the SAGE and EST databases of the Cancer Genome Anatomy Project to perform in-silico analysis of kallikrein gene expression in normal and cancerous pancreatic and colon tissues and cell lines using virtual Northern blotting (VNB), digital differential display (DDD) and X-profiler. At least two kallikreins, KLK6 and KLK10, are significantly up-regulated in pancreatic cancer. We probed 2 normal and 6 pancreatic cancer SAGE libraries with gene-specific tags for each of these kallikreins. KLK6 was found to be expressed in 5/6 cancer libraries and showed the most marked (5-fold) increase in average expression levels in cancer vs. normal. These data were verified by screening the EST databases, where all mRNA clones isolated were from cancerous libraries, with no clones detected in normal pancreatic tissues or cell lines. X-profiler comparison of two pools of normal and cancerous pancreatic libraries further verified the significant increase of KLK6 expression levels in pancreatic cancer. DDD data showed a 13-fold increase in KLK10 expression in pancreatic cancer. Three kallikrein genes, KLK6, 8 and 10 are overexpressed in colon cancer compared to normal colon, while one kallikrein, KLK1, is down-regulated. While no expression of KLK6 was detected in normal colon, KLK6-specific tags were detectable in 2 cancer libraries. Similar results were obtained by EST screening; no KLK6 clones were detected in any of the 28 normal libraries examined, while 10 KLK6 EST clones were found in colon adenocarcinoma. KLK10 was not detectable in normal colon. Gene-specific tags were, however, detectable with high density in colon cancer and 7 EST clones were found to be expressed in colon Adenocarcinoma.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 117,
                "text": "15"
            }
        },
        {
            "context": "MITF: a stream flowing for pigment cells. Microphthalmia-associated transcription factor (MITF) is a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLHZip) structure. Mutations of the MITF gene cause a variety of phenotypes, most notably in pigmented cells, in several species. In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome. Four isoforms have been cloned so far: MITF-M is the most abundant and is expressed in neural-crest-derived melanocytes; MITF-A is expressed in various cultured cells including retinal pigment epithelium (RPE) and enriched in RPE of embryonal and developing eyes; MITF-H are expressed in many types of cultured cells and in the heart tissue; MITF-C is expressed in many types of cultured cells, but not in melanocytes. Many growth factor signaling pathways have been implicated for regulation of MITF at both protein and promoter levels. Most notably, Steel factor/c-Kit signaling pathway was linked to phosphorylation of MITF at Ser73 and Ser409 through activation of MAP kinase and RSK-1, respectively. Phosphorylation of MITF is also conducted at Ser298 through GSK3beta, although the signaling pathway for this event still remains to be elucidated. IGF-1 and HGF/SF pathways may merge with the c-Kit signaling pathway. WNT and MSH signaling pathways regulate MITF positively at the promoter level. Endothelins may regulate MITF at the protein and promoter levels. MITF is involved in the differentiation, growth and survival of pigment cells, employing a number of signaling pathways.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 332,
                "text": "MITF"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 321,
                "text": "SCFbeta-Trcp"
            }
        },
        {
            "context": "Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1780,
                "text": "CD38"
            }
        },
        {
            "context": "Non-invasive prenatal testing for fetal sex determination: is ultrasound still relevant? Early prenatal diagnosis of fetal sex is necessary to optimize pregnancy management in families known to be at risk of some heritable disorders. The demonstration of cell-free fetal DNA (cffDNA) in the mother's blood has made it possible to identify Y chromosome sequences in maternal blood and to determine fetal sex noninvasively, during the first trimester. This procedure can significantly reduce the number of invasive procedures for women with fetuses at risk of sex-linked diseases and optimize the management of these pregnancies. Fetal sex can be diagnosed by ultrasound with the same sensitivity and specificity, but later in pregnancy. We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy. We present the feasibility of the two methods and their impact on clinical practice. We applied a sensitive search of multiple bibliographic databases including Pubmed (MEDLINE), EMBASE, the Cochrane Library and Web of science between 1998 and 2013. Sixteen reports of the determination of fetal sex in maternal blood and 13 reports of the determination by ultrasound met our inclusion criteria. We found a sensitivity and specificity of nearly 100% from 8 weeks of gestation for cffDNA and from 13 weeks of gestation for ultrasound respectively. Based on this review, we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA and at an earlier gestation than ultrasound. Ten years after the first feasibility study, the French National Authority for Health (HAS) released a technological assessment report on the determination of fetal sex in maternal blood, which has resulted in validating this test for reimbursement by the national health insurance fund for the following indications: X-linked recessive disease and congenital adrenal hyperplasia.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 881,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage. OBJECTIVE: To evaluate gender differences in score on 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) and Signals Of Functional Impairment (SOFI) and to relate these scores to radiographic joint destruction. METHODS: In all, 549 patients with early RA (62% women) from the BARFOT (for \"Better Anti-Rheumatic FarmacOTherapy\") study were included. At baseline, 1, 2 and 5 years DAS28, HAQ and SOFI scoring, and radiographs of hands and feet were performed. The radiographs were scored using the van der Heijde-Sharp score. RESULTS: In women the DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were rated significantly higher in women. The SOFI score was worse in men during the first 2 years, depending on higher upper limb scores. Total Sharp score (TotSharp), erosion score and joint space narrowing score did not differ between the sexes at any time point. The DAS28 area under the curve (AUC) correlated significantly with TotSharp at 5 years in both genders (r = 0.316, r = 0.313) mainly owing to swollen joints and erythrocyte sedimentation rate (ESR). The SOFI AUC correlated significantly with TotSharp in women (r = 0.135 to 0.220) but not in men. CONCLUSIONS: Despite a similar degree of radiographic joint destruction women had, compared with men, worse scores for DAS28 and HAQ, possibly due to higher pain perception and less muscular strength and perhaps because men overestimate their functional capacity.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 704,
                "text": "women"
            }
        },
        {
            "context": "Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density. Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.",
            "question": "What is the Drosophila melanogaster Groucho protein?",
            "answers": {
                "answer_start": 108,
                "text": "Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor"
            }
        },
        {
            "context": "Stress responses in alfalfa (Medicago sativa L). XXII. cDNA cloning and characterization of an elicitor-inducible isoflavone 7-O-methyltransferase. Medicarpin, the major phytoalexin in alfalfa, is synthesized via the isoflavonoid branch of phenylpropanoid metabolism. The methyl group at the 9 position of medicarpin is generally accepted to arise via the methylation of the 4' position (B-ring) of daidzein. Surprisingly, the isoflavone-O-methyltransferase (IOMT), which is induced along with other enzymes involved in medicarpin biosynthesis, methylates the A-ring 7-hydroxyl group of daidzein in vitro, a reaction that probably does not occur in vivo. Utilizing internal amino acid sequence information from purified alfalfa IOMT, we have isolated three full-length IOMT cDNA clones. A search of the protein databases revealed sequence similarities to O-methyltransferases from various sources. The highest match (50.5% identity) was found between IOMT8 and 6a-hydroxymaackiain 3-O-methyltransferase from Pisum sativum. The molecular weight of alfalfa IOMT expressed in Escherichia coli was similar to that of purified IOMT from alfalfa cell cultures (41 kDa by SDS-PAGE). The recombinant enzyme catalyzed the O-methylation of A-ring hydroxyl group(s) of isoflavones, and could also methylate the pterocarpan (+) 6a-hydroxymaackiain. Alfalfa contains multiple IOMT genes, and closely related sequences are present in the genomes of chickpea and cowpea, species that also produce B-ring methylated isoflavonoids in vivo. Northern blot analysis indicated that IOMT transcripts are rapidly induced following elicitation, prior to the increase in IOMT activity and medicarpin accumulation. The possible role of the isoflavone 7-OMT in the synthesis of formononetin in vivo is discussed.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 148,
                "text": "Medicarpin"
            }
        },
        {
            "context": "Acupuncture in the management of post-partum headache following neuraxial analgesia. Women presenting with low pressure post-partum headache following neuraxial techniques are frequently offered an epidural blood patch, despite its inherent risks. We present two parturients with classical symptoms of low-pressure headache, who each received neuraxial labour analgesia without a documented dural puncture with a Tuohy needle. Both parturients were successfully managed using acupuncture rather than an epidural blood patch.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 503,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease. Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 291,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "[Puffy hand syndrome]. Puffy hand syndrome is an unrecognized complication of intravenous drug abuse. This painless syndrome appears during or after a long period of drug addiction. It involves the hands and sometimes the forearms, and may cause functional, aesthetic and social disturbances when the hand volume is important. Physiopathological mechanisms of the puffy hand syndrome are unclear and include venous and lymphatic insufficiencies, infectious complications and direct toxicity of injected drugs and their adulterants. Low-stretch bandage and elastic garment, usually used in lymphedema treatment, are proposed to treat the puffy hand syndrome.",
            "question": "What causes \"Puffy hand syndrome\"?",
            "answers": {
                "answer_start": 78,
                "text": "intravenous drug abuse"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 958,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "[The malaria vaccine candidate RTS,S/AS is in phase III clinical trials]. This review paper describes the development of the RTS,S/AS vaccine, from concept to phase III testing. The rationale for selection of the circumsporozoite protein (CSP) as the target antigen and the preclinical development history of the vaccine are described. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and was shown to have a favorable safety profile and to be well tolerated in both adults and children. Consistent and significant efficacy has been observed in the target population of infants and children against Plasmodium falciparum infection and disease in different transmission settings, in different age groups, with or without Expanded Program of Immunization (EPI) vaccine co-administration. The RTS,S/AS01(E) malaria vaccine candidate has recently entered phase III testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline, their partners and collaborators. If the phase III results confirm the observations made during phase II testing, the RTS,S/AS01(E) vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in sub-Saharan Africa.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 1229,
                "text": "malaria"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy (SUDEP) refers to the sudden death of a seemingly healthy individual with epilepsy, usually occurring during, or immediately after, a tonic-clonic seizure. The frequency of SUDEP varies depending on the severity of the epilepsy, but overall the risk of sudden death is more than 20 times higher than that in the general population. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. Data from a pooled analysis of risk factors indicate that the higher the frequency of tonic-clonic seizures, the higher the risk of SUDEP; furthermore, risk of SUDEP is also elevated in male patients, patients with long-duration epilepsy, and those on antiepileptic polytherapy. SUDEP usually occurs when the seizures are not witnessed and often at night. In this Seminar, we provide advice to clinicians on ways to minimise the risk of SUDEP, information to pass on to patients, and medicolegal aspects of these deaths.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 37,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 200,
                "text": "TYR"
            }
        },
        {
            "context": "Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is universally fatal. Despite surgical resection, radiotherapy, and systemic chemotherapy, the median overall survival is less than 15 months. As current therapies are not tumor-specific, treatment commonly results in toxicity. The epidermal growth factor receptor variant III (EGFRvIII) is a naturally occurring mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune responses. Phase I and II clinical trials have demonstrated significantly higher progression-free and overall survival times in vaccinated patients with EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it is a promising therapy for patients with GBM. Currently, rindopepimut is undergoing clinical testing in an international Phase III trial for newly diagnosed GBM and a Phase II trial for relapsed GBM.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 708,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "[Interdigital erythrasma: clinical, epidemiologic, and microbiologic findings]. BACKGROUND: Erythrasma is a superficial infection caused by Corynebacterium minutissimum and affects the major skin folds and the interdigital regions of the feet. It is characterized by erythematous, brown, scaly patches and maceration, and exhibits coral-red fluorescence under Wood light. OBJECTIVE: The aim of this study was to determine the frequency of erythrasma in patients with interdigital lesions. METHODS: An open, prospective, longitudinal, observational study was performed in a hospital in Mexico City between March and December, 2006. All patients with interdigital lesions were examined with a Wood lamp and direct examination was performed with 20 % potassium hydroxide. Cultures were done in Sabouraud dextrose agar and brain heart infusion agar, and smears were analyzed. General characteristics and concomitant diseases were recorded. RESULTS: We examined 73 patients, of whom 24 (32.8 %) were diagnosed with erythrasma based on coral-red fluorescence under Wood light and identification of corynebacteria by Gram staining. The disease was more common in women (83.33 %) and the mean age of the patients was 43.5 years. The main clinical findings were scaling and maceration, and the fourth interdigital web was the most commonly affected. Corynebacterium could not be isolated in any of the cases. Mycology was positive in 15 cases (62.5 %) and the following microorganisms were isolated: Candida (16.6 %), dermatophytes (12.5 %), and Trichosporon (4.1 %). CONCLUSIONS: Interdigital erythrasma is a common condition and can be easily confused with interdigital tinea. It persists if not treated appropriately. Rapid diagnosis is easily obtained by examination with a Wood lamp, while culture is difficult and unnecessary for diagnosis. The coexistence of erythrasma with dermatophytes and Candida should be considered when the interdigital webs are affected.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 140,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 794,
                "text": "xa"
            }
        },
        {
            "context": "X-chromosome inactivation during the development of the male urogenital ridge of the mouse. In the mouse, the activity of Sry (sex-determining gene on the Y chromosome) initiates the transformation of the indifferent gonad into a testis. In humans, a partial Xp21 duplication leads to the development of ovaries instead of testes in XY individuals. This observation indicates that sex determination might also be influenced by a gene-dosage compensation mechanism, in addition to a dominant action of the Sry gene. In female mammals, the regulation of X-linked gene dosage at early embryogenesis is achieved through the inactivation of one of the two X chromosomes. Here we have investigated the possibility that inactivation of the X chromosome may play a role in male sex determination. We have shown, using an X-linked lacZ transgenic mouse line, that loss of beta-galactosidase activity occurs in certain somatic cells of the developing male urogenital ridge. When changes associated with apoptosis of mesonephric tubules in the developing urogenital ridges are taken into account, expression of the Xist (X inactive specific transcript) gene correlates with X inactivation revealed by loss of beta-galactosidase activity in very early mesonephric tubule epithelial cells, gonadal interstitial mesenchymal cells and coelomic epithelial cells.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 1104,
                "text": "Xist"
            }
        },
        {
            "context": "Self-methylation of BspRI DNA-methyltransferase. The DNA (cytosine-5)-methyltransferase (m5C-MTase) M.BspRI is able to accept the methyl group from the methyl donor S-adenosyl-L-methionine (AdoMet) in the absence of DNA. Transfer of the methyl group to the enzyme is a slow reaction relative to DNA methylation. Self-methylation is dependent on the native conformation of the enzyme and is inhibited by S-adenosyl-L-homocysteine, DNA and sulfhydryl reagents. Amino acid sequencing of proteolytic peptides obtained from M.BspRI, which had been methylated with [methyl-3H]AdoMet, and thin layer chromatography of the modified amino acid identified two cysteines, Cys156 and Cys181 that bind the methyl group in form of S-methylcysteine. One of the acceptor residues, Cys156 is the highly conserved cysteine which plays the role of the catalytic nucleophile of m5C-MTases.",
            "question": "What is the methyl donor of DNA (cytosine-5)-methyltransferases?",
            "answers": {
                "answer_start": 165,
                "text": "S-adenosyl-L-methionine"
            }
        },
        {
            "context": "New synthetic antithrombotic agents for venous thromboembolism: pentasaccharides, direct thrombin inhibitors, direct Xa inhibitors. Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 814,
                "text": "xa"
            }
        },
        {
            "context": "Effect of the mutant microphthalmia-associated transcription factor found in Tietz syndrome on the in vitro development of mast cells. Mutations in microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome type 2 (WS2), a dominantly inherited disorder involving hearing loss and pigment disturbances caused by a lack of melanocytes. On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. The MITF gene is the human homolog of the mouse microphthalmia (mi) gene in some families. Mi/mi mice show decreased numbers and an abnormal phenotype of mast cells (MC). In contrast, the number and phenotype of MC in WS2/TS patients who also have an alteration in their MITF gene are unclear. In this study, we identified a mutation in the MITF gene, delR217, which was equivalent to that found in mi/mi mice, in a case of TS. None of the MITF isoforms with the mutation were able to transactivate the tyrosinase gene promoter. In addition, mutant MITF-M showed dominant negative activity toward wild-type MITF-M, inhibiting its transactivation of the tyrosinase gene promoter. The patient's peripheral blood CD34 cells showed no differences with respect to total cell number or their expression levels of tryptase mRNA in a serum-deprived liquid culture system for 6 weeks when compared with normal control cells. These findings suggest that MITF does not play a critical role in MC development in humans.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 390,
                "text": "MITF"
            }
        },
        {
            "context": "Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations. The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 316,
                "text": "5p15.3"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. The aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 185,
                "text": "FBN1"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 508,
                "text": "MethPed"
            }
        },
        {
            "context": "Monitoring and reversal strategies for new oral anticoagulants. Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and edoxaban form a new class of non-vitamin K antagonist oral anticoagulants and have been extensively studied in patients with venous thromboembolism and atrial fibrillation. They offer anticoagulation that is as effective and at least as safe compared to warfarin without the need for routine laboratory monitoring; however, no reversal strategies are currently validated in case of a non-vitamin K antagonist oral anticoagulant-associated bleed. In emergency situations, laboratory drug measurement and well-defined management for non-vitamin K antagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. In this review, the merits and limitations of the routine coagulation tests and some of the more specific laboratory assays are compared. Furthermore, prohemostatic measures are reviewed and the recommended strategies in case of bleeding are summarized. Specific reversal agents are currently under development (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and PER977 for both Xa- and thrombin inhibitors), which will facilitate clinical management of severe bleeding and emergency surgery.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1114,
                "text": "xa"
            }
        },
        {
            "context": "Role of c-Jun N-terminal kinase isoforms in the cellular activity of melanoma cell lines. BACKGROUND: The c-Jun N-terminal kinase (JNK) is thought to be involved in inflammation, proliferation and apoptosis. AIM: To examine the role of JNK isoforms in metastasis, proliferation, migration and invasion of the malignant melanoma (MM) cell lines SK-MEL-28, SK-MEL-3 and WM164, using a kinase-specific inhibitor or isoform-specific small interfering (si)RNAs. RESULTS: SK-MEL-3, a cell line established from metastatic MM, showed slightly increased phosphorylation of both JNK1 and JNK2, whereas WM164, a cell line derived from primary MM, showed significant phosphorylation of JNK1. A JNK inhibitor, SP600125, inhibited cell proliferation of SK-MEL-3 but not SK-MEL-28 or WM164. Transfection of JNK1-specific siRNA reduced the migratory activity of WM164 cells, while silencing of either JNK1 or JNK2 strongly suppressed the invasive activity of SK-MEL-3. CONCLUSIONS: Our study suggests that JNK isoforms have different roles in MM. Metastasis of MM may be regulated by JNK2, while invasion is regulated by both JNK1 and JNK2. JNK1 and JNK2 respectively mediate cell migration and cell proliferation. Further understanding of the specific roles of JNK isoforms in the pathogenesis of MM may lead to the development of therapies targeting specific isoforms.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 131,
                "text": "JNK"
            }
        },
        {
            "context": "Immunogenicity and safety of the candidate RTS,S/AS01 vaccine in young Nigerian children: a randomized, double-blind, lot-to-lot consistency trial. BACKGROUND: For regulatory approval, consistency in manufacturing of vaccine lots is expected to be demonstrated in confirmatory immunogenicity studies using two-sided equivalence trials. This randomized, double-blind study (NCT01323972) assessed consistency of three RTS,S/AS01 malaria vaccine batches formulated from commercial-scale purified antigen bulk lots in terms of anti-CS-responses induced. METHODS: Healthy children aged 5-17 months were randomized (1:1:1:1) to receive RTS,S/AS01 at 0-1-2 months from one of three commercial-scale purified antigen bulk lots (1600 litres-fermentation scale; commercial-scale lots), or a comparator vaccine batch made from pilot-scale purified antigen bulk lot (20 litres-fermentation scale; pilot-scale lot). The co-primary objectives were to first demonstrate consistency of antibody responses against circumsporozoite (CS) protein at one month post-dose 3 for the three commercial-scale lots and second demonstrate non-inferiority of anti-CS antibody responses at one month post-dose 3 for the commercial-scale lots compared to the pilot-scale lot. Safety and reactogenicity were evaluated as secondary endpoints. RESULTS: One month post-dose-3, anti-CS antibody geometric mean titres (GMT) for the 3 commercial scale lots were 319.6 EU/ml (95% confidence interval (CI): 268.9-379.8), 241.4 EU/ml (207.6-280.7), and 302.3 EU/ml (259.4-352.3). Consistency for the RTS,S/AS01 commercial-scale lots was demonstrated as the two-sided 95% CI of the anti-CS antibody GMT ratio between each pair of lots was within the range of 0.5-2.0. GMT of the pooled commercial-scale lots (285.8 EU/ml (260.7-313.3)) was non-inferior to the pilot-scale lot (271.7 EU/ml (228.5-323.1)). Each RTS,S/AS01 lot had an acceptable tolerability profile, with infrequent reports of grade 3 solicited symptoms. No safety signals were identified and no serious adverse events were considered related to vaccination. CONCLUSIONS: RTS,S/AS01 lots formulated from commercial-scale purified antigen bulk batches induced a consistent anti-CS antibody response, and the anti-CS GMT of pooled commercial-scale lots was non-inferior to that of a lot formulated from a pilot-scale antigen bulk batch.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 427,
                "text": "malaria"
            }
        },
        {
            "context": "Transcriptional regulation by MAP kinases. Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 2055,
                "text": "c-Jun NH2-terminal kinase"
            }
        },
        {
            "context": "Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. PDS5B is a sister chromatid cohesion protein that is crucial for faithful segregation of duplicated chromosomes in lower organisms. Mutations in cohesion proteins are associated with the developmental disorder Cornelia de Lange syndrome (CdLS) in humans. To delineate the physiological roles of PDS5B in mammals, we generated mice lacking PDS5B (APRIN). Pds5B-deficient mice died shortly after birth. They exhibited multiple congenital anomalies, including heart defects, cleft palate, fusion of the ribs, short limbs, distal colon aganglionosis, abnormal migration and axonal projections of sympathetic neurons, and germ cell depletion, many of which are similar to abnormalities found in humans with CdLS. Unexpectedly, we found no cohesion defects in Pds5B(-/-) cells and detected high PDS5B expression in post-mitotic neurons in the brain. These results, along with the developmental anomalies of Pds5B(-/-) mice, the presence of a DNA-binding domain in PDS5B in vertebrates and its nucleolar localization, suggest that PDS5B and the cohesin complex have important functions beyond their role in chromosomal dynamics.",
            "question": "Which syndrome is caused by deletion of Pds5b in mice?",
            "answers": {
                "answer_start": 104,
                "text": "Cornelia de Lange syndrome."
            }
        },
        {
            "context": "BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 219,
                "text": "PARP"
            }
        },
        {
            "context": "Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.",
            "question": "What do nerve-associated peripheral glial progenitors give rise to?",
            "answers": {
                "answer_start": 18,
                "text": "Parasympathetic neurons"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 286,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Despite numerous reports implicating NADPH oxidases (Nox) in the pathogenesis of many diseases, precise regulation of this family of professional reactive oxygen species (ROS) producers remains unclear. A unique member of this family, Nox1 oxidase, functions as either a canonical or hybrid system using Nox organizing subunit 1 (NoxO1) or p47(phox), respectively, the latter of which is functional in vascular smooth muscle cells (VSMC). In this manuscript, we identify critical requirement of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50; aka NHERF1) for Nox1 activation and downstream responses. Superoxide (O2 (•-)) production induced by angiotensin II (AngII) was absent in mouse EBP50 KO VSMC vs. WT. Moreover, ex vivo incubation of aortas with AngII showed a significant increase in O2 (•-) in WT but not EBP50 or Nox1 nulls. Similarly, lipopolysaccharide (LPS)-induced oxidative stress was attenuated in femoral arteries from EBP50 KO vs. WT. In silico analyses confirmed by confocal microscopy, immunoprecipitation, proximity ligation assay, FRET, and gain-/loss-of-function mutagenesis revealed binding of EBP50, via its PDZ domains, to a specific motif in p47(phox) Functional studies revealed AngII-induced hypertrophy was absent in EBP50 KOs, and in VSMC overexpressing EBP50, Nox1 gene silencing abolished VSMC hypertrophy. Finally, ex vivo measurement of lumen diameter in mouse resistance arteries exhibited attenuated AngII-induced vasoconstriction in EBP50 KO vs. WT. Taken together, our data identify EBP50 as a previously unidentified regulator of Nox1 and support that it promotes Nox1 activity by binding p47(phox) This interaction is pivotal for agonist-induced smooth muscle ROS, hypertrophy, and vasoconstriction and has implications for ROS-mediated physiological and pathophysiological processes.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 369,
                "text": "Nox1"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 0,
                "text": "methylKit"
            }
        },
        {
            "context": "Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis. A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and a major component of the inclusion bodies commonly found with a wide variety of ALS. ALS-linked mutations in UBQLN2 are clustered in a unique proline-X-X repeat region, reportedly leading to impairment of the ubiquitin proteasome system. However, the molecular properties of mutant UBQLN2 remain unclear. To gain insight into the pathogenesis of UBQLN2-linked ALS/FTD, we examined the biochemical and cellular characteristics of mutant UBQLN2 in vitro. UBQLN2 localized in Rab11-positive endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN). These vesicles were ubiquitin- and p62-immunopositive and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN vesicles. UBQLN2 was found to be a potent regulator of the levels of the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. These data suggest a novel disease spectrum and provide new pathological insights into OPTN and UBQLN2, enhancing our understanding of the molecular basis of ALS/FTD.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 179,
                "text": "amyotrophic lateral sclerosis"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 900,
                "text": "GBshape"
            }
        },
        {
            "context": "Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged > 18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING: Merck KGaA, Darmstadt, Germany.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 624,
                "text": "PD-L1"
            }
        },
        {
            "context": "SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 475,
                "text": "NCX"
            }
        },
        {
            "context": "Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. BACKGROUND: Screening medullary thyroid carcinomas (MTCs) for rearranged during transfection (RET) mutations becomes increasingly important for clinical assessment of the disease. The role of mutations in other genes including RAS (i.e. HRAS, KRAS, and NRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-akt murine thymoma viral oncogene homolog 1 (AKT1), and CTNNB1 (β-catenin) is unknown or not fully explored yet for this disease. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded (FFPE) material was the primary source for screening 13 sporadic and inherited MTCs and matched non-tumor specimens. Multiplex PCR was included in the PCR protocol. Sequence analysis encompassed mutational hotspot regions in RET exons 5, 8, 10, 11, and 13 to 16; HRAS exons 1 and 2; KRAS exons 1 and 2; NRAS exons 1 and 2; BRAF exon 15; AKT1 exon 2, and CTNNB1 exon 3. RESULTS: We identified RET mutations in seven of 13 MTCs: five RET-positive cases revealed a mutation in exon 16 (M918T) and two a mutation in exon 10 (C618S and C620S). In four of the RET-positive cases, the mutation was inherited, out of which three were reportedly associated with a multiple endocrine neoplasia type 2 (MEN2) syndrome, i.e. MEN2A (C618S), MEN2A/familial MTC (FMTC) (C620S), and MEN2B (M918T). These cases reflect the known MEN2 genotype-phenotype correlation. Three of the five stage IVc MTCs were inherited RET-positive cases. Mutational screening in HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 disclosed one sporadic RET-negative MTC (stage III) with mutation in HRAS codon 13 (G13R). CONCLUSION: Our study supports the clinical relevance of screening MTC patients for RET mutations. The role of RAS mutations, in particular HRAS mutations, in sporadic RET-negative MTC has not been fully explored yet. Mutations in BRAF, AKT1, and CTNNB1 are likely not to play a role in MTC.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1041,
                "text": "RET"
            }
        },
        {
            "context": "Update on emerging drugs for insomnia. In recent years, there has been no evidence that the problem of chronic insomnia has faded in the least in US adults; on the contrary, a recent estimate of annual lost productivity due to insomnia was $63.2 billion dollars. However, the proportion of insomniacs who are treated continues to be low, indicating the need for continued development and dissemination of effective therapies. Hypnotic drug development has arguably become more focused in recent years, particularly upon the highly anticipated novel target, the orexin (hypocretin) system. Merck's suvorexant (MK-4305) is the first compound of the so-called dual orexin receptor antagonist (DORA) class expected to be submitted for FDA approval, with a new drug application anticipated in 2012. While there has also been some new activity in the modulation of well-characterized targets with well-characterized agents, such as CNS histamine receptors with low-dose doxepin, a decades-old antidepressant and GABA(A) with sublingual zolpidem, experience with melatonin and serotonin modulators suggests that other targets also exist. Diversifying insomnia drug targets may expand possibilities for customizing hypnotic administration to individualized patient presentation and mechanistic underpinnings. In addition, it may offer improved avenues for combining medications with non-drug treatments such as cognitive behavioral therapy for insomnia (CBT-I).",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 561,
                "text": "orexin"
            }
        },
        {
            "context": "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia. BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic. METHODOLOGY AND PRINCIPLE FINDINGS: In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006. The severity of the core clinical picture with predominant sensory ataxia, gait apraxia, lower limb spasticity, cognitive impairment and bladder dysfunction correlated with the degree of MRI findings showing enlargement of inner ventricular spaces as in communicating hydrocephalus. Laboratory studies revealed transient eosinophilia during the preceding acute meningitis-like phase, but no ongoing inflammatory process in the CSF. We found immune reactions against Toxocara canis in the majority of chronic VE patients but rarely in controls (P = 0.025; Fisher's exact test). Histological analysis of subacute to subchronic VE brain samples showed eosinophilic infiltrations with no signs of persistent Toxocara canis infection. CONCLUSIONS AND SIGNIFICANCE: Our data showed that pressure by the communicating hydrocephalus as a mechanical factor is the major pathogenic mechanism in chronic VE, most likely triggered by eosinophilic meningitis. There are no signs for an ongoing inflammatory process in chronic VE. The past eosinophilic reaction in VE might be caused by Toxocara ssp. infection and might therefore represent the first hint for an initial cause leading to the development of chronic VE. Our data provide a framework for future studies and potential therapeutic interventions for this enigmatic epidemic neurological disease potentially spreading in Sakha Republic.",
            "question": "Viliuisk encephalomyelitis is diagnosed in which geographical area?",
            "answers": {
                "answer_start": 222,
                "text": "Northeast Siberia"
            }
        },
        {
            "context": "Communicating hydrocephalus following eosinophilic meningitis is pathogenic for chronic Viliuisk encephalomyelitis in Northeastern Siberia. BACKGROUND: Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeast Siberia and generally considered to be a chronic encephalomyelitis of unknown origin actually spreading in the Sakha (Yakutian) Republic. METHODOLOGY AND PRINCIPLE FINDINGS: In search for the pathophysiology and causative agent of VE, we performed a cross-sectional study on clinical, serological and neuroimaging data on chronic VE patients during two medical expeditions to three villages within the Viliuiski river basin in the Republic of Sakha in 2000 and to the capital Yakutsk in 2006. The severity of the core clinical picture with predominant sensory ataxia, gait apraxia, lower limb spasticity, cognitive impairment and bladder dysfunction correlated with the degree of MRI findings showing enlargement of inner ventricular spaces as in communicating hydrocephalus. Laboratory studies revealed transient eosinophilia during the preceding acute meningitis-like phase, but no ongoing inflammatory process in the CSF. We found immune reactions against Toxocara canis in the majority of chronic VE patients but rarely in controls (P = 0.025; Fisher's exact test). Histological analysis of subacute to subchronic VE brain samples showed eosinophilic infiltrations with no signs of persistent Toxocara canis infection. CONCLUSIONS AND SIGNIFICANCE: Our data showed that pressure by the communicating hydrocephalus as a mechanical factor is the major pathogenic mechanism in chronic VE, most likely triggered by eosinophilic meningitis. There are no signs for an ongoing inflammatory process in chronic VE. The past eosinophilic reaction in VE might be caused by Toxocara ssp. infection and might therefore represent the first hint for an initial cause leading to the development of chronic VE. Our data provide a framework for future studies and potential therapeutic interventions for this enigmatic epidemic neurological disease potentially spreading in Sakha Republic.",
            "question": "Viliuisk encephalomyelitis is diagnosed in which geographical area?",
            "answers": {
                "answer_start": 222,
                "text": "Northeast Siberia"
            }
        },
        {
            "context": "Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 989,
                "text": "FSHD"
            }
        },
        {
            "context": "Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 310,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Salivary adiponectin levels are associated with training intensity but not with bone mass or reproductive function in elite Rhythmic Gymnasts. Elite Rhythmic Gymnasts (RGs) constitute a unique metabolic model and they are prone to developing Anorexia Athletica. The aim of the present study was to evaluate the effect of training intensity on salivary adiponectin levels and assess a possible role of salivary adiponectin levels as a predictive factor of reproductive dysfunction and bone mass acquisition in elite RGs. The study included 80 elite female RGs participating in the World Rhythmic Gymnastics Championship tournament held in Montpellier, France on September 2011. Anthropometric values were assessed, training data and menstrual pattern were recorded, bone mass was measured with Broadband ultrasound attenuation (dB/Mhz) and baseline salivary adiponectin levels were determined. The athletes were classified as intensely and very intensely trained, considering the mean training intensity (40.84h/week). Moreover, considering their reproductive status, they were divided into RG's with normal menstruation, primary amenorrhea and oligomenorrhea. All comparisons were adjusted to age, BMI and body fat percentage differences. Very intensely trained RGs showed higher salivary adiponectin levels (p=0.05). Moreover, salivary adiponectin levels showed significant correlation with training intensity (r=0.409, p=0.003). On the other hand, no association of salivary adiponectin levels was documented with either reproductive function or bone mass acquisition. The results of the present study suggest that, in elite RGs, salivary adiponectin levels are associated with the intensity of training, possibly reflecting the deterioration of energy balance rather than the training stress. On the other hand, a predictive role of salivary adiponectin levels in reproductive dysfunction or bone mass acquisition could not be supported.",
            "question": "What is the name for anorexia in gymnasts?",
            "answers": {
                "answer_start": 242,
                "text": "Anorexia Athletica"
            }
        },
        {
            "context": "Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that manifests in females, typically after the first year of life. It is a leading cause of mental retardation and autistic behavior in girls and women; a hallmark of the disease is incessant hand movements in the form of wringing, twisting, or clapping. It was recently discovered that RTT is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. MECP2 assists in the transcriptional silencing process via DNA methylation; we hypothesize that disruption of this gene alters the normal developmental expression of various other genes, some of which must account for the peculiar neurologic phenotype of RTT. Molecular studies have identified MECP2 mutations in up to 80% of classic RTT patients; mutation type has some effect on the phenotypic manifestation of RTT, but the pattern of X inactivation seems to determine phenotypic severity. Favorable (skewed) X inactivation can so spare a patient from the effects of mutant MECP2 that they display only the mildest learning disability or no phenotype at all. The unmitigated impact of mutant MECP2 can be inferred from the few males who have been born into RTT kindreds with such severe neonatal encephalopathy that they did not survive their second year. MECP2 mutations thus manifest in a far broader array of phenotypes than classic RTT. This discovery should prove helpful in diagnosing cases of mild learning disability or severe neonatal encephalopathies of unknown cause and also should provide insight into the pathogenesis of RTT.",
            "question": "Which methyl-CpG-binding protein when mutant becomes the hallmark for Rett syndrome?",
            "answers": {
                "answer_start": 484,
                "text": "methyl-CpG-binding protein 2 (MECP2)"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 222,
                "text": "SERCA"
            }
        },
        {
            "context": "Lewy Bodies and the Mechanisms of Neuronal Cell Death in Parkinson's Disease and Dementia with Lewy Bodies. Neuronal loss in specific brain regions and neurons with intracellular inclusions termed Lewy bodies are the pathologic hallmark in both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies comprise of aggregated intracellular vesicles and proteins and α-synuclein is reported to be a major protein component. Using human brain tissue from control, PD and DLB and light and confocal immunohistochemistry with antibodies to superoxide dismutase 2 as a marker for mitochondria, α-synuclein for Lewy bodies and βIII Tubulin for microtubules we have examined the relationship between Lewy bodies and mitochondrial loss. We have shown microtubule regression and mitochondrial and nuclear degradation in neurons with developing Lewy bodies. In PD, multiple Lewy bodies were often observed with α-synuclein interacting with DNA to cause marked nuclear degradation. In DLB, the mitochondria are drawn into the Lewy body and the mitochondrial integrity is lost. This work suggests that Lewy bodies are cytotoxic. In DLB, we suggest that microtubule regression and mitochondrial loss results in decreased cellular energy and axonal transport that leads to cell death. In PD, α-synuclein aggregations are associated with intact mitochondria but interacts with and causes nuclear degradation which may be the major cause of cell death.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 382,
                "text": "α-synuclein"
            }
        },
        {
            "context": "Regulated specific proteolysis of the Cajal body marker protein coilin. Cajal bodies (CB) are subnuclear domains that contain various proteins with diverse functions including the CB marker protein coilin. In this study, we investigate the proteolytic activity of calpain on coilin. Here, we report a 28-kDa cleaved coilin fragment detected by two coilin antibodies that is cell cycle regulated, with levels that are consistently reduced during mitosis. We further show that an in vitro calpain assay with full-length or C-terminal coilin recombinant protein releases the same size cleaved fragment. Furthermore, addition of exogenous RNA to purified coilin induces proteolysis by calpain. We also report that the relative levels of this cleaved coilin fragment are susceptible to changes induced by various cell stressors, and that coilin localization is affected by inhibition or knockdown of calpain both under normal and stressed conditions. Collectively, our data suggest that coilin is subjected to regulated specific proteolysis by calpain, and this processing may play a role in the regulation of coilin activity and CB formation.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 198,
                "text": "coilin"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 822,
                "text": "Xa"
            }
        },
        {
            "context": "Phosphorylation of serine-515 activates the Mammalian maintenance methyltransferase Dnmt1. DNA methyltransferase 1 methylates hemi-methylated CG sites generated during DNA replication. Serine 515 of this enzyme has been shown to be phosphorylated. To explore the importance of S515 phosphorylation, we generated mutants of Dnmt1 which removed the phosphorylation potential (S515A) or mimic phosphoserine (S515E), purified the proteins from insect cells and analyzed their DNA methylation activity in vitro. The S515E mutant was found to be active, while S515A mutant had severe loss in activity when compared to the wild type protein. The loss of activity of the S515A variant was not due to loss of DNA binding capacity. Furthermore, we show that a phosphorylated peptide whose sequence mimics the surrounding of Ser515 (EKIYIS(P)KIVVE) inhibited the activity of wild type Dnmt1 ten-fold more than the non-phosphorylated peptide. The inhibition was specific for Dnmt1 and for the particular peptide sequence. Our data suggest that phosphorylation of Ser515 is important for an interaction between the N-terminal domain of Dnmt1 and its catalytic domain that is necessary for activity and that this interaction is specifically disrupted by the phosphorylated peptide. We conclude that phosphorylation of Dnmt1 at Ser515 could be an important regulator of Dnmt1 activity during cell cycle and after proliferative stimuli.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 84,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 486,
                "text": "NCX"
            }
        },
        {
            "context": "Digital dermatoglyphics of Turner's syndrome. The proposition that finger print variability between individuals might be reduced by the absence of an X-chromosome in Turner's syndrome was rejected. In the present study of 58 XO patients, aged 15-50 years, relatives of several cases, unrelated female control samples and three unrelated male samples were investigated. The higher mean value of the TRC among patients supported the hypothesis forwarded by Penrose that an added X- or Y-chromosome reduces the TRC and a missing one increasing it. The figures do not speak against the hypothesis that genes affecting the TRC are located on the X-chromosome. A summary of the major dermatoglyphic investigations in Turner's syndrome is presented.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 150,
                "text": "X"
            }
        },
        {
            "context": "Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. In cells of the immune system that are stimulated by antigen or antigen-antibody complexes, Ca(2+) entry from the extracellular medium is driven by depletion of endoplasmic reticulum Ca(2+) stores and occurs through specialized store-operated Ca(2+) channels known as Ca(2+)-release-activated Ca(2+) (CRAC) channels. The process of store-operated Ca(2+) influx is essential for short-term as well as long-term responses by immune-system cells. Short-term responses include mast cell degranulation and killing of target cells by effector cytolytic T cells, whereas long-term responses typically involve changes in gene transcription and include T and B cell proliferation and differentiation. Transcription downstream of Ca(2+) influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin. The importance of the Ca(2+)/calcineurin/NFAT signalling pathway for lymphocyte activation is underscored by the finding that the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca(2+) entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defence. We recently used a two-pronged genetic approach to identify Orai1 as the pore subunit of the CRAC channel. On the one hand, we initiated a positional cloning approach in which we utilised genome-wide single nucleotide polymorphism (SNP) mapping to identify the genomic region linked to the mutant gene in the SCID family described above. In parallel, we used a genome-wide RNAi screen in Drosophila to identify critical regulators of NFAT nuclear translocation and store-operated Ca(2+) entry. These approaches, together with subsequent mutational and electrophysiological analyses, converged to identify human Orai1 as a pore subunit of the CRAC channel and as the gene product mutated in the SCID patients.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 1106,
                "text": "calcineurin"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 1618,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1600,
                "text": "CD38"
            }
        },
        {
            "context": "[Apert syndrome. Ultrasonic diagnosis, obstetrical management]. We report two observations of antenatal diagnosis of Apert syndrome. This uncommon genetic disorder suggest an autosomal dominant inheritance, but almost all cases described are sporadic; the responsible gene is yet not located. Ultrasonographic detection is difficult, based on the following signs: brachycephalic skull (unusually detected), flat facial profile with a nasal bridge depression, tall appearance of the forehead (inconstant), total bilateral and symmetrical syndactylies of the hands and feet. At last we present our arguments for medical abortion, when this disorder is detected.",
            "question": "What is the inheritance pattern of Apert syndrome?",
            "answers": {
                "answer_start": 175,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "dsPIG: a tool to predict imprinted genes from the deep sequencing of whole transcriptomes. BACKGROUND: Dysregulation of imprinted genes, which are expressed in a parent-of-origin-specific manner, plays an important role in various human diseases, such as cancer and behavioral disorder. To date, however, fewer than 100 imprinted genes have been identified in the human genome. The recent availability of high-throughput technology makes it possible to have large-scale prediction of imprinted genes. Here we propose a Bayesian model (dsPIG) to predict imprinted genes on the basis of allelic expression observed in mRNA-Seq data of independent human tissues. RESULTS: Our model (dsPIG) was capable of identifying imprinted genes with high sensitivity and specificity and a low false discovery rate when the number of sequenced tissue samples was fairly large, according to simulations. By applying dsPIG to the mRNA-Seq data, we predicted 94 imprinted genes in 20 cerebellum samples and 57 imprinted genes in 9 diverse tissue samples with expected low false discovery rates. We also assessed dsPIG using previously validated imprinted and non-imprinted genes. With simulations, we further analyzed how imbalanced allelic expression of non-imprinted genes or different minor allele frequencies affected the predictions of dsPIG. Interestingly, we found that, among biallelically expressed genes, at least 18 genes expressed significantly more transcripts from one allele than the other among different individuals and tissues. CONCLUSION: With the prevalence of the mRNA-Seq technology, dsPIG has become a useful tool for analysis of allelic expression and large-scale prediction of imprinted genes. For ease of use, we have set up a web service and also provided an R package for dsPIG at http://www.shoudanliang.com/dsPIG/.",
            "question": "How many genes are imprinted in the human genome?",
            "answers": {
                "answer_start": 304,
                "text": " fewer than 100"
            }
        },
        {
            "context": "The emergence and importation of diverse genotypes of methicillin-resistant Staphylococcus aureus (MRSA) harboring the Panton-Valentine leukocidin gene (pvl) reveal that pvl is a poor marker for community-acquired MRSA strains in Ireland. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) carrying pvl is an emerging problem worldwide. CA-MRSA tends to harbor staphylococcal cassette chromosome mec type IV (SCCmec IV), to be non-multiantibiotic resistant, and to have different genotypes from the local hospital-acquired MRSA (HA-MRSA). However, in Ireland, 80% of HA-MRSA isolates have the non-multiantibiotic-resistant genotype ST22-MRSA-IV. This study investigated MRSA isolates from Ireland (CA-MRSA, health care-associated MRSA, and HA-MRSA) for the carriage of pvl and determined the genotypic characteristics of all pvl-positive isolates identified. All 1,389 MRSA isolates were investigated by antibiogram-resistogram typing and SmaI DNA macrorestriction analysis. pvl-positive isolates were further characterized by multilocus sequence typing and SCCmec, agr, and toxin gene typing. Twenty-five (1.8%) MRSA isolates belonging to six genotypes (ST30, ST8, ST22, ST80, ST5, and ST154) harbored pvl. Nineteen of these (76%) were CA-MRSA isolates, but a prospective study of MRSA isolates from 401 patients showed that only 6.7% (2/30) of patients with CA-MRSA yielded pvl-positive isolates. Thus, pvl cannot be used as a sole marker for CA-MRSA. Fifty-two percent of pvl-positive MRSA isolates were recovered from patients with skin and soft tissue infections; thirty-six percent were from patients of non-Irish ethnic origin, reflecting the increasing heterogeneity of the Irish population due to immigration. All 25 pvl-positive isolates carried SCCmec IV; 14 (56%) harbored SCCmec IV.1 or IV.3, and the remaining 11 isolates could not be subtyped. This study demonstrates that pvl is not a reliable marker for CA-MRSA in Ireland and reveals the emergence and importation of diverse genotypes of pvl-positive MRSA in Ireland.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 99,
                "text": "MRSA"
            }
        },
        {
            "context": "The partial 5-HT(1A) agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy. Dopamine (DA) replacement therapy with l-DOPA remains the standard pharmacotherapy for Parkinson's disease (PD). Unfortunately, chronic l-DOPA treatment is accompanied by development of motor fluctuations and l-DOPA-induced dyskinesia (LID). While serotonin (5-HT)(1A) agonists acutely reduce these complications, their prophylactic and long-term effects are not well-delineated. To test this, male Sprague-Dawley rats received unilateral 6-hydroxydopamine (6-OHDA) lesions. In experiment 1, l-DOPA-primed rats were pre-treated with Vehicle (0.9% NaCl), various doses of the partial 5-HT(1A) agonist, buspirone (0.25, 1.0 or 2.5 mg/kg, ip) or buspirone (2.5 mg/kg, ip)+the 5-HT(1A) antagonist, WAY100635 (0.5 mg/kg, ip) 5 min prior to l-DOPA (12 mg/kg+15 mg/kg benserazide, ip). Rats were tested for LID using the abnormal involuntary movements (AIMs) scale and motor performance using the forepaw adjusting steps test (FAS). In experiment 2, l-DOPA-naïve rats received co-administration of l-DOPA+buspirone (1.0 or 2.5 mg/kg, ip) for 2 weeks. AIMs and FAS were measured throughout. In l-DOPA-primed rats, buspirone dose-dependently reduced LID and improved l-DOPA-related motor performance due to action at the 5-HT(1A) receptor. In l-DOPA-naïve rats, buspirone delayed LID development while improving l-DOPA's anti-parkinsonian efficacy indicating the potential long-term benefits of 5-HT(1A) agonists for reduction of l-DOPA-related side effects.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 637,
                "text": "l-DOPA"
            }
        },
        {
            "context": "The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes. Nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase (JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured astrocytes. In view of the previous observation that NO stimulates the activity of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 606,
                "text": "NCX"
            }
        },
        {
            "context": "Risk stratification and role of implantable defibrillators for prevention of sudden death in patients with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young people, including trained athletes. It is now 30 years since the introduction of implantable cardioverter-defibrillators (ICDs) to clinical cardiovascular practice and coronary artery disease, and now device therapy represents the most significant therapeutic innovation and the only definitive strategy for prolonging the life of HCM patients. ICDs have proved effective in preventing SCD in young HCM patients with appropriate intervention rates of 11% for secondary and 4% for primary prevention, despite massive left ventricular (LV) hypertrophy, LV outflow obstruction, diastolic dysfunction or microvascular ischemia. Targeting candidates for prophylactic ICD therapy can be complex, compounded by the unpredictability of the arrhythmogenic substrate, the absence of a dominant risk factor, and difficulty in assembling randomized trials. However, a single major risk factor is often sufficient to justify an ICD, although additional markers and other disease features can resolve ambiguous decision-making. Nevertheless, the absence of all risk factors does not convey absolute immunity to SCD. The current risk factor algorithm, when combined with a measure of individual physician judgment (and patient autonomy considerations), is an effective guide to identifying high-risk HCM patients. ICDs have altered the natural history of HCM for many patients and provided an opportunity to achieve many decades of productive life, and the potential for normal or near-normal longevity. Indeed, prevention of SCD has now become a new paradigm in the management of HCM.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 136,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Distribution of Clostridium difficile PCR ribotypes and high proportion of 027 and 176 in some hospitals in four South Eastern European countries. While Clostridium difficile epidemiology is well documented in many European countries, data are largely missing for South Eastern European region. Here we report the PCR ribotype distribution of 249 C. difficile isolates received for typing from six hospital settings from Croatia, Bosnia and Herzegovina, Republic of Macedonia and Serbia in time period from 2008 to 2015. Twenty-four PCR ribotypes were detected. The majority of strains from Bosnia and Herzegovina and Serbia belonged to PCR ribotype 027 (65.8%). Other three dominating PCR ribotypes were 176 (18 strains; Croatia), 001/072 (15 strains; all countries) and 014/020 (15 strains; all countries).",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 641,
                "text": "ribotype 027"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 0,
                "text": "chromDraw"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 75,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 433,
                "text": "Xa"
            }
        },
        {
            "context": "Specific targeted therapy of chronic myelogenous leukemia with imatinib. Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 446,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Direct comparison of [(18) F]MH.MZ and [(18) F] altanserin for 5-HT2A receptor imaging with PET. Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 1411,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1644,
                "text": "Xa"
            }
        },
        {
            "context": "BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1126,
                "text": "7"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 337,
                "text": "OikoBase"
            }
        },
        {
            "context": "Investigating genotype-phenotype relationships in Rett syndrome using an international data set. BACKGROUND: Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort. METHOD: The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). RESULTS: Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. CONCLUSIONS: This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.",
            "question": "Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2?",
            "answers": {
                "answer_start": 1273,
                "text": "Rett syndrome"
            }
        },
        {
            "context": "Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. OBJECTIVE: To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia. METHODS: We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep. RESULTS: Suvorexant showed significant (p values <0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated. CONCLUSIONS: The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 0,
                "text": "Orexin"
            }
        },
        {
            "context": "Expression and function of Noxo1gamma, an alternative splicing form of the NADPH oxidase organizer 1. Activation of the superoxide-producing NADPH oxidase Nox1 requires both the organizer protein Noxo1 and the activator protein Noxa1. Here we describe an alternative splicing form of Noxo1, Noxo1gamma, which is expressed in the testis and fetal brain. The Noxo1gamma protein contains an additional five amino acids in the N-terminal PX domain, a phosphoinositide-binding module; the domain plays an essential role in supporting superoxide production by NADPH oxidase (Nox) family oxidases including Nox1, gp91(phox)/Nox2, and Nox3, as shown in this study. The PX domain isolated from Noxo1gamma shows a lower affinity for phosphoinositides than that from the classical splicing form Noxo1beta. Consistent with this, in resting cells, Noxo1gamma is poorly localized to the membrane, and thus less effective in activating Nox1 than Noxo1beta, which is constitutively present at the membrane. On the other hand, cell stimulation with phorbol 12-myristate 13-acetate (PMA), an activator of Nox1-3, facilitates membrane translocation of Noxo1gamma; as a result, Noxo1gamma is equivalent to Noxo1beta in Nox1 activation in PMA-stimulated cells. The effect of the five-amino-acid insertion in the Noxo1 PX domain appears to depend on the type of Nox; in activation of gp91(phox)/Nox2, Noxo1gamma is less active than Noxo1beta even in the presence of PMA, whereas Noxo1gamma and Noxo1beta support the superoxide-producing activity of Nox3 to the same extent in a manner independent of cell stimulation.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 155,
                "text": "Nox1"
            }
        },
        {
            "context": "The JNK phosphatase M3/6 is inhibited by protein-damaging stress. Cells respond to stresses such as osmotic shock and heat shock by activating stress-activated protein kinases (SAPKs), including c-Jun N-terminal kinase (JNK) [1]. Activation of JNK requires phosphorylation of threonine and tyrosine residues in the TPY activation loop motif [2, 3] and can be reversed by the removal of either phosphate group. Numerous JNK phosphatases including dual-specificity phosphatases [4, 5], have been identified. Many stimuli activate JNK by increasing its rate of phosphorylation; however, JNK dephosphorylation is inhibited in cells after heat shock [6], suggesting that a JNK phosphatase(s) is inactivated. M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]. We have previously expressed M3/6 in the mouse bone marrow cell line BAF3 in order to show that JNK activation by IL-3 is necessary for cell survival and proliferation [9]. Here we report that M3/6 dissociates from JNK and appears in an insoluble fraction after heat shock. These data identify M3/6 as a JNK phosphatase that is inactivated by heat shock and provide a molecular mechanism for the activation of JNK by heat shock.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 756,
                "text": "JNK"
            }
        },
        {
            "context": "Incremental diagnostic quality gain of CTA over V/Q scan in the assessment of pulmonary embolism by means of a Wells score Bayesian model: results from the ACDC collaboration. OBJECTIVE: Our objective was to evaluate the diagnostic value of computed tomography angiography (CTA) and ventilation perfusion (V/Q) scan in the assessment of pulmonary embolism (PE) by means of a Bayesian statistical model. METHODS: Wells criteria defined pretest probability. Sensitivity and specificity of CTA and V/Q scan for PE were derived from pooled meta-analysis data. Likelihood ratios calculated for CTA and V/Q were inserted in the nomogram. Absolute (ADG) and relative diagnostic gains (RDG) were analyzed comparing post- and pretest probability. Comparative gain difference was calculated for CTA ADG over V/Q scan integrating ANOVA p value set at 0.05. RESULTS: The sensitivity for CT was 86.0% (95% CI: 80.2%, 92.1%) and specificity of 93.7% (95% CI: 91.1%, 96.3%). The V/Q scan yielded a sensitivity of 96% (95% CI: 95%, 97%) and a specificity of 97% (95% CI: 96%, 98%). Bayes nomogram results for CTA were low risk and yielded a posttest probability of 71.1%, an ADG of 56.1%, and an RDG of 374%, moderate-risk posttest probability was 85.1%, an ADG of 56.1%, and an RDG of 193.4%, and high-risk posttest probability was 95.2%, an ADG of 36.2%, and an RDG of 61.35%. The comparative gain difference for low-risk population was 46.1%; in moderate-risk 41.6%; and in high-risk a 22.1% superiority. ANOVA analysis for LR+ and LR- showed no significant difference (p = 0.8745, p = 0.9841 respectively). CONCLUSIONS: This Bayesian model demonstrated a superiority of CTA when compared to V/Q scan for the diagnosis of pulmonary embolism. Low-risk patients are recognized to have a superior overall comparative gain favoring CTA.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 78,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Antimigraine efficacy of telcagepant based on patient's historical triptan response. OBJECTIVE: To evaluate whether the same or different patients respond to triptans and telcagepant. BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans. It is currently unknown whether migraine patients who cannot be adequately helped with triptans might benefit from treatment with telcagepant. METHODS: Post-hoc analysis of data from a randomized, controlled trial of telcagepant (150 mg, 300 mg) zolmitriptan 5 mg, or placebo for a moderate/severe migraine. Responder rates were analyzed according to patients' self-reported historical triptan response (HTR): (1) good HTR (N = 660): response in 75-100% of attacks; (2) intermediate HTR (N = 248): response in 25-74% of attacks; (3) poor HTR/no use (N = 407): response in < 25% of attacks, or patient did not take triptans. A limitation of the analysis is that the last subgroup comprised mainly (91%) patients who reported that they did not take triptans, but it was not known whether these patients were triptan-naïve or had previously used triptans and stopped taking them. RESULTS: For zolmitriptan, 2-hour pain relief rates were higher in the good HTR subgroup (116/162, 72%) than in the intermediate (29/62, 47%) and poor/no use (44/111, 40%) HTR subgroups. The 2-hour pain relief rates were similar across HTR subgroups for telcagepant 150 mg (48-58%), 300 mg (52-58%), and placebo (26-31%). In the poor/no use HTR subgroup, more patients receiving telcagepant 300 mg (56/98, 57.1%) had 2-hour pain relief than those receiving zolmitriptan (44/111, 39.6%; odds ratio = 2.11 [95% CI: 1.20,3.71], P = .009); the percentage for telcagepant 150 mg (57/119, 47.9%) was not significantly different from zolmitriptan (odds ratio = 1.41 [95% CI: 0.82, 2.40], P = .211). CONCLUSIONS: This suggests that different patients may respond to triptans or telcagepant 300 mg. Caution should be exercised in interpreting the results because of the post-hoc nature of the analysis (clinical trial registry: NCT00442936).",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 219,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: microcephaly, developmental delay and delayed bone age. Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors. Here, we report on a 14-month-old boy with a reverse phenotype of Sotos syndrome due to the reciprocal duplication of the 5q35.3 region, including the NSD1 gene, detected by array CGH. The phenotype includes delayed bone age, microcephaly, seizures, and failure to thrive. Our case suggests that the gene dosage effect of the NSD1 gene is the likely cause for the reversed phenotype of Sotos syndrome in this patient.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 184,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.",
            "question": "Which peptide plays a pivotal role in human cystatin C fibrillization?",
            "answers": {
                "answer_start": 767,
                "text": "LQVVR"
            }
        },
        {
            "context": "Coilin, more than a molecular marker of the cajal (coiled) body. The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 0,
                "text": "Coilin"
            }
        },
        {
            "context": "Is there a SERM in your menopause toolkit? Over the past 3 decades, compounds called selective estrogen receptor modulators (SERMs) have been developed that block the estrogen receptor in some tissues (estrogen receptor antagonists) or stimulate the estrogen receptor in other tissues (estrogen receptor agonists). This Practice Pearl focuses on SERMs that clinicians can use for menopausal patients.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 85,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on human non-small cell lung cancer cells. The antitumor effect of CGP41251 (4'-N-benzoyl staurosporine), a selective protein kinase C (PKC) inhibitor, was examined on two kinds of human non-small cell lung cancer (NSCLC) cell lines (adenocarcinoma: A549 and squamous cell carcinoma: NCI-H520). CGP41251 at 0.5 or 1.0 microM inhibited the proliferation of these tumor cell lines significantly; However, at 0.1 microM, it did not show any significant inhibition. Cell cycle analysis indicated that CGP41251 at 0.5 or 1.0 microM arrested the cell cycle progression at the G2/M phase up to 24 hr, but 0.1 microM did not. It seems that the antiproliferative action of CGP41251 against human NSCLC is related to G2/M accumulation. In NCI-H520, CGP41251 caused DNA re-replication without mitosis. In a nude mice xenograft, CGP41251 at a dose of 200 mg/kg showed antitumor activity against these cell lines. Histopathologically, expansion of central necrosis was observed, although no destruction of tumor nests was seen by CGP41251 administration. In both tumor tissues, the PKC activity of the particulate fraction was significantly decreased by CGP41251 treatment. From these results, it is thought that the antitumor activity of CGP41251 against human NSCLS is accompanied by the decrease of PKC activity in the particulate fraction. Moreover, the G2/M arrest of the cell cycle induced by CGP41251 might be important for the growth inhibitory action of this compound.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 261,
                "text": "non-small cell lung cancer"
            }
        },
        {
            "context": "Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. Although pharmacologic therapies have provided gains in reducing the mortality of heart failure, the rising incidence of the disease requires new approaches to combat its health burden. Twenty-five years ago, abnormal calcium cycling was identified as a characteristic of failing human myocardium. Sarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling. With the advancement of gene vectors, SERCA2a emerged as an attractive clinical target for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a upregulation has been found to improve myocardial function in animal models. The clinical benefits of overexpressing SERCA2a have been demonstrated in the phase I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID). This study has demonstrated that a persistent expression of the transgene SERCA2a is associated with a significant improvement in associated biochemical alterations and clinical symptoms of heart failure. In the coming years, additional targets will likely emerge that are amenable to genetic manipulations along with the development of more advanced vector systems with safer delivery approaches.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 402,
                "text": "SERCA"
            }
        },
        {
            "context": "Novel anticoagulants for stroke prevention in atrial fibrillation: current clinical evidence and future developments. Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 726,
                "text": "xa"
            }
        },
        {
            "context": "Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 708,
                "text": "NF1"
            }
        },
        {
            "context": "Molecular interaction of NADPH oxidase 1 with betaPix and Nox Organizer 1. It is well established that growth-factor-induced reactive oxygen species (ROS) act as second messengers in cell signaling. We have previously reported that betaPix, a guanine nucleotide exchange factor for Rac, interacts with NADPH oxidase 1 (Nox1) leading to EGF-induced ROS generation. Here, we report the identification of the domains of Nox1 and betaPix responsible for the interaction between the two proteins. GST pull-down assays show that the PH domain of betaPix binds to the FAD-binding region of Nox1. We also show that overexpression of the PH domain of betaPix results in inhibition of superoxide anion generation in response to EGF. Additionally, NADPH oxidase Organizer 1 (NoxO1) is shown to interact with the NADPH-binding region of Nox1. These results suggest that the formation of the complex consisting of Nox1, betaPix, and NoxO1 is likely to be a critical step in EGF-induced ROS generation.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 25,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "Can the FAST and ROSIER adult stroke recognition tools be applied to confirmed childhood arterial ischemic stroke? BACKGROUND: Stroke recognition tools have been shown to improve diagnostic accuracy in adults. Development of a similar tool in children is needed to reduce lag time to diagnosis. A critical first step is to determine whether adult stoke scales can be applied in childhood stroke.Our objective was to assess the applicability of adult stroke scales in childhood arterial ischemic stroke (AIS) METHODS: Children aged 1 month to < 18 years with radiologically confirmed acute AIS who presented to a tertiary emergency department (ED) (2003 to 2008) were identified retrospectively. Signs, symptoms, risk factors and initial management were extracted. Two adult stroke recognition tools; ROSIER (Recognition of Stroke in the Emergency Room) and FAST (Face Arm Speech Test) scales were applied retrospectively to all patients to determine test sensitivity. RESULTS: 47 children with AIS were identified. 34 had anterior, 12 had posterior and 1 child had anterior and posterior circulation infarcts. Median age was 9 years and 51% were male. Median time from symptom onset to ED presentation was 21 hours but one third of children presented within 6 hours. The most common presenting stroke symptoms were arm (63%), face (62%), leg weakness (57%), speech disturbance (46%) and headache (46%). The most common signs were arm (61%), face (70%) or leg weakness (57%) and dysarthria (34%). 36 (78%) of children had at least one positive variable on FAST and 38 (81%) had a positive score of > 1 on the ROSIER scale. Positive scores were less likely in children with posterior circulation stroke. CONCLUSION: The presenting features of pediatric stroke appear similar to adult strokes. Two adult stroke recognition tools have fair to good sensitivity in radiologically confirmed childhood AIS but require further development and modification. Specificity of the tools also needs to be determined in a prospective cohort of children with stroke and non-stroke brain attacks.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 774,
                "text": "stroke"
            }
        },
        {
            "context": "Accelerated growth in the absence of DNA replication origins. DNA replication initiates at defined sites called origins, which serve as binding sites for initiator proteins that recruit the replicative machinery. Origins differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins. Initiation mechanisms that rely on homologous recombination operate in some viruses. Here we show that such mechanisms also operate in archaea. We use deep sequencing to study replication in Haloferax volcanii and identify four chromosomal origins of differing activity. Deletion of individual origins results in perturbed replication dynamics and reduced growth. However, a strain lacking all origins has no apparent defects and grows significantly faster than wild type. Origin-less cells initiate replication at dispersed sites rather than at discrete origins and have an absolute requirement for the recombinase RadA, unlike strains lacking individual origins. Our results demonstrate that homologous recombination alone can efficiently initiate the replication of an entire cellular genome. This raises the question of what purpose replication origins serve and why they have evolved.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 469,
                "text": "multiple"
            }
        },
        {
            "context": "Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease. Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 229,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 310,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Clinical, electrophysiologic and pathologic findings in 10 patients with myotonic dystrophy 2. BACKGROUND: Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystem disorder caused by a CCTG tetranucleotide repeat expansion located in intron 1 of the zinc finger protein 9 gene (ZNF9 gene) on chromosome 3q 21.3. OBJECTIVES: To describe the clinical, electrophysiologic and pathologic findings in patients with myotonic dystrophy 2. METHODS: We evaluated 10 patients genetically, clinically and electrophysiologically during the years 2007 to 2008. RESULTS: All patients were of Jewish European ancestry. Among affected individuals, eight patients had symptoms of proximal muscle weakness, two had muscle pain, and two exhibited myotonia. On physical examination six patients had severe weakness of hip flexor muscles. Seven individuals underwent cataract surgery, and cardiac involvement was seen in one case. On the initial electromyographic (EMG) examination five patients demonstrated myotonic discharges; repeated studies showed these discharges in nine cases. Six muscle biopsies showed non-specific pathological changes. Seven patients had an affected first-degree relative with either a diagnosed or an undiagnosed muscular disorder consistent with an autosomal dominant trait. CONCLUSIONS: DM2 may often present with proximal muscle weakness without myotonia. EMG may initially fail to show myotonic discharges, but these discharges may eventually show in most cases on repeated EMG. Thus, DM2 may be underdiagnosed and should be included in the differential diagnosis of adult patients of Jewish European ancestry presenting with proximal lower limb weakness.",
            "question": "How is myotonic dystrophy inherited?",
            "answers": {
                "answer_start": 145,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 98,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Color blindness among multiple sclerosis patients in Isfahan. BACKGROUND: Multiple sclerosis (MS) is a disease of young and middle aged individuals with a demyelinative axonal damage nature in central nervous system that causes various signs and symptoms. As color vision needs normal function of optic nerve and macula, it is proposed that MS can alter it via influencing optic nerve. In this survey, we evaluated color vision abnormalities and its relationship with history of optic neuritis and abnormal visual evoked potentials (VEPs) among MS patients. MATERIALS AND METHODS: The case group was included of clinically definitive MS patients and the same number of normal population was enrolled as the control group. Color vision of all the participants was evaluated by Ishihara test and then visual evoked potential (VEPs) and history of optic neuritis (ON) was assessed among them. Then, frequency of color blindness was compared between the case and the control group. Finally, color blinded patients were compared to those with the history of ON and abnormal VEPs. RESULTS: 63 MS patients and the same number of normal populations were enrolled in this study. 12 patients had color blindness based on the Ishihara test; only 3 of them were among the control group, which showed a significant different between the two groups (P = 0.013). There was a significant relationship between the color blindness and abnormal VEP (R = 0.53, P = 0.023) but not for the color blindness and ON (P = 0.67). CONCLUSIONS: This study demonstrates a significant correlation between color blindness and multiple sclerosis including ones with abnormal prolonged VEP latencies. Therefore, in individuals with acquired color vision impairment, an evaluation for potentially serious underlying diseases like MS is essential.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 1215,
                "text": "Ishihara"
            }
        },
        {
            "context": "The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway. Nearly all flowering plants produce red/violet anthocyanin pigments. Caryophyllales is the only order containing families that replace anthocyanins with unrelated red and yellow betalain pigments. Close biological correlation of pigmentation patterns suggested that betalains might be regulated by a conserved anthocyanin-regulating transcription factor complex consisting of a MYB, a bHLH and a WD repeat-containing protein (the MBW complex). Here we show that a previously uncharacterized anthocyanin MYB-like protein, Beta vulgaris MYB1 (BvMYB1), regulates the betalain pathway in beets. Silencing BvMYB1 downregulates betalain biosynthetic genes and pigmentation, and overexpressing BvMYB1 upregulates them. However, unlike anthocyanin MYBs, BvMYB1 will not interact with bHLH members of heterologous anthocyanin MBW complexes because of identified nonconserved residues. BvMYB1 resides at the historic beet pigment-patterning locus, Y, required for red-fleshed beets. We show that Y and y express different levels of BvMYB1 transcripts. The co-option of a transcription factor regulating anthocyanin biosynthesis would be an important evolutionary event allowing betalains to largely functionally replace anthocyanins.",
            "question": "Which trancription factor activates the betalain pathway?",
            "answers": {
                "answer_start": 0,
                "text": "The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway."
            }
        },
        {
            "context": "Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight into the mechanism by which ubiquitination directly enhances the activity of ataxin-3, a DUb implicated in protein quality control and the disease protein in the polyglutamine neurodegenerative disorder, Spinocerebellar Ataxia Type 3. We identify Lys-117, which resides near the catalytic triad, as the primary site of ubiquitination in wild type and pathogenic ataxin-3. Further studies indicate that ubiquitin-dependent activation of ataxin-3 at Lys-117 is important for its ability to reduce high molecular weight ubiquitinated species in cells. Ubiquitination at Lys-117 also facilitates the ability of ataxin-3 to induce aggresome formation in cells. Finally, structure-function studies support a model of activation whereby ubiquitination at Lys-117 enhances ataxin-3 activity independent of the known ubiquitin-binding sites in ataxin-3, most likely through a direct conformational change in or near the catalytic domain.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 408,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/kexin type 9: the available clinical evidence. INTRODUCTION: Despite the proven efficacy of statins, they are often reported to be inadequate to achieve low-density lipoprotein cholesterol (LDL-C) goals (especially in high-risk patients). Moreover, a large number of subjects cannot tolerate statins or full doses of these drugs. Thus, there is a need for additional effective LDL-C reducing agents. AREAS COVERED: Evolocumab (AMG145) is a monoclonal antibody inhibiting the proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL receptor and prevents it from normal recycling by targeting it for degradation. Phase I and II trials revealed that its subcutaneous injection, either alone or in combination with statins, is able to reduce LDL-C from 40 to 80%, apolipoprotein B100 from 30 to 59% and lipoprotein(a) from 18 to 36% in a dose-dependent manner. The incidence of side effects seems to be low and mainly limited to nasopharyngitis, injection site pain, arthralgia and back pain. EXPERT OPINION: Evolocumab is an innovative powerful lipid-lowering drug, additive to statins and with an apparently large therapeutic range associated to a low rate of mild adverse events. If available data will be confirmed in long-term trials with strong outcomes, Evolocumab will provide an essential tool to treat high-risk patients who need to reach ambitious LDL-C target.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 83,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Is pulmonary arterial hypertension in neurofibromatosis type 1 secondary to a plexogenic arteriopathy? BACKGROUND: Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1. Pulmonary arterial hypertension (PAH) in patients with NF1 is hypothesized to be secondary to an underlying vasculopathy. METHODS: We describe the entity we term NF1-associated PAH (NF1-PAH) in four new patients and update the data on four previously published reports of patients with PAH and NF1. We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH. We report, for the first time, pathologic findings in the autopsy-obtained lung of one patient with NF1-PAH. RESULTS: Patients with NF1-PAH have a generally poor long-term prognosis. In four patients, we observed the mosaic pattern of lung attenuation on a CT scan of the chest, a radiographic finding that can be consistent with an underlying vasculopathy. No mutations or rearrangements in the BMPR2 gene were found. We observed complex plexiform lesions in the one available autopsy specimen. Similar lesions are a hallmark of plexogenic pulmonary arteriopathy and are associated with several severe types of PAH. (Plexiform lesions should not be confused with plexiform neurofibromas, which are distinctive tumors seen in NF1.) CONCLUSIONS: Our findings suggest that NF1 should be considered as being \"associated with PAH as outlined in the Revised Clinical Classification of Pulmonary Hypertension. Understanding the mechanism of PAH in NF1 may inform the pathogenesis of PAH, NF1-PAH itself, and other NF1-associated vasculopathies. The pulmonary vasculature should now be included among the arterial beds affected by NF1 vasculopathy.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 249,
                "text": "NF1"
            }
        },
        {
            "context": "Clonal size-variation of rDNA cluster region on chromosome XII of Saccharomyces cerevisiae. Using pulsed-field gel electrophoresis (PFGE), we have demonstrated clonal variation in the size of chromosome XII in a diploid strain of Saccharomyces cerevisiae X2180-2D. The sizes of the two chromosome XII homologues were very different: 2600 (L-type) and 1450 kb (S-type). The frequency with which we detected clonal size variation in the diploid, compared to that of the parental clones, was about 15-50% of the progeny clones and the range of the size variation of the homologues was 2580-2680 kb (L-type) and 1340-1500 kb (S-type), respectively. The homologue of the L-type appeared to be more frequently variable than that of the S-type. The size variation was shown to be derived from size changes in the rDNA cluster region, which is present in chromosome XII, by digesting the chromosome with XhoI, whose cutting site is not present in a rDNA repeat unit, and hybridizing to rDNA probes. The clonal size variation was also investigated in haploids from spores after meiosis. The L-type and S-type chromosomes segregated 2:2 in an ascus and the sizes of all the S-type chromosomes were shifted up, compared to the original diploid, though the L-type ones were stable. The S-type sizes of 1340, 1450 and 1780 kb in the original diploids changed into the ranges of 1475-1610 kb, 1520-1680 kb and 1820-2010 kb, respectively, in the segregants. Furthermore, we observed that the size of S-type chromosomes in haploid cells was gradually increasing in mitosis during successive subcultures.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 48,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Diagnosing diabetic foot osteomyelitis: is the combination of probe-to-bone test and plain radiography sufficient for high-risk inpatients? AIMS: To investigate the accuracy of the sequential combination of the probe-to-bone test and plain X-rays for diagnosing osteomyelitis in the foot of patients with diabetes. METHODS: We prospectively compiled data on a series of 338 patients with diabetes with 356 episodes of foot infection who were hospitalized in the Diabetic Foot Unit of La Paloma Hospital from 1 October 2002 to 31 April 2010. For each patient we did a probe-to-bone test at the time of the initial evaluation and then obtained plain X-rays of the involved foot. All patients with positive results on either the probe-to-bone test or plain X-ray underwent an appropriate surgical procedure, which included obtaining a bone specimen that was processed for histology and culture. We calculated the sensitivity, specificity, predictive values and likelihood ratios of the procedures, using the histopathological diagnosis of osteomyelitis as the criterion standard. RESULTS: Overall, 72.4% of patients had histologically proven osteomyelitis, 85.2% of whom had positive bone culture. The performance characteristics of both the probe-to-bone test and plain X-rays were excellent. The sequential diagnostic approach had a sensitivity of 0.97, specificity of 0.92, positive predictive value of 0.97, negative predictive value of 0.93, positive likelihood ratio of 12.8 and negative likelihood ratio of 0.02. Only 6.6% of patients with negative results on both diagnostic studies had osteomyelitis. CONCLUSIONS: Clinicians seeing patients in a setting similar to ours (specialized diabetic foot unit with a high prevalence of osteomyelitis) can confidently diagnose diabetic foot osteomyelitis when either the probe-to-bone test or a plain X-ray, or especially both, are positive.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 11,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 351,
                "text": "Genomiser"
            }
        },
        {
            "context": "TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a new therapeutic strategy for disorders of lipid metabolism.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 355,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Regulation of hTERT by BCR-ABL at multiple levels in K562 cells. BACKGROUND: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells. METHODS: Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels. RESULTS: Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. CONCLUSIONS: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 224,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. OBJECTIVE: To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies. METHODS: A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score. RESULTS: The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level. CONCLUSION: Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 312,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 165,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 114,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove. Our studies identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides are occluded from the active site to ensure that only hemimethylated CpG dinucleotides undergo methylation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 191,
                "text": "DNMT1"
            }
        },
        {
            "context": "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.",
            "question": "Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?",
            "answers": {
                "answer_start": 449,
                "text": "TBC1D7"
            }
        },
        {
            "context": "Attenuated spread of X-inactivation in an X;autosome translocation. X inactivation in female mammals involves transcriptional silencing of an entire chromosome in response to a cis-acting noncoding RNA, the X inactive-specific transcript (Xist). Xist can also inactivate autosomal sequences, for example, in X;autosome translocations; but here, silencing appears to be relatively inefficient. This variation has been attributed to either attenuated spreading of Xist RNA at the onset of X inactivation or inefficient maintenance of autosomal silencing. Evidence to date has favored the latter. Here, we demonstrate attenuated spreading of Xist RNA at the onset of X inactivation in the T(X;4)37H X;autosome translocation. Our findings provide direct evidence that underlying chromosome/chromatin features can disrupt spreading of the primary inactivating signal.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 239,
                "text": "Xist"
            }
        },
        {
            "context": "Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype. Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early-onset CHS with a homozygous missense mutation (c.11362 G>A, p.G3725R) in the LYST/CHS1 gene. This molecular change results in a reduction at the CHS1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T>C, p.C258R, which seemed to have minor effect on the structure of the CHS1/LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 119,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Inappropriate use of naloxone in cancer patients with pain. Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 518,
                "text": "naloxone"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "Direct Visualization of RNA-DNA Primer Removal from Okazaki Fragments Provides Support for Flap Cleavage and Exonucleolytic Pathways in Eukaryotic Cells. During DNA replication in eukaryotic cells, short single-stranded DNA segments known as Okazaki fragments are first synthesized on the lagging strand. The Okazaki fragments originate from ∼35-nucleotide-long RNA-DNA primers. After Okazaki fragment synthesis, these primers must be removed to allow fragment joining into a continuous lagging strand. To date, the models of enzymatic machinery that removes the RNA-DNA primers have come almost exclusively from biochemical reconstitution studies and some genetic interaction assays, and there is little direct evidence to confirm these models. One obstacle to elucidating Okazaki fragment processing has been the lack of methods that can directly examine primer removal in vivo In this study, we developed an electron microscopy assay that can visualize nucleotide flap structures on DNA replication forks in fission yeast (Schizosaccharomyces pombe). With this assay, we first demonstrated the generation of flap structures during Okazaki fragment processing in vivo The mean and median lengths of the flaps in wild-type cells were ∼51 and ∼41 nucleotides, respectively. We also used yeast mutants to investigate the impact of deleting key DNA replication nucleases on these flap structures. Our results provided direct in vivo evidence for a previously proposed flap cleavage pathway and the critical function of Dna2 and Fen1 in cleaving these flaps. In addition, we found evidence for another previously proposed exonucleolytic pathway involving RNA-DNA primer digestion by exonucleases RNase H2 and Exo1. Taken together, our observations suggest a dual mechanism for Okazaki fragment maturation in lagging strand synthesis and establish a new strategy for interrogation of this fascinating process.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 161,
                "text": "DNA replication"
            }
        },
        {
            "context": "RNA editing in Drosophila melanogaster: New targets and functional consequences. Adenosine deaminases that act on RNA [adenosine deaminase, RNA specific (ADAR)] catalyze the site-specific conversion of adenosine to inosine in primary mRNA transcripts. These re-coding events affect coding potential, splice sites, and stability of mature mRNAs. ADAR is an essential gene, and studies in mouse, Caenorhabditis elegans, and Drosophila suggest that its primary function is to modify adult behavior by altering signaling components in the nervous system. By comparing the sequence of isogenic cDNAs to genomic DNA, we have identified and experimentally verified 27 new targets of Drosophila ADAR. Our analyses led us to identify new classes of genes whose transcripts are targets of ADAR, including components of the actin cytoskeleton and genes involved in ion homeostasis and signal transduction. Our results indicate that editing in Drosophila increases the diversity of the proteome, and does so in a manner that has direct functional consequences on protein function.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 154,
                "text": "ADAR"
            }
        },
        {
            "context": "Tecfidera(®): an approach for repurposing. As a case study of patent coverage for a repurposed drug, Biogen Idec's approach for Tecfidera(®), an oral formulation of dimethyl fumarate, was analyzed. While mixtures of fumarates have been used for over 50 years to treat psoriasis, Tecifidera is approved for the treatment of relapsing-remitting multiple sclerosis. Biogen pursued claims to pharmaceutical formulations and useful doses for treating multiple sclerosis, an approach that is relevant to pharmaceutical lifecycle management in general. A survey of recent US, EP, and PCT patent applications indicate other companies are developing competing fumarate formulations. While it is possible to pursue secondary patents for compounds without composition of matter coverage, regulatory data exclusivity provides additional protection to delay competitors.",
            "question": "What is the drug Tecfidera used against?",
            "answers": {
                "answer_start": 279,
                "text": "Tecifidera is approved for the treatment of relapsing-remitting multiple sclerosis"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 1272,
                "text": "IgG4"
            }
        },
        {
            "context": "From animal models to human disease: a genetic approach for personalized medicine in ALS. Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 189,
                "text": "ALS"
            }
        },
        {
            "context": "NSD1 mutations in Sotos syndrome. Sotos syndrome is a genetic disorder characterized by a typical facial appearance, macrocephaly, accelerated growth, developmental delay, and a variable range of associated abnormalities. The NSD1 gene was recently found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have been identified. A significant ethnic difference is found in the prevalence of different types of mutation, with a high percentage of microdeletions identified in Japanese Sotos syndrome patients and with intragenic mutations in most non-Japanese patients. NSD1 aberrations are rather specific for Sotos syndrome, but have also been detected in patients lacking one or more major criteria of the disorder, namely overgrowth, macrocephaly, and advanced bone age. Thus, new diagnostic criteria should be considered. Studies have reported different frequencies of mutations versus non-mutations in Sotos syndrome, thus indicating allelic or locus hetereogeneity. Although some authors have suggested genotype/phenotype correlations, further studies are needed.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 226,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 175,
                "text": "SERCA"
            }
        },
        {
            "context": "Phthiriasis palpebrarum misdiagnosed as allergic blepharoconjunctivitis in a 6-year-old girl. Phthiriasis palpebrarum is an infestation of the eyelashes caused by the louse Pthirus pubis (Linnaeus, 1758). We report a case of phthiriasis palpebrarum in a 6-year-old girl, which was initially misdiagnosed as allergic blepharoconjunctivitis. Parasites and their nits were found adhering to the eyelashes and eyelids of her right eye as well as scalp hairs. No abnormality was found in the left eye. The histopathology exam revealed the presence of adults and eggs of Pthirus pubis. We mechanically removed all the eyelashes of the right eye at their base, with lice and nits. The scalp was shaved and washed with phenothrin shampoo. No recurrence was found during 3 months of follow-up. Removal of the eyelashes, cutting of scalp hairs, and phenothrin shampoo may be effective in treating phthiriasis palpebrarum. In cases of blepharoconjunctivitis, eyelids and eyelashes should be carefully examined by slit lamp to avoid misdiagnosis.",
            "question": "What is the cause of Phthiriasis Palpebrarum?",
            "answers": {
                "answer_start": 173,
                "text": "Pthirus pubis"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "The RNA cleavage activity of RNA polymerase III is mediated by an essential TFIIS-like subunit and is important for transcription termination. Budding yeast RNA polymerase III (Pol III) contains a small, essential subunit, named C11, that is conserved in humans and shows a strong homology to TFIIS. A mutant Pol III, heterocomplemented with Schizosaccharomyces pombe C11, was affected in transcription termination in vivo. A purified form of the enzyme (Pol III Delta), deprived of C11 subunit, initiated properly but ignored pause sites and was defective in termination. Remarkably, Pol III Delta lacked the intrinsic RNA cleavage activity of complete Pol III. In vitro reconstitution experiments demonstrated that Pol III RNA cleavage activity is mediated by C11. Mutagenesis in C11 of two conserved residues, which are critical for the TFIIS-dependent cleavage activity of Pol II, is lethal. Immunoelectron microscopy data suggested that C11 is localized on the mobile thumb-like stalk of the polymerase. We propose that C11 allows the enzyme to switch between an RNA elongation and RNA cleavage mode and that the essential role of the Pol III RNA cleavage activity is to remove the kinetic barriers to the termination process. The integration of TFIIS function into a specific Pol III subunit may stem from the opposite requirements of Pol III and Pol II in terms of transcript length and termination efficiency.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 76,
                "text": "TFIIS"
            }
        },
        {
            "context": "Idarucizumab for Dabigatran Reversal. BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 17,
                "text": "Dabigatran"
            }
        },
        {
            "context": "No aberrant methylation of neurofibromatosis 1 gene (NF1) promoter in pilocytic astrocytoma in childhood. Tumors of the central nervous system are the most frequent solid tumors in childhood. With 30-40% of this heterogenous group, low-grade astrocytomas represent the most common subtype. Neurofibromatosis type 1 (NF1) is strongly associated with the development of pilocytic astrocytoma (PA), frequently appearing as optic glioma. Neurofibromatosis 1 gene (NF1 ) fulfills the criteria of a tumor suppressor gene and is deleted or mutated heterozygously in patients with NF1. This suggests an involvement in the development of PA. To clarify whether silencing of NF1 by promoter methylation plays a role in PA and especially in optic glioma, the authors investigated the methylation status in 30 PA, 6 of which had optic glioma. However, no methylation was found at the NF1 promoter region in PA. To rule out that silencing of NF1 by promoter methylation is restricted to higher-grade astrocytomas, 15 pediatric WHO II degree and IV degree astrocytomas were analyzed: 12 astrocytomas II and 3 glioblastomas displayed no NF1 promoter methylation. The authors conclude that NF1 silencing by methylation plays no role in low-grade astrocytoma.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 573,
                "text": "NF1"
            }
        },
        {
            "context": "Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay. Epidermal growth factor receptor (EGFR) gene mutations have been found in a subset of non-small cell lung cancer (NSCLC) with good clinical response to gefitinib therapy. A quick and sensitive method with large throughput is required to utilize the information to determine whether the molecular targeted therapy should be applied for the particular NSCLC patients. Using probes for the 13 different mutations including 11 that have already been reported, we have genotyped the EGFR mutation status in 94 NSCLC patients using the TaqMan PCR assay. We have also genotyped the EGFR mutations status in additional 182 NSCLC patients, as well as 63 gastric, 95 esophagus and 70 colon carcinoma patients. In 94 NSCLC samples, the result of the TaqMan PCR assay perfectly matched with that of the sequencing excluding one patient. In one sample in which no EGFR mutation was detected by direct sequencing, the TaqMan PCR assay detected a mutation. This patient was a gefitinib responder. In a serial dilution study, the assay could detect a mutant sample diluted in 1/10 with a wild-type sample. Of 182 NSCLC samples, 46 mutations were detected. EGFR mutation was significantly correlated with gender, smoking status, pathological subtypes, and differentiation of lung cancers. There was no mutation detected by the TaqMan PCR assay in gastric, esophagus and colon carcinomas. TaqMan PCR assay is a rapid and sensitive method of detection of EGFR mutations with high throughput, and may be useful to determine whether gefitinib should be offered for the treatment of NSCLC patients. The TaqMan PCR assay can offer us a complementary and confirmative test.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 127,
                "text": "Epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Targeting chronic myeloid leukemia stem cells. Chronic myeloid leukemia (CML) arises as a consequence of a chromosomal translocation giving rise to the Philadelphia chromosome and Bcr-Abl oncogene. CML is a clonal disease of stem cell origin and an excellent example of a malignancy in which tumor-initiating cells may hold the key to disease eradication. The known molecular basis of CML has enabled the development of Abl-specific tyrosine kinase inhibitors, such as imatinib mesylate. However, the success of tyrosine kinase inhibitors, as rationally designed first-line therapies, has been tempered by problems of disease persistence and resistance. Residual disease has been shown to be enriched within the stem cell compartment and to persist at stable levels for up to 5 years of complete cytogenetic response. This finding has led to further searches for novel strategies aimed at eliminating these cells; such strategies may be essential in achieving cure. The most significant recent findings are discussed in this review.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 180,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Evidence for a complex of transcription factor IIB with poly(A) polymerase and cleavage factor 1 subunits required for gene looping. Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB). We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner (El Kaderi, B., Medler, S., Raghunayakula, S., and Ansari, A. (2009) J. Biol. Chem. 284, 25015-25025). The presence of TFIIB at the 3' end of a gene required its interaction with cleavage factor 1 (CF1) 3' end processing complex subunit Rna15. Here, employing affinity chromatography and glycerol gradient centrifugation, we show that TFIIB associates with poly(A) polymerase and the entire CF1 complex in yeast cells. The factors required for general transcription such as TATA-binding protein, RNA polymerase II, and TFIIH are not a component of the TFIIB complex. This holo-TFIIB complex was resistant to MNase digestion. The complex was observed only in the looping-competent strains, but not in the looping-defective sua7-1 strain. The requirement of Rna15 in gene looping has been demonstrated earlier. Here we provide evidence that poly(A) polymerase (Pap1) as well as CF1 subunits Rna14 and Pcf11 are also required for loop formation of MET16 and INO1 genes. Accordingly, cross-linking of TFIIB to the 3' end of genes was abolished in the mutants of Pap1, Rna14, and Pcf11. We further show that in sua7-1 cells, where holo-TFIIB complex is not formed, the kinetics of activated transcription is altered. These results suggest that a complex of TFIIB, CF1 subunits, and Pap1 exists in yeast cells. Furthermore, TFIIB interaction with the CF1 complex and Pap1 is crucial for gene looping and transcriptional regulation.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1724,
                "text": "TFIIB"
            }
        },
        {
            "context": "Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1β-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 279,
                "text": "IL-1β"
            }
        },
        {
            "context": "Evidence of nestin-positive cells in the human cutaneus Meissner and Pacinian corpuscles. Nestin is an intermediate filament protein expressed in neuroepithelial stem cells during development and it is later replaced by cell specific neuronal or glial filaments. Nevertheless, nestin⁺ cells remain within adult tissues and they can be regarded as potential neural stem cell (NSC). Nestin⁺ cells have been detected in Schwann cells related with sensory corpuscles of rodent and they have been demonstrated to be NSC. We have investigated the existence of nestin⁺ in human cutaneous cells Meissner and Pacinian corpuscles through the use of immunohistochemistry techniques and in situ hybridization. S100 protein (also regarded as a marker for NSC) and vimentin (the intermediate filament of mature Schwann cells in sensory corpuscles) were also investigated. The results show that the adult human cutaneous sensory Meissner and Pacinian corpuscles contains a small population of Schwann-related cells (vimentin⁺) which on the basis of their basic immunohistochemical characteristics (S100 protein⁺, nestin⁺) can be potential NSCs. Cells sharing identical immunohistochemical profile were also found in the close vicinity of Meissner corpuscles. Because their localization they are easily accessible and may represent a peripheral niche of NSC to be used for therapeutic goals.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 90,
                "text": "Nestin"
            }
        },
        {
            "context": "A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 80,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Bladder weight and detrusor thickness as parameters of progression of benign prostatic hyperplasia. PURPOSE OF REVIEW: This manuscript reviews the information that became available over the last 12 months on the measurement of bladder/detrusor wall thickness and ultrasound-estimated bladder weight in patients with benign prostatic enlargement. The subject is of particular interest because novel technological developments may help to standardize and automate the measurement technique. RECENT FINDINGS: Preliminary data on the automatic measurement of bladder wall thickness were reported, suggesting a good repeatability and agreement with conventional ultrasound imaging, although variance is higher than with conventional ultrasound, and thicknesses above 4 mm were not measured correctly. Some controversies emerged in the most recent peer-review literature on the possibility to diagnose bladder outlet obstruction and detrusor overactivity by measuring bladder wall thickness, and this certainly pleaded for further collaborative research and standardization. Preliminary results from new technological developments suggest a very accurate measure of bladder volume and good repeatability of bladder wall and bladder weight measurements. CONCLUSION: After a decade of research, automated measurement of bladder is here to stay. Standardization of bladder wall and weight measurement will allow better understanding of the physiopathology of detrusor hypertrophy in lower urinary tract dysfunction and possibly provide useful prognosticator indexes for our daily practice.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 657,
                "text": "ultrasound"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 286,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor. Phosphorylation-dependent ubiquitination and ensuing down-regulation and lysosomal degradation of the interferon alpha/beta receptor chain 1 (IFNAR1) of the receptor for Type I interferons play important roles in limiting the cellular responses to these cytokines. These events could be stimulated either by the ligands (in a Janus kinase-dependent manner) or by unfolded protein response (UPR) inducers including viral infection (in a manner dependent on the activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation. Casein kinase 1 alpha (CK1 alpha) was shown to directly phosphorylate Ser(535) within the ligand-independent pathway. Yet given the constitutive activity of CK1 alpha, it remained unclear how this pathway is stimulated by UPR. Here we report that induction of UPR promotes the phosphorylation of a proximal residue, Ser(532), in a pancreatic endoplasmic reticulum kinase-dependent manner. This serine serves as a priming site that promotes subsequent phosphorylation of IFNAR1 within its degron by CK1 alpha. These events play an important role in regulating ubiquitination and degradation of IFNAR1 as well as the extent of Type I interferon signaling.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 778,
                "text": "beta-Trcp"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 479,
                "text": "xa"
            }
        },
        {
            "context": "Calcium/calmodulin-dependent protein kinase IIalpha mediates activation of mitogen-activated protein kinase and cytosolic phospholipase A2 in norepinephrine-induced arachidonic acid release in rabbit aortic smooth muscle cells. We have investigated the contribution of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and mitogen-activated protein kinase (MAP kinase) in norepinephrine (NE)-induced arachidonic acid (AA) release in rabbit aortic vascular smooth muscle cells (VSMC). NE enhanced release of AA via activation of cytosolic phospholipase A2 (cPLA2) but not secretory PLA2 in VSMC prelabeled with [3H]AA. NE (10 microM) enhanced CaM kinase II and MAP kinase activity. In cells transiently transfected with antisense oligonucleotides complementary to the translation initiation sites of CaM kinase II and MAP kinase, NE-induced AA release was inhibited by 100 and 35% respectively. Treatment of cells with PD-098059, a MAP kinase kinase inhibitor, or with MAP kinase antisense oligonucleotide reduced NE-induced activation of MAP kinase and cPLA2. NE-induced MAP kinase and cPLA2 activation was also inhibited in cells treated with a CaM kinase II inhibitor, KN-93, or with CaM kinase II antisense oligonucleotide. On the other hand, inhibition of MAP kinase kinase with PD-098059 or of MAP kinase with antisense oligonucleotides did not alter the NE-induced increase in CaM kinase II activity. Phosphorylation of MAP kinase and CaM kinase II by NE, studied by 32P incorporation and immune complex kinase assays, was inhibited by KN-93. Collectively, these data suggest that CaM kinase II can activate MAP kinase, which in turn activates cPLA2 to release AA for prostacyclin synthesis in the rabbit VSMC. This novel pathway for activation of MAP kinase by CaM kinase II appears to be mediated through stimulation of MAP kinase kinase. Activation of adrenergic receptors with NE in VSMC caused translocation of CaM kinase II, MAP kinase, and cPLA2 to the nuclear envelope only in the presence of extracellular Ca2+. Okadaic acid, which increased phosphorylation and activity, did not translocate these enzymes. Therefore, it appears that in rabbit VSMC, NE, by promoting extracellular Ca2+ influx, increases CaM kinase II activity, leading to activation of MAP kinase and cPLA2 and translocation to the nuclear envelope, resulting in release of AA from the nuclear envelope for prostacyclin synthesis.",
            "question": "Which kinase is inhibited by the small molecule KN-93?",
            "answers": {
                "answer_start": 1156,
                "text": "CaM kinase II"
            }
        },
        {
            "context": "Porcine kallikrein gene family: genomic structure, mapping, and differential expression analysis. Kallikreins belong to a family of serine proteases that are widespread throughout living organisms, expressed in diverse tissue-specific patterns, and known to have highly diverse physiological functions. The 15 human and 24 mouse kallikreins have been implicated in pathophysiology of brain, kidney, and respiratory and reproductive systems and often are used as cancer biomarkers. To better elucidate the structure and evolutionary origin of this important gene family in the pig, we have constructed a contiguous BAC clone-derived physical map of the porcine kallikrein gene region and have fully sequenced a BAC clone containing 13 kallikrein genes, 11 of which are novel. Radiation hybrid mapping assigns this kallikrein-gene-rich region to porcine chromosome 6. Phylogenetic and percent identity plot-based analyses revealed strong structure and order conservation of kallikreins among four mammalian species. Reverse transcriptase-polymerase chain reaction-based expression analysis of porcine kallikreins showed a complex expression pattern across different tissues with the thymus being the only tissue expressing all 13 kallikrein genes. [The sequence data described in this paper has been submitted to GenBank under Accession No. AC149292].",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 307,
                "text": "15"
            }
        },
        {
            "context": "Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 620,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Large pleural tumor revealed by severe hypoglycemia: Doege-Potter syndrome. AIM: Doege-Potter syndrome is a rare condition consisting of a mesenchymal tumor, either benign or malignant, accompanied by severe hypoglycemia. The syndrome was first described independently by two American physicians, Karl Walter Doege (1867-1932) and Roy Pilling Potter (1879-1968), in 1930, but it was not before 1988 that it was associated with non-islet cell tumor production of insulin growth factor (IGF) that induces hypoglycemia as a paraneoplastic syndrome. CASE PRESENTATION: We present the case of a 61-year-old woman with severe hypoglycemia that induced seizures. On the general check-up, a massive tumor occupying the lower part of left hemi-thorax was discovered. Initially, corticosteroids, glucose i.v. and high carbohydrate diet managed to prevent the severe blood glucose drop. Surgery exposed a massive well-defined pleural tumor. After surgical removal, blood glucose stabilized. Histological examination confirmed the fibrous tumor that proved to be malignant on immunochemistry. DISCUSSION: The authors discuss other cases reported in the literature of this rare condition and its pathogenic mechanisms, the presented case being the first reported in Romania. CONCLUSIONS: The clinician should be aware of the possible existence of a pleural tumor in a patient presenting an unexplained hypoglycemia because the surgical removal of the tumor can solve the clinical manifestations.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 208,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "The nucleotide sequence of Saccharomyces cerevisiae chromosome IV. The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome IV has been determined. Apart from chromosome XII, which contains the 1-2 Mb rDNA cluster, chromosome IV is the longest S. cerevisiae chromosome. It was split into three parts, which were sequenced by a consortium from the European Community, the Sanger Centre, and groups from St Louis and Stanford in the United States. The sequence of 1,531,974 base pairs contains 796 predicted or known genes, 318 (39.9%) of which have been previously identified. Of the 478 new genes, 225 (28.3%) are homologous to previously identified genes and 253 (32%) have unknown functions or correspond to spurious open reading frames (ORFs). On average there is one gene approximately every two kilobases. Superimposed on alternating regional variations in G+C composition, there is a large central domain with a lower G+C content that contains all the yeast transposon (Ty) elements and most of the tRNA genes. Chromosome IV shares with chromosomes II, V, XII, XIII and XV some long clustered duplications which partly explain its origin.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 177,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1006,
                "text": "Xa"
            }
        },
        {
            "context": "Characterization of a human carcinoma cell line selected for resistance to the farnesyl transferase inhibitor 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336). Farnesyl protein transferase inhibitors (FTIs) have demonstrated clinical activity in certain solid tumors and hematological malignancies. Little is known about mechanisms of resistance to these agents. To provide a basis for better understanding FTI resistance, the colorectal carcinoma cell line HCT 116 was selected by stepwise exposure to increasing 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336) concentrations. The resulting line, HCT 116R, was 100-fold resistant to SCH66336 and other FTIs, including methyl {N-[2-phenyl-4-N[2(R)-amino-3-mercaptopropylamino] benzoyl]}-methionate (FTI-277), but was less than 2-fold resistant to the standard agents gemcitabine, cisplatin, and paclitaxel. Accumulation of the unfarnesylated forms of prelamin A and HDJ-2, two substrates that reflect farnesyl transferase inhibition, was similar in FTI-treated parental and HCT 116R cells, indicating that alterations in drug uptake or inhibition of farnesyl protein transferase is not the mechanism of resistance. Changes in signal-transduction pathways that might account for this resistance were examined by immunoblotting and confirmed pharmacologically. There was no difference in activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase pathway or sensitivity to the MEK1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059) in HCT 116R cells. In contrast, increased phosphorylation of the molecular target of rapamycin (mTOR) and its downstream target p70 S6 kinase and increased levels of Akt1 and Akt2 were demonstrated in HCT 116R cells. Further experiments demonstrated that the mTOR inhibitor rapamycin selectively sensitized HCT 116R cells to SCH66336 but not to gemcitabine, cisplatin, or paclitaxel. These findings provide evidence that alterations in the phosphatidylinositol-3 kinase/Akt pathway can contribute to FTI resistance and suggest a potential strategy for overcoming this resistance.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 1837,
                "text": "mTOR"
            }
        },
        {
            "context": "The CURB65 pneumonia severity score outperforms generic sepsis and early warning scores in predicting mortality in community-acquired pneumonia. BACKGROUND: The performance of CURB65 in predicting mortality in community-acquired pneumonia (CAP) has been tested in two large observational studies. However, it has not been tested against generic sepsis and early warning scores, which are increasingly being advocated for identification of high-risk patients in acute medical wards. METHOD: A retrospective analysis was performed of data prospectively collected for a CAP quality improvement study. The ability to stratify mortality and performance characteristics (sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating curve) were calculated for stratifications of CURB65, CRB65, the systemic inflammatory response syndrome (SIRS) criteria and the standardised early warning score (SEWS). RESULTS: 419 patients were included in the main analysis with a median age of 74 years (men = 47%). CURB65 and CRB65 stratified mortality in a more clinically useful way and had more favourable operating characteristics than SIRS or SEWS; for example, mortality in low-risk patients was 2% when defined by CURB65, but 9% when defined by SEWS and 11-17% when defined by variations of the SIRS criteria. The sensitivity, specificity, positive predictive value and negative predictive value of CURB65 was 71%, 69%, 35% and 91%, respectively, compared with 62%, 73%, 35% and 89% for the best performing version of SIRS and 52%, 67%, 27% and 86% for SEWS. CURB65 had the greatest area under the receiver operating curve (0.78 v 0.73 for CRB65, 0.68 for SIRS and 0.64 for SEWS). CONCLUSIONS: CURB65 should not be supplanted by SIRS or SEWS for initial prognostic assessment in CAP. Further research to identify better generic prognostic tools is required.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 11,
                "text": "pneumonia"
            }
        },
        {
            "context": "Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. In yeast, the macromolecular complex Set1/COMPASS is capable of methylating H3K4, a posttranslational modification associated with actively transcribed genes. There is only one Set1 in yeast; yet in mammalian cells there are multiple H3K4 methylases, including Set1A/B, forming human COMPASS complexes, and MLL1-4, forming human COMPASS-like complexes. We have shown that Wdr82, which associates with chromatin in a histone H2B ubiquitination-dependent manner, is a specific component of Set1 complexes but not that of MLL1-4 complexes. RNA interference-mediated knockdown of Wdr82 results in a reduction in the H3K4 trimethylation levels, although these cells still possess active MLL complexes. Comprehensive in vitro enzymatic studies with Set1 and MLL complexes demonstrated that the Set1 complex is a more robust H3K4 trimethylase in vitro than the MLL complexes. Given our in vivo and in vitro observations, it appears that the human Set1 complex plays a more widespread role in H3K4 trimethylation than do the MLL complexes in mammalian cells.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 165,
                "text": "H3K4"
            }
        },
        {
            "context": "Expression of cln3 in human NT2 neuronal precursor cells and neonatal rat brain. During brain development, excess neurons that are formed die by apoptosis. cln3 was recently identified as the gene defective in juvenile Batten disease, an inherited neurodegenerative disease of childhood. In this disease, neurons die by apoptosis. Overexpression of this gene increases survival of human NT2 neuronal precursor cells. We, therefore, hypothesized that cln3 may be present in developing neurons and may play an important role in regulating the developmental process. NT2 neuronal cells were induced to develop into mature neurons. We evaluated cln3 expression by reverse transcription PCR and immunohistochemistry over a 7-wk period of differentiation. Also, cln3 expression was characterized in neonatal rat brain during the first week of life (P-1, P0, P4, and P8) and at P30. cln3 was differentially expressed during neuronal development into nondividing post-mitotic neurons. The greatest expression was noted during wk 6 and then dropped to predifferentiation levels during wk 7. cln3 expression was detected in all the rat brain developmental stages evaluated. The greatest expression was seen at P0 and was double compared with the other stages. We conclude that cln3 is present during critical periods of neuronal cell differentiation and brain development. As cln3 is antiapoptotic, we hypothesize that cln3 plays an important role in regulating brain development. These findings may have implications for identifying strategies aimed at neuroprotection and neuronal survival during development.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 219,
                "text": "Batten disease"
            }
        },
        {
            "context": "Bertolotti syndrome: a diagnostic and management dilemma for pain physicians. BACKGROUND: Bertolotti's syndrome (BS), a form of lumbago in lumbosacral transitional vertebrae, is an important cause of low back pain in young patients. The purpose of this study was to assess the etiology of low back pain and the efficacy of treatment offered to patients with BS. METHODS: All patients of BS Castellvi type1a during a period of 6 months were enrolled in the study. The patients underwent interventional pain procedures for diagnosis and pain relief. Response to the therapy was assessed based on VAS and ODI scores. A 50% decrease in VAS score or a VAS score less than 3 would be considered adequate pain relief. RESULTS: All 20 patients diagnosed with BS during the 6-month observation period had scoliosis. Common causes of back pain were the ipsilateral L5-S1 facet joint, neoarticulation, the SI joint, and disc degeneration. Responses to various interventions for pain relief were different and inconsistent from patient to patient. In particular, responses to interventions for neoarticular pain were generally poor. CONCLUSIONS: Pain in patients with BS does not usually respond to interventional pain treatment. A very dynamic treatment approach must be pursued while managing BS patients, and the treatment plan must be individualized at various stages in order to obtain satisfactory pain relief.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 139,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Peroxiredoxin-2 represses melanoma metastasis by increasing E-Cadherin/β-Catenin complexes in adherens junctions. In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654-dependent retention of β-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 347,
                "text": "antioxidant"
            }
        },
        {
            "context": "Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance. PURPOSE: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. METHODS AND RESULTS: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨm) depolarization, exhibited attenuated insulin signaling and 2-deoxy-d-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H2O2), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨm depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H2O2-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨm depolarization and impaired 2-DG uptake, however they improved insulin signaling. CONCLUSIONS: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 404,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 312,
                "text": "orally"
            }
        },
        {
            "context": "Proton pump inhibitors and pain. There may be a relationship between proton pump inhibitors (PPIs) and iron absorption. PPIs may decrease the amount of iron absorbed gastrointestinally specifically due to alteration of the pH in the duodenum. Restless legs syndrome (RLS) is a sensorimotor disorder that includes an urge to move legs, accompanied or caused by uncomfortable and unpleasant sensations in the legs; the urge to move begins or worsens during periods of rest or inactivity, the urge to move is partially or totally relieved by movement, and the urge is worse or only occurs at night. In the majority of the restless leg syndrome population, the sensation is deep seated, often described as being in the shin bones, and most commonly felt between the knee and ankle. It may be described as a creepy, shock-like, tense, electric, buzzing, itchy, or even numb sensation. A subpopulation of this restless leg syndrome patient population experiences restless leg syndrome associated pain (RLSAP) that has been described as a deep \"achy pain.\" This pain has not been found to be relieved by many of the typical over the counter analgesics. Often, constant movement of the legs appears to be the only remedy, as these sensations usually appear during periods of rest. Furthermore, there appears to be an association between iron deficiency and those suffering from Restless Leg Syndrome (RLS). The authors theorize that there may be a possible correlation between PPIs and the symptoms (e.g. pain) associated with RLS. The authors propose that PPIs, such as omeprazole, may interfere with iron absorption in certain patients and that a subpopulation of patients who develop significant iron deficiency characterized by low serum ferritin levels while on PPIs may also develop RLS-like symptoms (including RLSAP). While there is no robust direct evidence to support any associations of PPIs and iron deficiency or PPIs associated with RLS-like symptoms (including RLSAP), it is hoped that this manuscript may spark research efforts on this issue.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1691,
                "text": "iron"
            }
        },
        {
            "context": "Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. DNA methylation is an epigenetic mark critical for regulating transcription, chromatin structure and genome stability. Although many studies have shed light on how methylation impacts transcription and interfaces with the histone code, far less is known about how it regulates genome stability. We and others have shown that DNA methyltransferase 1 (DNMT1), the maintenance methyltransferase, contributes to the cellular response to DNA damage, yet DNMT1's exact role in this process remains unclear. DNA damage, particularly in the form of double-strand breaks (DSBs), poses a major threat to genome integrity. Cells therefore possess a potent system to respond to and repair DSBs, or to initiate cell death. In the current study, we used a near-infrared laser microirradiation system to directly study the link between DNMT1 and DSBs. Our results demonstrate that DNMT1 is rapidly but transiently recruited to DSBs. DNMT1 recruitment is dependent on its ability to interact with both PCNA and the ATR effector kinase CHK1, but is independent of its catalytic activity. In addition, we show for the first time that DNMT1 interacts with the 9-1-1 PCNA-like sliding clamp and that this interaction also contributes to DNMT1 localization to DNA DSBs. Finally, we demonstrate that DNMT1 modulates the rate of DSB repair and is essential for suppressing abnormal activation of the DNA damage response in the absence of exogenous damage. Taken together, our studies provide compelling additional evidence for DNMT1 acting as a regulator of genome integrity and as an early responder to DNA DSBs.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 612,
                "text": "DNMT1"
            }
        },
        {
            "context": "Tanezumab in the treatment of chronic musculoskeletal conditions. The management of pain associated with chronic musculoskeletal conditions represents a significant challenge for the clinician. There remains a need for novel medications that have a significant analgesic benefit and are also safe and well tolerated. Both pre-clinical and clinical data have provided evidence of the role of nerve growth factor (NGF) in a multitude of pain eliciting conditions. Therefore, the development of monoclonal antibodies to NGF for chronic painful musculoskeletal conditions has generated interest. Areas covered: This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. In addition, the safety and tolerability profile and development history of tanezumab are also discussed. Expert opinion: Most studies provide strong support for the ability of tanezumab to provide clinically meaningful pain relief in individuals with these conditions, with longer-term studies suggesting durability of effect. The adverse event profile appears favorable, assuming the risk mitigation strategies are effective at reducing the incidence of joint-related side effects. Further data are being collected to define the optimal dose and dosing strategy in both OA and chronic low back pain.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 756,
                "text": "NGF"
            }
        },
        {
            "context": "Autosomal XX sex reversal caused by duplication of SOX9. SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We report here evidence supporting that SOX9 duplication can cause XX sex reversal. A newborn infant was referred for genetic evaluation because of abnormal male external genitalia. The infant had severe penile/scrotal hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY was ruled out by FISH with a probe containing the SRY gene and polymerase chain reaction with SRY-specific primers. Microsatellite analysis with 13 markers on 17q23-24 determined that the duplication is maternal in origin and defined the boundary of the duplication to be approximately 12 centimorgans (cM) proximal and 4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for the sex reversal in this case because it plays an important role in male sex determination and differentiation. This study suggests that extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. Other SRY-negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene.",
            "question": "Which is the main abnormality that arises with Sox9 locus duplication?",
            "answers": {
                "answer_start": 0,
                "text": "Autosomal XX sex reversal"
            }
        },
        {
            "context": "[Benzodiazepine antagonists in the treatment of heptic encephalopathy]. For the first time a causal treatment of hepatic encephalopathy may be possible by the benzodiazepine antagonist flumazenil. In contrast to all other treatments used so far by flumazenil hepatic encephalopathy improves within minutes. Flumazenil is the first benzodiazepine antagonist which can be used in humans and is a well established for treatment of benzodiazepine overdose. For treatment of hepatic encephalopathy development of a new antagonist with a longer half-life is desirable. However, ut should be stressed that the current experience with flumazenil is limited and that the effects of flumazenil on hepatic encephalopathy is not proven by randomized controlled studies. Therefore, this drug should only be used in clinical studies.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 307,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1763,
                "text": "CD38"
            }
        },
        {
            "context": "The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 585,
                "text": "NCX"
            }
        },
        {
            "context": "Crystallization of Ranasmurfin, a blue-coloured protein from Polypedates leucomystax. Ranasmurfin, a previously uncharacterized approximately 13 kDa blue protein found in the nests of the frog Polypedates leucomystax, has been purified and crystallized. The crystals are an intense blue colour and diffract to 1.51 A with P2(1) symmetry and unit-cell parameters a = 40.9, b = 59.9, c = 45.0 A, beta = 93.3 degrees . Self-rotation function analysis indicates the presence of a dimer in the asymmetric unit. Biochemical data suggest that the blue colour of the protein is related to dimer formation. Sequence data for the protein are incomplete, but thus far have identified no model for molecular replacement. A fluorescence scan shows a peak at 9.676 keV, indicating that the protein binds zinc and suggesting a route for structure solution.",
            "question": "What is the color of the protein Ranasmurfin?",
            "answers": {
                "answer_start": 282,
                "text": "blue"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1433,
                "text": "CD38"
            }
        },
        {
            "context": "Histone deacetylase inhibitors synergize p300 autoacetylation that regulates its transactivation activity and complex formation. p300/cyclic AMP-responsive element binding protein-binding protein (CBP) are general coactivators for multiple transcription factors involved in various cellular processes. Several highly conserved domains of p300/CBP serve as interacting sites for transcription factors and regulatory proteins. Particularly, the intrinsic histone acetyltransferase (HAT) activity and transactivation domains (TAD) play essential roles for their coactivating function. Autoacetylation of p300/CBP is commonly observed in cell-free HAT assays and has been implicated in the regulation of their HAT activity. Here, we show that six lysine-rich regions in several highly conserved functional domains of p300 are targeted by p300HAT for acetylation in cell-free systems. We show that p300 is susceptible to acetylation in cultured tumor cells and that its acetylation status is affected by histone deacetylase inhibitor trichostatin A. We further show that either treatment with deacetylase inhibitors or coexpression of Gal4-p300HAT, which alone has no transactivation activity, stimulates the activity of the COOH-terminal TAD of p300 (p300C-TAD). We have defined the minimal p300C-TAD and show that it is sufficient to respond to deacetylase inhibitors and is a substrate for p300HAT. Finally, we show that acetylated p300 possesses enhanced ability to interact with p53. Taken together, our data suggest that acetylation regulates p300C-TAD and that acetylation of p300/CBP may contribute to the dynamic regulation of their complex formation with various interacting partners.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 498,
                "text": "transactivation domain"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Modulation of rabbit muscle sarcoplasmic reticulum Ca(2+)-ATPase activity by novel quercetin derivatives. Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is the pump crucial for calcium homeostasis and its impairment results in pathologies such as myopathy, heart failure or diabetes. Modulation of SERCA activity may represent an approach to the therapy of diseases with SERCA impairment involvment. Quercetin is flavonoid known to modulate SERCA activity. We examined the effect of nine novel quercetin derivatives on the activity of the pump. We found that 5-morpholinohydroxypoxyquercetin, di(prenylferuoyl)quercetin, di(diacetylcaffeoyl)-mono-(monoacetylcaffeoyl)quercetin and monoacetylferuloylquercetin stimulated the activity of SERCA. On the contrary, monochloropivaloylquercetin, tri(chloropivaloyl)quercetin, pentaacetylquercetin, tri(trimethylgalloyl)quercetin and diquercetin inhibited the activity of the pump. To identify compounds with a potential to protect SERCA against free radicals, we assessed the free radical scavenging activity of quercetin derivatives. We also related lipophilicity, an index of the ability to incorporate into the membrane of sarcoplasmic reticulum, to the modulatury effect of quercetin derivatives on SERCA activity. In addition to its ability to stimulate SERCA, di(prenylferuloyl)quercetin showed excellent radical scavenging activity.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 144,
                "text": "SERCA"
            }
        },
        {
            "context": "Liquid chromatography/isotope ratio mass spectrometry measurement of δ13C of amino acids in plant proteins. In archaeological studies, the isotopic enrichment values of carbon and nitrogen in bone collagen give a degree of information on dietary composition. The isotopic enrichments of individual amino acids from bone collagen and dietary protein have the potential to provide more precise information about the components of diet. A limited amount of work has been done on this, although the reliability of these studies is potentially limited by fractionation arising through hydrolysis of whole plant tissue (where reaction between amino acids and carbohydrates may occur) and, for certain amino acids, the use of derivatives (particularly trifluoroacetyl derivatives) for gas chromatography/isotope ratio mass spectrometry (GC/IRMS) analysis. The present study takes the approach of extracting the protein components of plant tissues before hydrolysis and using liquid chromatography/isotope ratio mass spectrometry (LC/IRMS), which does not require derivatisation, for measurement of the isotopic enrichment of the amino acids. The protocol developed offers a methodology for consistent measurement of the δ(13)C values of amino acids, allowing isotopic differences between the individual amino acids from different plant tissues to be identified. In particular, there are highly significant differences between leaf and seed protein amino acids (leaf minus grain) in the cases of threonine (-4.1‰), aspartic acid (+3.5‰) and serine (-3.2‰). In addition to its intended application in archaeology, the technique will be of value in the fields of plant sciences, nutrition and environmental food-web studies.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 197,
                "text": "collagen"
            }
        },
        {
            "context": "An animal model of cortical and callosal pathology in multiple sclerosis. The pathological and radiological hallmarks of multiple sclerosis (MS) include multiple demyelinated lesions disseminated throughout the white matter of the central nervous system (CNS). More recently, the cerebral cortex has been shown to be affected in MS, but the elucidation of events causing cortical demyelination has been hampered by the lack of animal models reflecting such human cortical pathology. In this report, we have described the presence of cortical gray matter and callosal white matter demyelinating lesions in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Similar to the pathological lesions of MS patients, EAE lesions have been classified as type I-leukocortical, type II-intracortical and type III-subpial. All of these lesions had varying degrees of demyelination, inflammatory cells and reactive astrocytes. Similar to MS, cortical layers during EAE showed demyelination, microglia activation, synaptic protein alterations and apoptotic cells. In addition, the callosal white matter during EAE had many inflammatory demyelinating lesions and axon degeneration. Functional electrophysiological conduction analysis showed deficits in both myelinated and unmyelinated callosal axons during early and late EAE. The chronic EAE mouse model has features that mimic cortical and callosal pathology of MS, and can be potentially used to screen agents to prevent these features of disease.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 617,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Jervell and Lange-Nielsen syndrome (JLNS) is characterized by sensorineural deafness, QT prolongation, abnormal T waves, ventricular tachyarrhythmias, and autosomal recessive inheritance. Previously homozygous mutations in the potassium channel-encoding genes, KvLQT1 (alpha-subunit) and KCNE1 (beta-subunit), have been described in consanguineous families with JLNS. We screened two nonconsanguineous families with JLNS for mutations in KvLQT1, using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing. In one family, a missense mutation was identified in exon 6 of KvLQT1 on the maternal side, resulting in a glycine to aspartic acid substitution at codon 269 (G269D). The apparently normal father had an incompletely penetrant missense mutation in exon 3 of KvLQT1, introducing a premature stop codon at position 171. In the other family, a missense mutation resulting in the substitution of asparagine for aspartic acid at codon 202 (D202N) was identified in the mother and maternal grandmother, who had QTc prolongation (borderline in the mother), while the father and paternal grandfather, who were clinically normal, had a deletion of nucleotide 585, resulting in a frameshift and premature termination. In both families, the proband inherited both mutations. In this report we provide evidence that not only homozygous but also compound heterozygous mutations in KvLQT1 may cause JLNS in nonconsanguineous families. Incomplete penetrance in individuals with mutations appears to be frequent, indicating a higher prevalence of mutations than estimated previously. Interestingly, mutations resulting in truncation of the protein appear to be benign, with heterozygous carriers being asymptomatic.",
            "question": "What is the mode of inheritance of  long QT  Jervell and Lange-Nielsen syndrome?",
            "answers": {
                "answer_start": 239,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Gene transfer efficiency and genome-wide integration profiling of Sleeping Beauty, Tol2, and piggyBac transposons in human primary T cells. In this study, we compared the genomic integration efficiencies and transposition site preferences of Sleeping Beauty (SB or SB11), Tol2, and piggyBac (PB) transposon systems in primary T cells derived from peripheral blood lymphocytes (PBL) and umbilical cord blood (UCB). We found that PB demonstrated the highest efficiency of stable gene transfer in PBL-derived T cells, whereas SB11 and Tol2 mediated intermediate and lowest efficiencies, respectively. Southern hybridization analysis demonstrated that PB generated the highest number of integrants when compared to SB and Tol2 in both PBL and UCB T cells. Tol2 and PB appeared more likely to promote clonal expansion than SB, which may be in part due to the dysregulated expression of cancer-related genes near the insertion sites. Genome-wide integration analysis demonstrated that SB, Tol2, and PB integrations occurred in all the chromosomes without preference. Additionally, Tol2 and PB integration sites were mainly localized near transcriptional start sites (TSSs), CpG islands and DNaseI hypersensitive sites, whereas SB integrations were randomly distributed. These results suggest that SB may be a preferential choice of the delivery vector in T cells due to its random integration site preference and relatively high efficiency, and support continuing development of SB-mediated T-cell phase I trials.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 282,
                "text": "piggyBac"
            }
        },
        {
            "context": "SeqArray-a storage-efficient high-performance data format for WGS variant calls. Motivation: Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Results: Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. Availability and Implementation: http://www.bioconductor.org/packages/SeqArray. Contact: zhengx@u.washington.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm has been proposed for efficient storage of WGS variant calls?",
            "answers": {
                "answer_start": 550,
                "text": "SeqArray"
            }
        },
        {
            "context": "Monitoring plasma levels of factor Xa inhibitors: how, why and when? New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed. Several available anti-FXa assays are used for monitoring anticoagulant activity of heparins and fondaparinux. They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). The use of calibrators (lyophilized plasma with a known concentration of drug) allows an expression of the results in ng per ml of plasma. Two categories of assays - endogenous and exogenous assays are available. Endogenous assays are useful in pharmaceutical research, while exogenous assays are used in clinical laboratories. The preferred anti-FXa assay is a specific method in contrast to prothrombin time and activated partial thromboplastin time, but it is not available everywhere at any time. A specific measurement of direct FXa inhibitors is feasible with the use of a new test developed by the authors' group. The physicians must be aware of the possibility to measure the plasma concentration of FXa inhibitors in patients at high risk of bleeding and in several other special clinical situations.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 646,
                "text": "xa"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 831,
                "text": "CisMapper"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2853,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Mutation analysis in Rett syndrome. Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene. Mutations have been demonstrated in more than 80% of females with typical features of Rett syndrome. We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum. Bidirectional sequencing of the entire MECP2 coding region was performed. We diagnosed 65 patients with MECP2 mutations. Of these, 15 mutations had been reported previously and 13 are novel. Two patients have multiple deletions within the MECP2 gene. Eight common mutations were found in 43 of 65 patients (66.15%). The majority of patients with identified mutations have the classic Rett phenotype, and several had atypical phenotypes. MECP2 analysis identified mutations in almost all cases of typical Rett syndrome, as well as in some with atypical phenotypes. Eleven (20.4%) of the 54 patients with defined mutations and in whom phenotypic data were obtained did not develop acquired microcephaly. Hence, microcephaly at birth or absence of acquired microcephaly does not obviate the need for MECP2 analysis. We have initiated cascade testing starting with PCR analysis for common mutations followed by sequencing, when necessary. Analysis of common mutations before sequencing the entire gene is anticipated to be the most efficacious strategy to identify Rett syndrome gene mutations.",
            "question": "Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2?",
            "answers": {
                "answer_start": 333,
                "text": "Rett syndrome"
            }
        },
        {
            "context": "Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germline mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' and 3' breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12-kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 233,
                "text": "NF1"
            }
        },
        {
            "context": "The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells. BACKGROUND: Stromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. EXPERIMENTAL DESIGN: We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry. RESULTS: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases. CONCLUSIONS: MLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 4,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "[Influence of ketogenic diet on the clinical effects and electroencephalogram features in 31 children with pharmacoresistant epileptic encephalopathy]. OBJECTIVE: To investigate the effect of ketogenic diet (KD) on the clinical and electroencephalogram features in children with pharmacoresistant epileptic encephalopathy. METHOD: Thirty-one children (19 boys, 12 girls) aged 7 months to 7 years (mean 2 years 5 month) with epilepsy refractory to conventional antiepileptic drugs (AEDs) were included in this study. In addition to their original AED treatment, the children were assigned to different ketogenic diets based on their age. The prospective electro-clinical assessment was performed prior to the KD and then one week, one month and again 3 months after the initiation of therapy, respectively. RESULT: The reduction of seizure frequency in 52%, 68% and 71% of all patients exceeded 50% one week, one month and three months after KD treatment respectively. KD is particularly effective in myoclonic astatic epilepsy (MAE; Doose Syndrome) and West syndrome with 100% and 81.25% of the patients having a greater than 50% seizure reduction, respectively. After 3 months of KD treatment, more than 2/3 patients experienced a reduction in interictal epileptiform discharges (IEDs) and improvement in EEG background. CONCLUSION: The clinical and electroencephalographic improvement confirms that KD is beneficial in children with refractory epilepsy.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 1000,
                "text": "myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 179,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Evaluation of the Arabic version of STOP-Bang questionnaire as a screening tool for obstructive sleep apnea. PURPOSE: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is underdiagnosed. OSA is usually diagnosed by polysomnography (PSG) and, if untreated, could lead to life-threatening complications. Many screening questionnaires have been developed to screen and identify patients at high risk for OSA. This study aimed to evaluate and validate the Arabic version of Stop-Bang questionnaire as a screening tool for patients with OSA symptoms referred to a sleep clinic. METHODS: All referred Arabic-speaking adult patients presenting to a Sleep Disorders Specialized Clinic in Al Ain for PSG were requested to complete an Arabic STOP-Bang questionnaire. A score of 3 or more out of a possible 8 was taken to indicate high risk for presence of OSA. These scores were then evaluated versus results from the overnight, monitored PSG. Apnea/hypopnea index (AHI) of > 5/h was considered for diagnosis of OSA. RESULTS: One hundred ninety-three sleep clinic patients were enrolled in this study. PSG was positive (AHI > 5) in 85 % of the studied population. STOP-Bang questionnaire was positive ( > 3) in 87 % of the population. Reproducibility of STOP-Bang questionnaire was tested, and the intraclass correlation coefficient of the total score of STOP-Bang questionnaire was 0.931 (95 % CI 0.834-0.972). The sensitivities of the STOP-Bang screening tool for an AHI of > 5, > 15, and > 30 were 90, 96.75, and 99.70 %, respectively, with negative predictive values (NPVs) of 36, 84, and 92 %, respectively. ROC curve was 0.77. CONCLUSION: The Arabic version of STOP-Bang questionnaire is an easy-to-use tool that can be implemented as a reliable, quick screening tool for OSA in patients referred to sleep clinic. It demonstrated high sensitivity and NPV especially for patients with moderate to severe OSA. We believe that this tool will help physicians to earlier identify cases at risk of OSA.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 84,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "TAp73 is downregulated in oocytes from women of advanced reproductive age. Studies on oocyte transcriptome are important to understand the biological pathways involved in oogenesis, totipotence and early embryonic development. Moreover, genes regulating physiological pathways in gametes could represent potential candidates for reproductive disorders. In addition to oocyte specific transcription factors, also the members of the p53 family could be etiologically involved due to their biological functions. In fact, their role in the control of cell cycle, apoptosis, and germ-line genome stability is well known. Female reproductive aging is one of the causes of fertility reduction and it is often associated with egg aneuploidy increase. In order to verify the potential involvement of p73 in reproductive aging, we determined its expression in single mature MII oocytes from two groups of women, younger than 35 or older than 38 years, respectively. We found that TAp73 isoforms are down regulated in oocytes from women older than 38 years. We confirmed these data in pools of mouse oocytes. TAp73 down regulation in oocytes from women of advanced reproductive age could explain both the reduction of fertility and the increase of newborns with chromosomal abnormalities.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 973,
                "text": "7"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 527,
                "text": "thyroid"
            }
        },
        {
            "context": "Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. In mammals Dnmt1 is the DNA methyltransferase chiefly responsible for maintaining genomic methylation patterns through DNA replication cycles, but how its maintenance activity is controlled is still not well understood. Interestingly, Uhrf1, a crucial cofactor for maintenance of DNA methylation by Dnmt1, is endowed with E3 ubiquitin ligase activity. Here, we show that both Dnmt1 and Uhrf1 coprecipitate with ubiquitin specific peptidase 7 (Usp7), a de-ubiquitinating enzyme. Overexpression of Uhrf1 and Usp7 resulted in opposite changes in the ubiquitination status and stability of Dnmt1. Our findings suggest that, by balancing Dnmt1 ubiquitination, Usp7 and Uhrf1 fine tune Dnmt1 stability.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 111,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Comparison of antiproliferative and apoptotic effects of a novel proteasome inhibitor MLN2238 with bortezomib on K562 chronic myeloid leukemia cells. Inhibition of the proteasome has emerged as a clinically effective anticancer therapeutic approach in recent years. Bortezomib (Velcade®) showed extremely high potency against a wide range of cancer cell lines. Ixazomib (MLN9708-MLN2238), the second-generation proteasome inhibitor, selectivity and potency were similar to that of bortezomib, is currently being investigated in phase I studies. It shows superior antitumor activity in hematologic malignancy, especially multiple myelomas. In this study, for the first time, we evaluated and compared the antiproliferative and apoptotic effects of the novel proteasome inhibitor MLN2238 (the active form of MLN9708) with bortezomib using in vitro chronic myeloid leukemia. Cytotoxic and apoptotic effects of MLN2238 and bortezomib were determined by trypan blue dye exclusion assays, WST-1 cell proliferation assay, increased AnnexinV-PI binding capacity, changes in caspase-3 activity and loss of mitochondrial membrane potential (JC-1). Associated with proteasome pathway NFκB1 and c-myc mRNA expression levels were examined by the qRT-PCR method. We observed that cytotoxic and apoptotic effects on K562 cells were started at 5 μm of MLN2238 and 1 μm of bortezomib after 24 and 48 h. Also, MLN2238 and bortezomib downregulated NFκB1 and c-myc mRNA expression at 24 h. Our result revealed that MLN22238 and bortezomib had significant cytotoxic and apoptotic effects on K562 cells. Here, we first demonstrate in vitro data that support the development of MLN2238, by direct comparison with bortezomib on K562 cells.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 411,
                "text": "proteasome"
            }
        },
        {
            "context": "The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies. Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 569,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines. PURPOSE: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance. METHODS: The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance. RESULTS: The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested. CONCLUSIONS: These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 1313,
                "text": "EGFR"
            }
        },
        {
            "context": "Thyroid function and morphology in patients affected by Williams syndrome. OBJECTIVE: To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of patients with Williams syndrome (WS). METHODS: Serum concentrations of free-T3, free-T4, TSH, thyroperoxidase antibodies (TPOA) and thyroglobulin antibodies (TgA), as well as ultrasonographic data, of 20 patients with WS (12 females and eight males), aged 1.7-34.9 years, were evaluated. RESULTS: Three cases (15%) of subclinical hypothyroidism were identified. Overt hypothyroidism was diagnosed in two cases (10%). Thyroid antibodies were negative in all patients. Fourteen patients (70%) showed thyroid hypoplasia involving the entire gland. In these patients, the left thyroid lobe appeared usually, but not significantly, reduced compared with the right thyroid lobe. One patient (5%) showed thyroid hemiagenesis. Only five patients (25%) showed a thyroid with normal volume, and of these five, one patient showed marked thyroid hypoplasia of the left lobe. In all WS patients with diagnosis of subclinical or overt hypothyroidism, thyroid hypoplasia was detected. No cases of subclinical or overt hypothyroidism were found in WS with normal thyroid volume. CONCLUSIONS: This study confirms the presence of alterations of thyroid function in WS and also suggests the frequent occurrence of abnormalities of thyroid morphology in these patients. Patients with WS should be monitored for thyroid function and a thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 514,
                "text": "thyroid"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 1223,
                "text": "OikoBase"
            }
        },
        {
            "context": "Francisella tularensis LVS surface and membrane proteins as targets of effective post-exposure immunization for tularemia. Francisella tularensis causes disease (tularemia) in a large number of mammals, including man. We previously demonstrated enhanced efficacy of conventional antibiotic therapy for tularemia by postexposure passive transfer of immune sera developed against a F. tularensis LVS membrane protein fraction (MPF). However, the protein composition of this immunogenic fraction was not defined. Proteomic approaches were applied to define the protein composition and identify the immunogens of MPF. MPF consisted of at least 299 proteins and 2-D Western blot analyses using sera from MPF-immunized and F. tularensis LVS-vaccinated mice coupled to liquid chromatography-tandem mass spectrometry identified 24 immunoreactive protein spots containing 45 proteins. A reverse vaccinology approach that applied labeling of F. tularensis LVS surface proteins and bioinformatics was used to reduce the complexity of potential target immunogens. Bioinformatics analyses of the immunoreactive proteins reduced the number of immunogen targets to 32. Direct surface labeling of F. tularensis LVS resulted in the identification of 31 surface proteins. However, only 13 of these were reactive with MPF and/or F. tularensis LVS immune sera. Collectively, this use of orthogonal proteomic approaches reduced the complexity of potential immunogens in MPF by 96% and allowed for prioritization of target immunogens for antibody-based immunotherapies against tularemia.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 123,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 874,
                "text": "xa"
            }
        },
        {
            "context": "JTV-519 Japan Tobacco. Japan Tobacco is developing the mixed action ion channel blocker, JTV-519, which has potential use as an antiarrhythmic [285800]. The drug is a novel cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were completed in the third quarter of 1998; phase II trials started in the fourth quarter of 1998 for the potential treatment of myocardial infarction [320195]. Studies have shown that JTV-519 has a strong cardioprotective effect against catecholamine-induced myocardial injury and against ischemia/reperfusion injury [316749]. In experimental myofibrillar overcontraction models, it demonstrated greater cardioprotectant effects than propranolol, verapamil and diltiazem [171668].",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 208,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 482,
                "text": "7"
            }
        },
        {
            "context": "Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care). BACKGROUND AND PURPOSE: This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension. METHODS: The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure > 140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation. RESULTS: One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, -0.08 mL; 95% confidence interval, -0.30 to 0.15; P=0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes (P for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4-12.1; P=0.36). CONCLUSIONS: Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low. CLINICAL TRIAL INFORMATION: URL: http://www.isrctn.com/ISRCTN29711771. Unique identifier: ISRCTN29711771.",
            "question": "What is the preDIVA clinical trial?",
            "answers": {
                "answer_start": 135,
                "text": "Prevention of Dementia by Intensive Vascular Care"
            }
        },
        {
            "context": "Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.",
            "question": "Which mutated gene causes the Chédiak–Higashi Syndrome?",
            "answers": {
                "answer_start": 1367,
                "text": "LYST gene"
            }
        },
        {
            "context": "Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities. Rapid laboratory methods provide optimal support for active surveillance efforts to screen for methicillin-resistant Staphylococcus aureus (MRSA). Most laboratories struggle to determine the optimal use of resources, considering options to balance cost, speed, and diagnostic accuracy. To assess the performance of common methods, the first comparison of MRSASelect agar (MS) and CHROMagar MRSA (CA), with and without broth enrichment followed by a 24-h subculture to MS, was performed. Results were compared to those of the Xpert MRSA assay. For direct culture methods, the agreement between MS and CA was 98.8%. At 18 h, direct MS identified 93% of all positive samples from direct culture and 84% of those identified by the Xpert MRSA. For Trypticase soy broth-enriched MS culture, incubated overnight and then subcultured for an additional 24 h, the agreement with Xpert MRSA was 96%. The agreement between direct MS and Xpert MRSA was 100% when semiquantitative culture revealed a bacterial density of 2+ or greater; however, discrepancies between culture and Xpert MRSA arose for MRSA bacterial densities of 1+ or less, indicating low density as a common cause of false-negative culture results. Since 1+ or less was established as the most common MRSA carrier state, broth enrichment or PCR may be critical for the identification of all MRSA carriers who may be reservoirs for transmission. In this active-surveillance convenience sample, the use of broth enrichment followed by subculture to MS offered a low-cost but sensitive method for MRSA screening, with performance similar to that of Xpert MRSA PCR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 86,
                "text": "MRSA"
            }
        },
        {
            "context": "Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor. The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the world's pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G749T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C1351G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known \"Jewish\" mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known \"non-Jewish\" mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C1351G and G749T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor (theta) between the markers and mutated loci, and the population growth correction, we deduced that G749T occurred in a founder ancestor 44.8 +/- 14.2 generations (g) ago [95% confidence interval (CI) 17.0-72.6 g] and C1351G arose 80.4 +/- 35.9 g ago (95% CI 44.5-116.3 g). Thus, the estimated dates for introduction of mutations are: 626 +/- 426 A.D. (200-1052 A.D.) for G749T and 442 +/- 1077 B.C. (1519 B.C. to 635 A.D.) for C1351G.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 26,
                "text": "HEXA"
            }
        },
        {
            "context": "Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of patients and practical applications for pharmacy practitioners. OBJECTIVE: To summarize the use of tyrosine kinase inhibitors (TKIs) for treatment of patients with chronic myeloid leukemia (CML) and provide practical information for patient management. DATA SOURCES: Literature was retrieved from PubMed (2000-January 2011), using the search terms chronic myeloid leukemia and tyrosine kinase inhibitor. Abstracts presented at the 2008-2010 annual meetings of the American Society of Hematology and the American Society of Clinical Oncology, reference citations from identified publications, as well as the manufacturers' full prescribing information for cited drugs, also were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating the efficacy and safety of the TKIs imatinib, nilotinib, and dasatinib were evaluated. Focus was placed on publications supporting management of patients with CML in the chronic phase. Reports presenting clinical trial information of TKIs in development also were included. DATA SYNTHESIS: The discovery of targeted tyrosine kinase inhibition of BCR-ABL kinase dramatically changed the treatment of CML. Imatinib, the first TKI approved for treatment of patients with Philadelphia chromosome--positive CML, demonstrated significant superiority over the previous standard of care: interferon plus cytarabine. The newer, more potent TKIs, nilotinib and dasatinib, have demonstrated improved efficacy over imatinib as first-line therapy and provide an effective option for patients with resistance or intolerance to imatinib. CONCLUSIONS: To maximize efficacy of TKI therapy, close patient management, involving frequent monitoring of patient response, is essential. Given the importance of continuing TKI therapy, early recognition and management of adverse events are critical to optimizing outcomes in patients with CML. In addition to the safety profile and considerations of comorbidities, additional factors can affect therapeutic selection, including drug-drug and drug-food interactions. Research investigating new therapies, particularly for patients harboring the T315I mutation-which remains refractory to current TKIs-continues in the quest to improve outcomes in patients with CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 1169,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 426,
                "text": "methylKit"
            }
        },
        {
            "context": "In UV-irradiated Saccharomyces cerevisiae, overexpression of Swi2/Snf2 family member Rad26 increases transcription-coupled repair and repair of the non-transcribed strand. Nucleotide excision repair (NER) in eukaryotes is a pathway conserved from yeast to humans that removes many bulky chemical adducts and UV-induced photoproducts from DNA in a relatively error-free manner. In addition to the recognition and excision of DNA damage throughout the genome (GGR), there exists a mechanism, transcription-coupled nucleotide excision repair (TCR), for recognizing some types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast and mammalian cells. An obstacle in the repair of the transcribed strand of active genes is the RNA polymerase complex stalled at sites of DNA damage. The stalled RNA polymerase complex may then mediate recruitment of repair proteins to damage in the transcribed strand. Proteins enabling TCR are the Cockayne syndrome B (CSB) protein in humans and its yeast homologue Rad26. Both CSB and Rad26 belong to the Swi2/Snf2 family of DNA-dependent ATPases, which change DNA accessibility to proteins by altering chromatin structure. To address how Rad26 functions in yeast repair, we used the genetic approach of overexpressing Rad26 and examined phenotypic changes, i.e. changes in NER. We found that repair of both the transcribed and the non-transcribed strands is increased. In addition, overexpression of Rad26 partially bypasses the requirement for Rad7 in GGR, specifically in the repair of non-transcribed sequences. As TCR takes place in very localized regions of DNA (i.e. within genes) in wild-type cells, we propose that overexpression of recombinant Rad26 increases accessibility of the damaged DNA in chromatin for interaction with repair proteins.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 590,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 702,
                "text": "NGF"
            }
        },
        {
            "context": "Information on sudden deaths from epilepsy. Epilepsy Bereaved? is a charity representing those who have experienced the sudden death of a loved one due to epilepsy. Many individuals with epilepsy, as well as their partners, relatives, and friends, are unaware of the risk for sudden unexpected death in epilepsy (SUDEP). Much of the literature available does not include information on SUDEP. When information is given, the risk for SUDEP may be underestimated. Epilepsy Bereaved? believes that people with epilepsy and their partners, families, and friends have the same right to be informed as any others dealing with a chronic condition, unless they express a wish to the contrary. Information should include the risk for SUDEP. Bereaved families agree that they would rather have been informed of the risks than left ignorant. Increased awareness and understanding of this condition may help improve treatment compliance and enable individuals to take measures to reduce the risk for sudden death.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 276,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Thyroid anomalies in Williams syndrome: investigation of 95 patients. Thyroid involvement in Williams syndrome (WS) was recently reported in two small groups of patients, both showing an increased prevalence of elevation of TSH serum concentration; in one of the two reports, 70% of the patients demonstrated a hypoplasia of thyroid gland as well. In our institution, we currently follow a large population of WS patients who periodically undergo a multispecialist clinical evaluation that includes ultrasound evaluation of the thyroid gland, and levels of FT3, FT4, TSH, and anti-thyroid antibodies. Here, we report on the prevalence of thyroid structural and functional anomalies, in a population of 95 WS patients, half of them followed for more than 5 years. Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample) and thyroid gland hypoplasia (74.7%). Moreover, we demonstrated that TSH elevation declines with age. For this reason, we suggest that a complete thyroid evaluation be performed in every patient with WS, and that this medical complication should be periodically searched for in follow-up visits.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 866,
                "text": "thyroid"
            }
        },
        {
            "context": "[Atypical paraneoplastic myasthenic syndrome: Lambert-Eaton syndrome or myasthenia?]. We report a case of paraneoplastic myasthenic syndrome with clinical features suggesting Lambert Eaton syndrome but without the electromyographic elements required for diagnosis. Anti-calcium channel antibodies were also lacking. The electromyogram evidenced a block and the Tensilon test was positive. The efficacy of anticholinesterases argued in favor of myasthenia but anti-acetylcholine receptor antibodies were negative. The block was more of a mixed nature, involving both presynaptic transmission as in Lambert Eaton syndrome and post-synaptic transmission as in paraneoplastic myasthenia. The primary tumor was identified as a small-cell neuroendocrine lung carcinoma on mediastinal biopsies obtained directly on CT-scan guided puncture of a mediastinal node. Thoracotomy was thus avoided. The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer. A mixed paraneoplastic neuro-muscle junction disorder with aspects of each can be exceptionally observed.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 949,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1637,
                "text": "factor Xa"
            }
        },
        {
            "context": "Pathophysiology of carpal tunnel syndrome. Carpal tunnel syndrome (CTS) is the most common median nerve neuropathy, accounting for 90% of all neuropathies. Carpal tunnel syndrome presents in 3.8% of the general population, with a higher prevalence among women. There are several risk factors associated with CTS, including both medical and non medical factors. The pathophysiologic mechanisms involved in the median nerve compression and traction are thought to be complex, and as yet are not fully understood. The present review aimed to provide an overview of the pathophysiology of median nerve neuropathy in the carpal tunnel, and subsequent development of CTS.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 91,
                "text": "median"
            }
        },
        {
            "context": "Nascent-seq indicates widespread cotranscriptional RNA editing in Drosophila. The RNA editing enzyme ADAR chemically modifies adenosine (A) to inosine (I), which is interpreted by the ribosome as a guanosine. Here we assess cotranscriptional A-to-I editing in Drosophila by isolating nascent RNA from adult fly heads and subjecting samples to high throughput sequencing. There are a large number of edited sites within nascent exons. Nascent RNA from an ADAR-null strain was also sequenced, indicating that almost all A-to-I events require ADAR. Moreover, mRNA editing levels correlate with editing levels within the cognate nascent RNA sequence, indicating that the extent of editing is set cotranscriptionally. Surprisingly, the nascent data also identify an excess of intronic over exonic editing sites. These intronic sites occur preferentially within introns that are poorly spliced cotranscriptionally, suggesting a link between editing and splicing. We conclude that ADAR-mediated editing is more widespread than previously indicated and largely occurs cotranscriptionally.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 101,
                "text": "ADAR"
            }
        }
    ],
    "val": [
        {
            "context": "Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi. BACKGROUND: Microsporidia is one of the taxa that have experienced the most dramatic taxonomic reclassifications. Once thought to be among the earliest diverging eukaryotes, the fungal nature of this group of intracellular pathogens is now widely accepted. However, the specific position of microsporidia within the fungal tree of life is still debated. Due to the presence of accelerated evolutionary rates, phylogenetic analyses involving microsporidia are prone to methodological artifacts, such as long-branch attraction, especially when taxon sampling is limited. RESULTS: Here we exploit the recent availability of six complete microsporidian genomes to re-assess the long-standing question of their phylogenetic position. We show that microsporidians have a similar low level of conservation of gene neighborhood with other groups of fungi when controlling for the confounding effects of recent segmental duplications. A combined analysis of thousands of gene trees supports a topology in which microsporidia is a sister group to all other sequenced fungi. Moreover, this topology received increased support when less informative trees were discarded. This position of microsporidia was also strongly supported based on the combined analysis of 53 concatenated genes, and was robust to filters controlling for rate heterogeneity, compositional bias, long branch attraction and heterotachy. CONCLUSIONS: Altogether, our data strongly support a scenario in which microsporidia is the earliest-diverging clade of sequenced fungi.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 82,
                "text": "fungi"
            }
        },
        {
            "context": "Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people, including trained athletes. The implantable cardioverter-defibrillator (ICD), although initially designed as a treatment for older patients with coronary artery disease, has more recently proved to be a safe and effective therapeutic intervention in young patients with HCM, both for primary or secondary prevention of sudden death. The largest such report of >500 patients showed that the ICD intervened appropriately to abort ventricular tachycardia/fibrillation (VT/VF) in 20% of patients over an average follow-up period of only 3.7 years, at a rate of about 4% per year in those patients implanted prophylactically, and often with considerable delays of up to 10 years. Extensive experience with high-risk HCM patients showed that appropriate device discharges for VT/VF occur with similar frequency in patients with 1, 2, or > or = 3 noninvasive risk markers. Despite the extreme morphology characteristic of HCM, often with massive degrees of left ventricular (LV) hypertrophy and/or LV outflow tract obstruction, ICDs performed in a highly effective fashion, with failure to convert life-threatening arrhythmias extraordinarily rare. In conclusion, in a large high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm. An important proportion of ICD discharges occurred in primary prevention patients with only one risk factor. Therefore, a single marker of high risk may represent sufficient evidence to justify the recommendation for a prophylactic ICD in selected patients with HCM.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 90,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care. BACKGROUND: An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. METHODS: Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians. CONCLUSIONS: The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria. Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 70,
                "text": "malaria"
            }
        },
        {
            "context": "diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data?",
            "answers": {
                "answer_start": 476,
                "text": "diffloop"
            }
        },
        {
            "context": "Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent? Tuberculosis is responsible for more then 2 million deaths worldwide each year and vies with HIV as the world's most fatal infectious disease. In many developing countries, attempts to control the spread of infection rely solely on identification and treatment of those with active disease, ignoring subclinical infection. However, in developed countries, large efforts are also expended to identify and give prophylactic drugs to people with latent tuberculosis infection. Until recently, the 100-year-old tuberculin skin test (Mantoux) has been the only available diagnostic test for latent tuberculosis infection, despite its many well-known limitations. Advances in scientific knowledge have led to the development of tests for tuberculosis that measure the production of interferon-gamma by T-cells stimulated in vitro with Mycobacterium tuberculosis-specific antigens. These interferon-gamma tests are highly specific and unaffected by prior Bacille Calmette-Guérin vaccination or immune reactivity to most atypical mycobacteria. They are more sensitive than the tuberculin skin test in detecting people with active tuberculosis, and their results correlate more closely with M. tuberculosis exposure risk factors than the tuberculin skin test in people likely to have latent tuberculosis infection. Science has caught up with one of the oldest diagnostic tests still in use worldwide, and the adoption of new, tuberculosis-specific interferon-gamma-based tests should move us one step closer to better control of this insidious pathogen.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 695,
                "text": "tuberculosis"
            }
        },
        {
            "context": "The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl kinase fusion protein and its pivotal role in the pathogenesis of CML provided new opportunities to develop molecular-targeted therapies. Imatinib mesylate (IM, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), which specifically inhibits the autophosphorylation of the Abl TK, has improved the treatment of CML. However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Inhibitors of Abl TK are divided into two main groups, namely, ATP-competitive and ATP noncompetitive inhibitors. The ATP-competitive inhibitors fall into two subclasses, the Src/Abl inhibitors, and the 2-phenylaminopyrimidine-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606, and PD166326 are classified as Src/Abl inhibitors, while nilotinib (AMN107) and INNO-406 (NS-187) belong to the latter subclass of inhibitors. Of these agents, dasatinib and nilotinib underwent clinical trials earlier than the others and favorable results are now accumulating. Clinical studies of the other compounds, including SKI-606 and INNO-406, have been performed in rapid succession. Because of their strong affinities for the ATP-binding site compared to IM, most ATP-competitive inhibitors may be effective in IM-resistant patients. However, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. Instead, ATP noncompetitive inhibitors, such as ON012380, Aurora kinase inhibitor MK0457 (VX-680), and p38 MAP kinase inhibitor BIRB-796, have been developed to address this problem. This review provides an update on the underlying pathophysiologies of disease progression and IM resistance, and discusses the development of new targeted TK inhibitors for managing CML and the importance of future strategies targeting CML stem cells.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 271,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1562,
                "text": "FSHD"
            }
        },
        {
            "context": "Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas. BACKGROUND: Gamma Knife radiosurgery (GKRS) is commonly used in treating small vestibular schwannomas; however, its use for larger vestibular schwannomas is still controversial. OBJECTIVE: To assess the long-term safety and efficacy of treating eligible Koos grade 4 vestibular schwannomas with GKRS. METHODS: We conducted a single-center, retrospective evaluation of patient undergoing GKRS for Koos grade 4 vestibular schwannomas. We evaluated clinical, imaging, and treatment characteristics and assessed treatment outcome. Inclusion criteria were tumor size of > 4 cm and follow-up of at least 6 months. Patients with neurofibromatosis type 2 were excluded. Primary outcomes measured were tumor control rate, hearing and facial function preservation rate, and complications. All possible factors were analyzed to assess clinical significance. RESULTS: Sixty-eight patients met inclusion criteria. Median follow-up was 47 months (range, 6-125 months). Baseline hearing was serviceable in 60%. Median tumor volume at radiosurgery was 7.4 cm (range, 4-19 cm). The median marginal dose used was 12 Gy at the 50% isodose line. Actuarial tumor control rates were 95% and 92% at 2 and 10 years, respectively. Actuarial serviceable hearing preservation rates were 89% and 49% at 2 and 5 years, respectively. Facial nerve preservation was 100%. Clinical complications included balance disturbance (11%), facial pain (10%), facial numbness (5%), and tinnitus (10%). Most complications were mild and transient. Hydrocephalus occurred in 3 patients, requiring ventriculoperitoneal shunt insertion. Larger tumor size was significantly associated with persisting symptoms post-treatment. CONCLUSION: Patients with Koos grade 4 vestibular schwannomas and minimal symptoms can be treated safely and effectively with GKRS.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 83,
                "text": "Vestibular Schwannoma"
            }
        },
        {
            "context": "Differential regulation of Nox1, Nox2 and Nox4 in vascular smooth muscle cells from WKY and SHR. The functional significance and regulation of NAD(P)H oxidase (Nox) isoforms by angiotensin II (Ang II) and endothelin-1 (ET-1) in vascular smooth muscle cells (VSMCs) from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was studied. Expression of Nox1, Nox2, and Nox4 (gene and protein) and NAD(P)H oxidase activity were increased in SHR. Basal NAD(P)H oxidase activity was blocked by GKT136901 (Nox1/4 inhibitor) and by Nox1 siRNA in WKY cells and by siNOX1 and siNOX2 in SHR. Whereas Ang II increased expression of all Noxes in WKY, only Nox1 was influenced in SHR. Ang II-induced NAD(P)H activity was inhibited by siNOX1 in WKY and by siNOX1 and siNOX2 in SHR. ET-1 upregulated Nox expression only in WKY and increased NAD(P)H oxidase activity, an effect inhibited by siNOX1 and siNOX2. Nox1 co-localized with Nox2 but not with Nox4, implicating association between Nox1 and Nox2 but not between Nox1 and Nox4. These data highlight the complexity of Nox biology in VSMCs, emphasising that more than one Nox member, alone or in association, may be involved in NAD(P)H oxidase-mediated •O(2)(-) production. Nox1 regulation by Ang II, but not by ET-1, may be important in •O(2)(-) formation in VSMCs from SHR.",
            "question": "Which compound is a specific inhibitor for Nox1 and Nox4?",
            "answers": {
                "answer_start": 509,
                "text": "GKT136901"
            }
        },
        {
            "context": "Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. OBJECTIVE: It has been firmly established that mutations in the gene for fibrillin 1, FBN1, cause Marfan syndrome (MFS). FBN1 mutations can also cause other phenotypes, such as ectopia lentis (EL) and familial isolated thoracic aortic aneurysm and dissection (FAA). When the clinical presentation is typical, diagnosis of MFS is usually easy to make. However, there can be a marked phenotypic variation between affected subjects even in one family, and making the diagnosis can be challenging, especially in childhood. The objective of this study was to test the sensitivity of conformation sensitive gel electrophoresis (CSGE) for detecting mutations in FBN1 in MFS and related phenotypes. DESIGN: Setting up CSGE analysis for the FBN1 gene and testing the method first by screening coded samples from 17 MFS patients with previously detected FBN1 mutations. We then used a test set consisting of 46 coded samples representing MFS, related phenotypes, and controls. RESULTS: Sixteen of the 17 known mutations were detected. Altogether 23 mutations were detected in a test set consisting of 46 coded samples representing MFS, related phenotypes, and controls. Nineteen of the mutations were novel. The mutation was detected in 18 of the 20 MFS patients and in one patient with familial EL, but not in a patient with sporadic MASS syndrome, any of the five sporadic annuloaortic ectasia (AAE) patients, or any of the 15 controls. A FBN1 mutation was detected in four members of a multigeneration family with AAE, however. CONCLUSIONS: These results indicate that CSGE is highly sensitive for the detection of mutations in FBN1, and that molecular diagnostics is a useful means of confirming clinical diagnoses of MFS and related disorders. Further careful investigations are needed, however, in order to correlate the interfamilial and intrafamilial clinical variabilities of fibrillinopathies and mutations in FBN1.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 210,
                "text": "FBN1"
            }
        },
        {
            "context": "Ca2+ binding to site I of the cardiac Ca2+ pump is sufficient to dissociate phospholamban. Phospholamban (PLB) inhibits the activity of SERCA2a, the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum, by decreasing the apparent affinity of the enzyme for Ca(2+). Recent cross-linking studies have suggested that PLB binding and Ca(2+) binding to SERCA2a are mutually exclusive. PLB binds to the E2 conformation of the Ca(2+)-ATPase, preventing formation of E1, the conformation that binds two Ca(2+) (at sites I and II) with high affinity and is required for ATP hydrolysis. Here we determined whether Ca(2+) binding to site I, site II, or both sites is sufficient to dissociate PLB from the Ca(2+) pump. Seven SERCA2a mutants with amino acid substitutions at Ca(2+)-binding site I (E770Q, T798A, and E907Q), site II (E309Q and N795A), or both sites (D799N and E309Q/E770Q) were made, and the effects of Ca(2+) on N30C-PLB cross-linking to Lys(328) of SERCA2a were measured. In agreement with earlier reports with the skeletal muscle Ca(2+)-ATPase, none of the SERCA2a mutants (except E907Q) hydrolyzed ATP in the presence of Ca(2+); however, all were phosphorylatable by P(i) to form E2P. Ca(2+) inhibition of E2P formation was observed only in SERCA2a mutants retaining site I. In cross-linking assays, strong cross-linking between N30C-PLB and each Ca(2+)-ATPase mutant was observed in the absence of Ca(2+). Importantly, however, micromolar Ca(2+) inhibited PLB cross-linking only to mutants retaining a functional Ca(2+)-binding site I. The dynamic equilibrium between Ca(2+) pumps and N30C-PLB was retained by all mutants, demonstrating normal regulation of cross-linking by ATP, thapsigargin, and anti-PLB antibody. From these results we conclude that site I is the key Ca(2+)-binding site regulating the physical association between PLB and SERCA2a.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 91,
                "text": "Phospholamban"
            }
        },
        {
            "context": "ACS chemical neuroscience molecule spotlight on semagacestat (LY450139). Semagacestat (LY450139) is a novel γ-secretase inhibitor currently in late-stage development by Eli Lilly and Company as a potential treatment for Alzheimer's disease (AD). Semagacestat is currently being studied in two phase III clinical trials.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 73,
                "text": "Semagacestat"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 388,
                "text": "phosphatase 2B"
            }
        },
        {
            "context": "Probe-to-bone test for diagnosing diabetic foot osteomyelitis: reliable or relic? OBJECTIVE: We sought to assess the accuracy of the probe-to-bone (PTB) test in diagnosing foot osteomyelitis in a cohort of diabetic patients with bone culture proven disease. RESEARCH DESIGN AND METHODS: In this 2-year longitudinal cohort study, we enrolled 1,666 consecutive diabetic individuals who underwent an initial standardized detailed foot assessment, followed by examinations at regular intervals. Patients were instructed to immediately come to the foot clinic if they developed a lower-extremity complication. For all patients with a lower-extremity wound, we compared the results of the PTB test with those of a culture of the affected bone. We called PTB positive if the bone or joint was palpable and defined osteomyelitis as a positive bone culture. RESULTS: Over a mean of 27.2 months of follow-up, 247 patients developed a foot wound and 151 developed 199 foot infections. Osteomyelitis was found in 30 patients: 12% of those with a foot wound and 20% in those with a foot infection. When all wounds were considered, the PTB test was highly sensitive (0.87) and specific (0.91); the positive predictive value was only 0.57, but the negative predictive value was 0.98. CONCLUSIONS: The PTB test, when used in a population of diabetic patients with a foot wound among whom the prevalence of osteomyelitis was 12%, had a relatively low positive predictive value, but a negative test may exclude the diagnosis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 34,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "Benzodiazepine intoxication treated with flumazenil (Anexate, RO 15-1788). The efficacy and safety of flumazenil were assessed in comparison to placebo in a double-blind randomised study of 31 adults intoxicated with benzodiazepines. The criteria of efficacy were the degree of sedation, and orientation in time and space. Patients who received flumazenil awoke within minutes but central depression returned partly one hour later, which reflects the short elimination half-life of the drug. Side effects were few and the results indicate that flumazenil is effective in the primary management of benzodiazepine overdose and in states where benzodiazepines have been taken with other drugs.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 102,
                "text": "flumazenil"
            }
        },
        {
            "context": "Gender differences in Latin-American patients with rheumatoid arthritis. BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a large population with unique characteristics, including high admixture. OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in LAC. METHODS: This was a 2-phase study. First we conducted a cross-sectional and analytical study in which 1128 consecutive Colombian patients with RA were assessed. Second, a systematic review of the literature was done to evaluate the effect of gender in LAC patients with RA. RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man. Colombian women with RA are more at risk of having an early age at onset and developing polyautoimmunity and abdominal obesity, and they perform more household duties than their male counterparts. However, male gender was associated with the presence of extra-articular manifestations. Of a total of 641 potentially relevant articles, 38 were considered for final analysis, in which several factors and outcomes related to gender were identified. CONCLUSIONS: RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 1223,
                "text": "women"
            }
        },
        {
            "context": "Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), the predominating Ser/Thr phosphatase in the heart. Non-phosphorylated I-1 is inactive, whereas I-1 phosphorylated by protein kinase A (PKA) at Thr35 is a potent PP1 inhibitor. The phosphatases that dephosphorylate I-1Thr35 and thus deactivate I-1 in the heart are not established. Here we overexpressed I-1 in neonatal rat cardiac myocytes with recombinant adenovirus and determined phosphorylation of I-1, and one of the major target proteins of PKA/PP1 in the heart, phospholamban (PLB), by Western blot with phospho-specific antibodies. Incubation with the calcineurin inhibitor cyclosporine A or okadaic acid, used at a concentration preferentially inhibiting phosphatase 2A (PP2A), increased significantly I-1Thr35 (approximately 2- to 6-fold) and PLB Ser16 phosphorylation (approximately 2-fold). The results indicate that calcineurin and PP2A act to maintain a low basal level of phosphorylated (active) I-1 in living cardiac myocytes. Calcineurin may constitute a cross-talk between calcium- and cAMP-dependent pathways.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 113,
                "text": "Inhibitor 1"
            }
        },
        {
            "context": "Hypochondroplasia due to FGFR3 gene mutation (N540K) and mosaic form of Down syndrome in the same patient. The simultaneous presence of Down syndrome and achondroplasia has rarely been reported in the literature, and our search revealed only six patients with such an association. We are reporting the first case of a patient with Down syndrome and hypochondroplasia. In this patient, Down syndrome was clinically recognised and confirmed by the cytogenetic finding of mosaic karyotype (47,XX,+21/46,XX) shortly after birth. She was subsequently diagnosed with hypochondroplasia at the age of 6 years when disproportional short stature, stocky habitus and macrocephaly were observed. These phenotypic findings were later confirmed by the presence of fibroblast growth factor receptor 3 (FGFR3) gene mutation N540K. The overlapping common clinical features of Down syndrome and hypochondroplasia resulted in delayed diagnosis of hypochondroplasia in our patient and the associated deleterious effect on her linear growth. Her final height is 126.5 cm, which is -3.76 standard deviations (SD) lower than the median height in patients with Down syndrome, and is under the lower borderline of the adult height range for women with hypochondroplasia.",
            "question": "Mutation of which gene is associated with Achondroplasia?",
            "answers": {
                "answer_start": 750,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators. Nox3, a member of the superoxide-producing NADPH oxidase (Nox) family, participates in otoconia formation in mouse inner ears, which is required for perception of balance and gravity. The activity of other Nox enzymes such as gp91(phox)/Nox2 and Nox1 is known to absolutely require both an organizer protein (p47(phox) or Noxo1) andanactivatorprotein (p67(phox) or Noxa1); for the p47(phox)-dependent activation of these oxidases, treatment of cells with stimulants such as phorbol 12-myristate 13-acetate is also indispensable. Here we show that ectopic expression of Nox3 in various types of cells leads to phorbol 12-myristate 13-acetate-independent constitutive production of a substantial amount of superoxide under the conditions where gp91(phox) and Nox1 fail to generate superoxide, i.e. in the absence of the oxidase organizers and activators. Nox3 likely forms a functional complex with p22(phox); Nox3 physically interacts with and stabilizes p22(phox), and the Nox3-dependent superoxide production is totally dependent on p22(phox). The organizers p47(phox) and Noxo1 are capable of enhancing the superoxide production by Nox3 in the absence of the activators, and the enhancement requires the interaction of the organizers with p22(phox), further indicating a link between Nox3 and p22(phox). The p47(phox)-enhanced Nox3 activity is further facilitated by p67(phox) or Noxa1, whereas the activators cancel the Noxo1-induced enhancement. On the other hand, the small GTPase Rac, essential for the gp91(phox) activity, is likely dispensable to the Nox3 system. Thus Nox3 functions together with p22(phox) as an enzyme constitutively producing superoxide, which can be distinctly regulated by combinatorial use of the organizers and activators.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 388,
                "text": "Nox1"
            }
        },
        {
            "context": "Finkelstein's test: a biomechanical analysis. PURPOSE: Finkelstein's test is the classic diagnostic test for de Quervain's disease. Finkelstein hypothesized that the entry of the muscle bellies of the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons into the first extensor compartment was responsible for the findings observed in his now eponymous test. We agree with Finkelstein's hypothesis and further hypothesize that this position would induce measurable bulk (muscle mass within the retinaculum) and tethering (stretching of synovial tissue) effects within the compartment. To test this latter hypothesis we measured the excursion and gliding resistance of the EPB and APL tendons within the first compartment. METHODS: Fifteen fresh-frozen cadavers were used. Gliding resistance and excursion were measured in 4 different wrist positions, including the wrist position of Finkelstein's test (30 degrees ulnar deviation). The bulk and tethering effect was calculated based on the mean gliding resistance over the tendon proximal/distal excursion cycle and the gliding resistance at the terminal distal excursion. RESULTS: The EPB tendon excursion was significantly more distal in 30 degrees ulnar deviation than in 60 degrees extension. Additionally the bulk and tethering resistance was significantly greater in 30 degrees ulnar deviation compared with 60 degrees extension. For the APL tendon there was no significant difference in either the tendon excursion or the bulk and tethering resistance between 30 degrees ulnar deviation and 60 degrees extension. CONCLUSIONS: We showed that in the position of Finkelstein's test the EPB tendon is significantly more distal and has significantly greater bulk and tethering effect compared with the other EPB positions. This is not the case for the APL tendon in the position of Finkelstein's test. These results suggest that an abnormal Finkelstein's test reflects differences of the EPB more than it does the APL.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 109,
                "text": "de Quervain's disease"
            }
        },
        {
            "context": "Familial Turner syndrome. Seven women in three generations of a family have been affected by Turner syndrome. Turner phenotype in this family is the result of deletion of the entire short arm of one X chromosome. The short arm deletion is transmitted by carriers of a balanced X-1 translocation. Autoradiographic findings showed that the deleted X chromosome was late labeling in those persons with Turner syndrome, whereas the normal X chromosome was late replicating in carriers of the balanced translocation. The results of Xga typing of erythrocytes suggest that the Xg locus is on the short arm of the X chromosome. Because of the clinical implications, we believe that families of persons with structural chromosomal abnormalities should be studied to exclude familial transmission.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 199,
                "text": "X"
            }
        },
        {
            "context": "Unique properties of lamp2a compared to other lamp2 isoforms. Lamp2a acts as a receptor in the lysosomal membrane for substrate proteins of chaperone-mediated autophagy. Using antibodies specific for the cytosolic tail of lamp2a and others recognizing all lamp2 isoforms, we found that in rat liver lamp2a represents 25% of lamp2s in the lysosome. We show that lamp2a levels in the lysosomal membrane in rat liver and fibroblasts in culture directly correlate with rates of chaperone-mediated autophagy in a variety of physiological and pathological conditions. The concentration of other lamp2s in the lysosomal membrane show no correlation under the same conditions. Furthermore, substrate proteins bind to lamp2a but not to other lamp2s. Four positively-charged amino acids uniquely present in the cytosolic tail of lamp2a are required for the binding of substrate proteins. Lamp2a also distributes to an unique subpopulation of perinuclear lysosomes in cultured fibroblasts in response to serum withdrawal, and lamp2a, more than other lamp2s, tends to multimerize. These characteristics may be important for lamp2a to act as a receptor for chaperone-mediated autophagy.",
            "question": "Which is the receptor for substrates of Chaperone Mediated Autophagy?",
            "answers": {
                "answer_start": 62,
                "text": "Lamp2a"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 42,
                "text": "Xa"
            }
        },
        {
            "context": "Restless Legs Syndrome/Willis-Ekbom Disease Morbidity: Burden, Quality of Life, Cardiovascular Aspects, and Sleep. Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) has a significant negative effect on quality of life. The decreased quality of life is similar to that of other chronic diseases, such as diabetes type 2, depression, and osteoarthritis. RLS/WED disrupts sleep length, sleep quality, and daytime alertness. Sleep disruption can contribute to depression. RLS/WED has been associated with cardiovascular disease and high blood pressure, possibly because of increased sympathetic tone caused by periodic limb movements of sleep. RLS/WED is underdiagnosed, leading to chronic sleep disruption and daytime consequences. Patients with RLS/WED have decreased productivity at work, which potentially has far-reaching economic consequences.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 0,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 1368,
                "text": "LPIN2"
            }
        },
        {
            "context": "Current strategies for treatment of relapsed/refractory multiple myeloma. In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 885,
                "text": "orally"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 440,
                "text": "Telomerase"
            }
        },
        {
            "context": "A new procedure for extraction of collagen from modern and archaeological bones for 14C dating. Bones are potentially the best age indicators in a stratigraphic study, because they are closely related to the layer in which they are found. Collagen is the most suitable fraction and is the material normally used in radiocarbon dating. Bone contaminants can strongly alter the carbon isotopic fraction values of the samples, so chemical pretreatment for (14)C dating by accelerator mass spectrometry (AMS) is essential. The most widespread method for collagen extraction is based on the Longin procedure, which consists in HCl demineralization to dissolve the inorganic phase of the samples, followed by dissolution of collagen in a weak acid solution. In this work the possible side effects of this procedure on a modern bone are presented; the extracted collagen was analyzed by ATR-IR spectroscopy. An alternative procedure, based on use of HF instead of HCl, to minimize unwanted degradation of the organic fraction, is also given. A study by ATR-IR spectroscopic analysis of collagen collected after different demineralization times and with different acid volumes, and a study of an archaeological sample, are also presented.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 239,
                "text": "Collagen"
            }
        },
        {
            "context": "Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 312,
                "text": "orally"
            }
        },
        {
            "context": "Update of the FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation. The international Functional Annotation Of the Mammalian Genomes 4 (FANTOM4) research collaboration set out to better understand the transcriptional network that regulates macrophage differentiation and to uncover novel components of the transcriptome employing a series of high-throughput experiments. The primary and unique technique is cap analysis of gene expression (CAGE), sequencing mRNA 5'-ends with a second-generation sequencer to quantify promoter activities even in the absence of gene annotation. Additional genome-wide experiments complement the setup including short RNA sequencing, microarray gene expression profiling on large-scale perturbation experiments and ChIP-chip for epigenetic marks and transcription factors. All the experiments are performed in a differentiation time course of the THP-1 human leukemic cell line. Furthermore, we performed a large-scale mammalian two-hybrid (M2H) assay between transcription factors and monitored their expression profile across human and mouse tissues with qRT-PCR to address combinatorial effects of regulation by transcription factors. These interdependent data have been analyzed individually and in combination with each other and are published in related but distinct papers. We provide all data together with systematic annotation in an integrated view as resource for the scientific community (http://fantom.gsc.riken.jp/4/). Additionally, we assembled a rich set of derived analysis results including published predicted and validated regulatory interactions. Here we introduce the resource and its update after the initial release.",
            "question": "What was the purpose of the FANTOM4 project?",
            "answers": {
                "answer_start": 214,
                "text": "better understand the transcriptional network that regulates macrophage differentiation"
            }
        },
        {
            "context": "Distinction between upper and lower gastrointestinal perforation: usefulness of the periportal free air sign on computed tomography. PURPOSE: To evaluate the usefulness of the periportal free air (PPFA) sign on computed tomography (CT) to distinguish upper from lower gastrointestinal (GI) tract perforation. MATERIALS AND METHODS: During a 30-month period, we retrospectively analyzed abdominal CT images of 53 consecutive patients with surgically proven GI tract perforation. We divided the patients into two groups, i.e. upper and lower GI tract perforation groups. According to the distribution of free air, we divided the peritoneal cavity into supramesocolic compartment and inframesocolic compartment. We observed the presence or absence of free air in each compartment in each group. When there was free air in the periportal area, it was defined as periportal free air (PPFA) and the sign was positive. To evaluate the usefulness of the PPFA sign, we compared the PPFA sign with the falciform ligament sign and the ligamentum teres sign, both of which are well-known CT signs of pneumoperitoneum. Statistical analyses were performed with univariate and multivariate analyses using SPSS version 11.5 for significant findings among the CT signs. RESULTS: Free air was seen in supramesocolic compartment in 29 of 30 (97%) patients in the upper GI perforation group and in 17 of 23 (74%) in the lower GI perforation group. Free air in inframesocolic compartment did not show significant difference in either group (p=.16). The PPFA sign was seen in 28 of 30 (93%) patients with upper GI tract perforation, but in only 8 of 23 (35%) patients with lower GI tract perforation (p<.0001). The falciform ligament sign was seen in 24 of 30 (80%) patients with upper GI tract perforation and in 10 of 23 (43%) patients with lower GI tract perforation (p=.020). The ligamentum teres sign was seen in 16 of 30 (53%) patients with upper GI tract perforation and in 2 of 23 (8%) patients with lower GI tract perforation (p=.008). Multivariate logistic regression analysis showed that the PPFA sign was the only variable, which adjusted odds ratio of 15.5 (p=.002). CONCLUSION: The PPFA sign is a useful finding which can help to distinguish upper from lower GI tract perforation. When this sign is present, upper GI tract perforation is strongly suggested.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 1088,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "A novel frameshift mutation in the McLeod syndrome gene in a Japanese family. We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome. A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis. The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK. This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408. We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 121,
                "text": "XK"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1224,
                "text": "thyroid"
            }
        },
        {
            "context": "The effects of X monosomy on brain development: monozygotic twins discordant for Turner's syndrome. Monosomy for the X chromosome is the most frequent cause of Turner's syndrome, a common clinical syndrome associated with particular physical and neurobehavioral features. The results from comprehensive assessment of prepubertal monozygotic female twins discordant for X monosomy are presented. Zygosity was established with DNA Fingerprinting and no evidence of chromosomal mosaicism was seen in either child. Physical features in the affected twin were relatively mild with respect to the full spectrum of physical malformations and disabilities associated with Turner's syndrome. The neurobehavioral phenotypes of the twins were compared. Although both sisters scored in the superior range of intelligence, the affected twin's Performance IQ was 18 points less than her sister, whereas Verbal IQ showed only a 3-point difference between the sisters. Other relative differences were noted within the executive, visuospatial, and visuomotor domains of function. Behavioral evaluation indicated greater problems with attention, hyperactivity, and anxiety in the affected twin. Quantitative analysis of brain anatomy revealed evidence of both general and regional effects of X monosomy on neurodevelopment. Cerebrospinal fluid volume was increased by 25% in the affected twin compared with her sister with a corresponding decrease in gray matter volume. The right frontal, right parietal-occipital, and left parietal-perisylvian regions showed the greatest discrepancy between the sisters with respect to increased cerebrospinal fluid and decreased gray matter volumes in twin with X monosomy. Differences in the posterior fossa were also noted with a 50% relative increase in the volumes of the fourth ventricle and cisterna magna and a 10 to 15% relative reduction in size of the cerebellar vermis, pons, and medulla in the affected twin. The association between the neurobehavioral and neuroanatomical findings in the affected twin is discussed. The unique nature of the naturally occurring genetic phenomenon seen in this twin pair provides an opportunity to more fully elucidate the neurobehavioral phenotype associated with X monosomy and Turner's syndrome.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 117,
                "text": "X"
            }
        },
        {
            "context": "Acute migraine therapy: new drugs and new approaches. The conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT(1B/1D) receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT(1F) receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 1210,
                "text": "Calcitonin gene-related peptide"
            }
        },
        {
            "context": "Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. The aim of the present study is to describe and validate a method for accurate quantification of 5-hydroxytryptamine (5-HT)(2A) receptors using [18F]altanserin-positron emission tomography (PET) and the bolus/infusion approach. A bolus/infusion ratio of 1.75 h aimed at attaining rapid steady state in blood and brain was predicted from previous bolus studies performed in our laboratory. The infusion schedule was tested in normal subjects (n = 10) using dynamic PET and frequent plasma sampling for 6 h. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 3 h. To represent free and nonspecifically bound [18F]altanserin and its radiolabeled metabolites only, cerebellum must show no displacement in 5-HT(2A) displacement studies. To validate this, saturating doses of cold ketanserin were administered and it was found that specific binding of [18F]altanserin decreased uniformly to the level of the cerebellum and no change in the cerebellar time-activity curve was found after ketanserin administration. A shorter experimental setup was tested in a second group (n = 20) including patients with neuropsychiatric disorders. Dynamic PET (five frames of 8 minutes each) and venous blood sampling at midscan time started 2 h after [18F]altanserin administration. The mean percentage rate of change per hour in the outcome parameter, DV(3)', was low (mean -0.3% h-1; range -7.3-7.2% h-1) and no correlation of DV(3)' versus time was demonstrated. It is concluded that 5-HT(2A) receptor studies can be conducted within 2 h of [18F]altanserin infusion, yielding reliable results.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 18,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Neurobiological basis of dyskinetic effects induced by antipsychotics: the contribution of animal models. Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.",
            "question": "What is the cause of Tardive dyskinesia?",
            "answers": {
                "answer_start": 106,
                "text": "Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications."
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 910,
                "text": "xa"
            }
        },
        {
            "context": "Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes. Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such as IkappaBalpha or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-kappaB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-kappaB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-kappaB-activating pathway.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 1231,
                "text": "H3K4"
            }
        },
        {
            "context": "[Botulinum toxin as a biological weapon]. Botulism is caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum. It is a flaccid paralysis in which consciousness and nociception are preserved. Natural botulism typically results from ingestion of inadequately heated or unheated vacuum-packed foods. In addition, botulinum toxin is one of the most feared biological weapons. In the diagnosis and treatment of botulism early suspicion is essential. Several coinciding or local clusters without a typical connecting source, or an uncommon type of toxin may indicate an intentionally caused epidemic.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 111,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 609,
                "text": "xa"
            }
        },
        {
            "context": "Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate. Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreER and GFP from ten different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium, including sources for specific subtypes of amygdala neurons. We then focused on deciphering transcriptional mechanisms that control enhancer activity. Using machine-learning computations, in vivo chromosomal occupancy of 13 transcription factors that regulate subpallial patterning and differentiation and analysis of enhancer activity in Dlx1/2 and Lhx6 mutants, we elucidated novel molecular mechanisms that regulate region-specific enhancer activity in the developing brain. Thus, these subpallial enhancer transgenic lines are data and tool resources to study transcriptional regulation of GABAergic cell fate.",
            "question": "Which resource has been developed in order to study the transcriptional regulation of GABAergic cell fate?",
            "answers": {
                "answer_start": 1027,
                "text": "subpallial enhancer transgenic lines"
            }
        },
        {
            "context": "Benefits of sunlight: vitamin D deficiency might increase the risk of sudden unexpected death in epilepsy. Epilepsy is the most common serious neurological condition and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. In parallel, studies have shown a link between vitamin D dysfunction and epilepsy. Moreover, several evidences in the literature suggest an association between low vitamin D and seizures, indicating the possibility of anticonvulsant properties of this hormone. Quite interesting, a growing body of data suggests that low vitamin D levels may adversely affect cardiovascular health, directly associated with death from heart failure and sudden cardiac death. In view of the above findings, our research group focused in this review article that SUDEP, at least in some cases, could be related with low vitamin D levels.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 170,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Osteomyelitis of the accessory and body of the navicular bone: a case report. A 16-year-old boy developed left foot pain of unknown cause that was unresponsive to conservative treatment, associated with fever and difficulty walking. He was admitted to our hospital with osteomyelitis of the accessory and body of the navicular bone. Surgery could not be performed because the patient had been diagnosed with Wiskott-Aldrich syndrome. After antibiotic therapy, laboratory abnormalities and pain had resolved. One year after treatment, the patient had returned to his original level of sports activity. Both an accessory navicular and the body of the navicular bone may develop osteomyelitis in immunocompromised patients; early diagnosis is important for prescribing effective conservative treatment.",
            "question": "Where in the body would the navicular bone be found?",
            "answers": {
                "answer_start": 111,
                "text": "foot"
            }
        },
        {
            "context": "Francisella tularensis aortitis. Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans. The clinical manifestations of tularemia include pneumonia, ulceroglandular, oropharyngeal, or typhoidal disease. Rare manifestations are also described, but to our knowledge, we describe here the first case of F. tularensis aortitis in a human. Diagnosis was confirmed by the presence of F. tularensis in blood culture, by the presence of F. tularensis DNA in the aortic biopsy and by specific IgG and IgM responses against the bacteria. The outcome was favorable after surgery and specific antimicrobial therapy.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 33,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation. BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 142,
                "text": "SLC9A6"
            }
        },
        {
            "context": "[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 146,
                "text": "TYR"
            }
        },
        {
            "context": "Modifications of the bladder wall (organ damage) in patients with bladder outlet obstruction: ultrasound parameters. INTRODUCTION: Progressive changes in the bladder wall are observed in men with lower urinary tract obstruction secondary to benign prostatic enlargement (BPE). The high pressure voiding causes initially an increase in the proportion of smooth muscle (hyperplasia/hypertrophy of the detrusor) that develops to major changes in the advanced stages of bladder decompensationi (fibrosis), hyperactivity and decreased functional capacity. Early identification of bladder changes by noninvasive transabdominal ultrasound can suggest therapeutic choices that can prevent further organ damage in the bladder wall. Aim of our study is to review ultrasound (US) parameters, that could be considered reliable and reproducible, in order to demonstrate the damage of the bladder wall. METHODS: We performed a literature review to detect reported US parameters according to our aims. Our clinical experience was evaluated in retrospective manner to detect feasibility and limitations of the evaluation of these parameters in men with different degrees of bladder damage secondary to BPE. RESULTS: Measurement of the bladder wall thickness (BWT) or detrusor wall thickness (DWT) by US is reliable, with at least 3 measurements of the anterior bladder wall taken at a filling volume of 250 ml. In particular, the DWT [thickness of the hypoechoic muscle between two hyperechoic layers corresponding to serosa and mucosa] is considered the best diagnostic tool to measure detrusor hypertrophy using cut-off value > 2.9 mm in men. US derived measurements of bladder weight (Estimated Bladder Weight, EBW) is another noninvasive tool for assessing bladder modifications in patients with bladder outlet obstruction (BOO) with a cut-off value of 35 gr. Technique for measuring the BWT and EBW relies on conventional US 7.5-4 MHz using the automatic system of computation (BVM 6500 3.7 MHz). The variability of intra-operator (4.6 to 5.1%) and interoperator measurements (12.3%) is acceptable. Also conventional US detects established signs of bladder damage: diverticulosis, trabecolations in the bladder wall (pseudo-diverticula), calculi and post-void residual urine (PVR) (> 50 cc). Furthermore the Intravescical Prostate Protrusion (IPP), easy measured by transabdominal ultrasound, is strongly correlated to obstruction in men with BPE (cut-off 12 mm). Measurement, scoring and monitoring of the cervico-urethral obstruction in men with symptomatic BPE is possible by the non-invasive US of the bladder wall. Early identification by measuring DWTand EBW in addition to established US paremeters has the advantage of suggest the adoption of therapeutic measures sufficient to prevent progression of bladder damage. CONCLUSIONS: US derived measurements of DWT and EBW are reproducible and reliable. Transabdominal US also detect established bladder damage such as diverticula, stones and PVR, while IPP measurement seems to be correlated to BOO. US bladder parameters are considered potential noninvasive clinical tools for baseline assessment of patients with BOO. In particular noninvasive US parameters could be useful for longitudinal studies monitoring men with lower urinary tract obstruction secondary to BPE.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 621,
                "text": "ultrasound"
            }
        },
        {
            "context": "ddm1 plants are sensitive to methyl methane sulfonate and NaCl stresses and are deficient in DNA repair. UNLABELLED: Plant response to stress includes changes in gene expression and chromatin structure. Our previous work showed that Arabidopsis thaliana Dicer-like (DCL) mutants were impaired in transgenerational response to stress that included an increase in recombination frequency, cytosine methylation and stress tolerance. It can be hypothesized that changes in chromatin structure are important for an efficient stress response. To test this hypothesis, we analyzed the stress response of ddm1, a mutant impaired in DDM1, a member of the SWI/SNF family of adenosine triphosphate-dependent chromatin remodeling genes. We exposed Arabidopsis thaliana ddm1 mutants to methyl methane sulfonate (MMS) and NaCl and found that these plants were more sensitive. At the same time, ddm1 plants were similar to wild-type plants in sensitivity to temperature and bleomycin stresses. Direct comparison to met1 plants, deficient in maintenance methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl. The level of DNA strand breaks upon exposure to MMS increased in wild-type plants but decreased in ddm1 plants. DNA methylation analysis showed that heterozygous ddm1/DDM1 plants had lower methylation as compared to fourth generation of homozygous ddm1/ddm1 plants. Exposure to MMS resulted in a decrease in methylation in wild-type plants and an increase in ddm1 plants. Finally, in vitro DNA excision repair assay showed lower capacity for ddm1 mutant. Our results provided a new example of a link between genetic genome stability and epigenetic genome stability. KEY MESSAGE: We demonstrate that heterozygous ddm1/DDM1 plants are more sensitive to stress and have more severe changes in methylation than homozygous ddm1/ddm1 plants.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1000,
                "text": "met1"
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1009,
                "text": "PD-L1"
            }
        },
        {
            "context": "Does the linear Sry transcript function as a ceRNA for miR-138? The sense of antisense. Recently, the sex determining region Y ( Sry) and the cerebellar degeneration-related protein 1 ( CDR1as) RNA transcripts have been described to function as a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7, respectively. A special feature of the Sry gene is its ability to generate linear and circular transcripts, both transcribed in the sense orientation. Here we remark that both sense (e.g. Sry RNA) and antisense (e.g. CDR1as) transcripts could circularize and behave as miRNAs sponges, and importantly, that also protein-coding segments of mRNAs could also assume this role. Thus, it is reasonable to think that the linear Sry sense transcript could additionally act as a miRNA sponge, or as an endogenous competing RNA for miR-138.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 372,
                "text": "miR-138"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 379,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Yeast Elc1 plays an important role in global genomic repair but not in transcription coupled repair. Transcription coupled repair (TCR) is a nucleotide excision repair (NER) pathway that is dedicated to repair in the transcribed strand of an active gene. The genome overall NER is called global genomic repair (GGR). Elc1, the yeast homolog of the mammalian elongation factor elongin C, has been shown to be a component of a ubiquitin ligase complex that contains Rad7 and Rad16, two factors that are specifically required for GGR. Elc1 has also been suggested to be present in another ubiquitin ligase complex that lacks Rad7 and Rad16 and is involved in UV-induced ubiquitylation and subsequent degradation of RNA polymerase II. Here we show that elc1 deletion increases UV sensitivity of TCR-deficient cells but does not affect the UV sensitivity of otherwise wild type and GGR-deficient cells. Cells deleted for elc1 show normal NER in the transcribed strand of an active gene but have no detectable NER in the non-transcribed strand. Elc1 does not affect UV-induced mutagenesis when TCR is operative, but plays an important role in preventing the mutagenesis if TCR is defective. Furthermore, the levels of Rad7 and Rad16 proteins are not significantly decreased in elc1 cells, and overexpression of Rad7 and Rad16 individually or simultaneously in elc1 cells does not restore repair in the non-transcribed strand of an active gene. Our results suggest that Elc1 has no function in TCR but plays an important role in GGR. Furthermore, the role of Elc1 in GGR may not be subsidiary to that of Rad7 and Rad16.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 213,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor. Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 322,
                "text": "telomerase"
            }
        },
        {
            "context": "Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: Results of a multicenter analysis. OBJECTIVES: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed. MATERIALS AND METHODS: We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded. RESULTS: Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89). CONCLUSION: Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 230,
                "text": "cancer"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1423,
                "text": "53BP1"
            }
        },
        {
            "context": "SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1574,
                "text": "NCX"
            }
        },
        {
            "context": "Low dose vaccination with attenuated Francisella tularensis strain SchuS4 mutants protects against tularemia independent of the route of vaccination. Tularemia, caused by the gram-negative bacterium Francisella tularensis, is a severe, sometimes fatal disease. Interest in tularemia has increased over the last decade due to its history as a biological weapon. In particular, development of novel vaccines directed at protecting against pneumonic tularemia has been an important goal. Previous work has demonstrated that, when delivered at very high inoculums, administration of live, highly attenuated strains of virulent F. tularensis can protect against tularemia. However, lower vaccinating inoculums did not offer similar immunity. One concern of using live vaccines is that the host may develop mild tularemia in response to infection and use of high inoculums may contribute to this issue. Thus, generation of a live vaccine that can efficiently protect against tularemia when delivered in low numbers, e.g. <100 organisms, may address this concern. Herein we describe the ability of three defined, attenuated mutants of F. tularensis SchuS4, deleted for FTT0369c, FTT1676, or FTT0369c and FTT1676, respectively, to engender protective immunity against tularemia when delivered at concentrations of approximately 50 or fewer bacteria. Attenuated strains for use as vaccines were selected by their inability to efficiently replicate in macrophages in vitro and impaired replication and dissemination in vivo. Although all strains were defective for replication in vitro within macrophages, protective efficacy of each attenuated mutant was correlated with their ability to modestly replicate and disseminate in the host. Finally, we demonstrate the parenteral vaccination with these strains offered superior protection against pneumonic tularemia than intranasal vaccination. Together our data provides proof of principle that low dose attenuated vaccines may be a viable goal in development of novel vaccines directed against tularemia.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 199,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Molecular and cellular bases of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients. Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis. Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet. CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML. However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML. In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors. A critical issue to resolve this problem is to fully understand the biology of LSCs, and to identify key genes that play significant roles in survival and self-renewal of LSCs. In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 731,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "[Puffy hand syndrome in drug addiction treated by low-stretch bandages]. BACKGROUND: Puffy hand syndrome is a complication of intravenous drug abuse, which has no current available treatment. Arm and forearm edema are voluminous and cause functional and aesthetic disturbances. We report two cases successfully treated by low-stretch bandages. OBSERVATIONS: A 40-year-old man and a 34-year-old woman, both intravenous drug users, with puffy hand syndrome were hospitalized for 11 days. Treatment included daily multilayer bandaging. Lymphedema volumes calculated by utilizing the formula for a truncated cone decreased by 16% on the left side and 12% on the right side for the first patient and 31 and 17% for the second. Hand circumference decreased 4.3 cm on the left side and 3.2 cm on the right side in case 1, and 2.5 cm and 1.9 cm respectively for case 2. The patients were taught self-bandaging techniques during their hospital stays. Elastic gloves were fitted at the end of treatment. Reduction of lymphedema volume remained stable after 18 months in one patient while for the second patient further treatment and hospitalization were required due to poor compliance. DISCUSSION: The pathogenesis of this edema is probably multifactorial: venous, lymphatic insufficiency and the direct toxicity of injected drugs. Lymphedema treatment currently consists of low-stretch bandaging and wearing elastic garments, which is effective in decreasing the volume of puffy hand syndrome.",
            "question": "What causes \"Puffy hand syndrome\"?",
            "answers": {
                "answer_start": 126,
                "text": "intravenous drug abuse"
            }
        },
        {
            "context": "Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study. OBJECTIVES: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. METHODS: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. RESULTS: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. CONCLUSIONS: BMI appears to be associated with RA disease activity in women, but not in men.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 1708,
                "text": "women"
            }
        },
        {
            "context": "Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as \"rufous/red albinism,\" is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed \"OCA4.\" The encoded protein, MATP (for \"membrane-associated transporter protein\") is predicted to span the membrane 12 times and likely functions as a transporter.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 623,
                "text": "tyrosinase"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 4,
                "text": "telomerase"
            }
        },
        {
            "context": "Development and cancer of the cerebellum. Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is thought to arise from genetic anomalies in developmental pathways required for the normal maturation of the cerebellar cortex, notably developmental pathways for granule cell progenitor (GCP) neurogenesis. Over the past decade, a wide range of studies have identified genes and their regulators within signaling pathways, as well as noncoding RNAs, that have crucial roles in both normal cerebellar development and pathogenesis. These include the Notch, Wnt/β-catenin, bone morphogenic proteins (Bmp) and Sonic Hedgehog (Shh) pathways. In this review, we highlight the function of these pathways in the growth of the cerebellum and the formation of MB. A better understanding of the developmental origins of these tumors will have significant implications for enhancing the treatment of this important childhood cancer.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 42,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4(+) T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 438,
                "text": "tofacitinib"
            }
        },
        {
            "context": "The NF90-NF45 complex functions as a negative regulator in the microRNA processing pathway. The positive regulatory machinery in the microRNA (miRNA) processing pathway is relatively well characterized, but negative regulation of the pathway is largely unknown. Here we show that a complex of nuclear factor 90 (NF90) and NF45 proteins functions as a negative regulator in miRNA biogenesis. Primary miRNA (pri-miRNA) processing into precursor miRNA (pre-miRNA) was inhibited by overexpression of the NF90 and NF45 proteins, and considerable amounts of pri-miRNAs accumulated in cells coexpressing NF90 and NF45. Treatment of cells overexpressing NF90 and NF45 with an RNA polymerase II inhibitor, alpha-amanitin, did not reduce the amounts of pri-miRNAs, suggesting that the accumulation of pri-miRNAs is not due to transcriptional activation. In addition, the NF90 and NF45 complex was not found to interact with the Microprocessor complex, which is a processing factor of pri-miRNAs, but was found to bind endogenous pri-miRNAs. NF90-NF45 exhibited higher binding activity for pri-let-7a than pri-miR-21. Of note, depletion of NF90 caused a reduction of pri-let-7a and an increase of mature let-7a miRNA, which has a potent antiproliferative activity, and caused growth suppression of transformed cells. These findings suggest that the association of the NF90-NF45 complex with pri-miRNAs impairs access of the Microprocessor complex to the pri-miRNAs, resulting in a reduction of mature miRNA production.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 668,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B). MWS has been reported in association with Hirschsprung disease (HSCR). MWS is sometimes difficult to diagnose clinically, especially when HSCR is absent. Thus, it is necessary to detect gene abnormalities at the molecular level. Here we report two Japanese girls with MWS, who showed a distinct facial phenotype, severe intellectual disability and epileptic seizures. Major congenital anomalies of the patients were very different. Patient 1 suffered from severe congenital heart disease, but did not show apparent HSCR. Patient 2 suffered from typical HSCR and underwent surgical treatment, but did not have congenital heart disease. According to the gene analysis using white blood cells, they had nonsense mutations in ZFHX1B, R695X and Q433X, respectively. In conclusion, molecular genetic analysis of ZFHX1B is important for a definite diagnosis of MWS which has a wide phenotypic spectrum of congenital anomalies.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 965,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 114,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells. Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 338,
                "text": "malaria"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 344,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases. BACKGROUND: Genetic FBN1 testing is pivotal for confirming the clinical diagnosis of Marfan syndrome. In an effort to evaluate variant causality, FBN1 databases are often used. We evaluated the current databases regarding FBN1 variants and validated associated phenotype records with a new Marfan syndrome geno-phenotyping tool called the Marfan score. METHODS AND RESULTS: We evaluated four databases (UMD-FBN1, ClinVar, the Human Gene Mutation Database (HGMD), and Uniprot) containing 2,250 FBN1 variants supported by 4,904 records presented in 307 references. The Marfan score calculated for phenotype data from the records quantified variant associations with Marfan syndrome phenotype. We calculated a Marfan score for 1,283 variants, of which we confirmed the database diagnosis of Marfan syndrome in 77.1%. This represented only 35.8% of the total registered variants; 18.5-33.3% (UMD-FBN1 versus HGMD) of variants associated with Marfan syndrome in the databases could not be confirmed by the recorded phenotype. CONCLUSION: FBN1 databases can be imprecise and incomplete. Data should be used with caution when evaluating FBN1 variants. At present, the UMD-FBN1 database seems to be the biggest and best curated; therefore, it is the most comprehensive database. However, the need for better genotype-phenotype curated databases is evident, and we hereby present such a database.Genet Med advance online publication 01 December 2016.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 113,
                "text": "FBN1"
            }
        },
        {
            "context": "FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Fibrillin-1 gene (FBN1) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium-binding epidermal growth factor-like domains. We found preferential associations between The Cys-missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1-10 and 59-65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 136,
                "text": "FBN1"
            }
        },
        {
            "context": "Applying the discovery of the Philadelphia chromosome. The identification of the Philadelphia chromosome in cells from individuals with chronic myelogenous leukemia (CML) led to the recognition that the BCR-ABL tyrosine kinase causes CML. This in turn led to the development of imatinib mesylate, a clinically successful inhibitor of the BCR-ABL kinase. Incorporating the use of markers of BCR-ABL kinase inhibition into clinical trials led to the realization that imatinib-resistant kinase domain mutations are the major cause of relapse during imatinib therapy and the subsequent development of new inhibitors to treat CML patients. The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 203,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Sex-dependent insulin like growth factor-1 expression in preattachment equine embryos. An adjustment of sex ratio of offspring to the conditions present at conception is seen in many mammals including horses. This depends on preferential survival of male embryos under conditions of high energy intake. In several species, growth factors including insulin like growth factor (IGF)-1 have been shown to promote embryonic development by decreasing apoptosis and increasing cell proliferation. We hypothesized that sex-related differences in IGF-1 expression in equine embryos during the phase of maternal recognition of pregnancy might exist and thus contribute to preferential survival of embryos from either of both sexes under specific environmental conditions. Insulin like growth factor-1 mRNA expression of in vivo-produced equine embryos on different days of pregnancy (Day 8, N = 6; Day 10, N = 8; Day 12, N = 14) was analyzed. Insulin like growth factor-1 mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction. The sex of the embryo was determined by detection of X-inactivation specific transcript (Xist) RNA and equine sex determining region of the Y chromosome DNA. Embryos positive for Xist expression were classified as female, and Xist negative and equine sex determining region of the Y chromosome positive embryos were classified as male. From 28 embryos tested, 15 (54%) showed positive Xist expression and were thus classified as female. Insulin like growth factor-1 mRNA expression was influenced by sex (P = 0.01) but not by day of pregnancy (relative expression of IGF-1 in relation to β-actin, Day 8: male 5.1 ± 2.1, female 11.4; Day 10: male 5.2 ± 1.6, female 17.4 ± 6.7; Day 12: male 2.6 ± 0.3, female 11.6 ± 2.4). Results demonstrate an increased expression of IGF-1 in female equine embryos. Sex-related influences on expression of the IGF system are probably related to a gradual X chromosome inactivation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 1147,
                "text": "Xist"
            }
        },
        {
            "context": "Cardiac arrhythmias during or after epileptic seizures. Seizure-related cardiac arrhythmias are frequently reported and have been implicated as potential pathomechanisms of Sudden Unexpected Death in Epilepsy (SUDEP). We attempted to identify clinical profiles associated with various (post)ictal cardiac arrhythmias. We conducted a systematic search from the first date available to July 2013 on the combination of two terms: 'cardiac arrhythmias' and 'epilepsy'. The databases searched were PubMed, Embase (OVID version), Web of Science and COCHRANE Library. We attempted to identify all case reports and case series. We identified seven distinct patterns of (post)ictal cardiac arrhythmias: ictal asystole (103 cases), postictal asystole (13 cases), ictal bradycardia (25 cases), ictal atrioventricular (AV)-conduction block (11 cases), postictal AV-conduction block (2 cases), (post)ictal atrial flutter/atrial fibrillation (14 cases) and postictal ventricular fibrillation (3 cases). Ictal asystole had a mean prevalence of 0.318% (95% CI 0.316% to 0.320%) in people with refractory epilepsy who underwent video-EEG monitoring. Ictal asystole, bradycardia and AV-conduction block were self-limiting in all but one of the cases and seen during focal dyscognitive seizures. Seizure onset was mostly temporal (91%) without consistent lateralisation. Postictal arrhythmias were mostly found following convulsive seizures and often associated with (near) SUDEP. The contrasting clinical profiles of ictal and postictal arrhythmias suggest different pathomechanisms. Postictal rather than ictal arrhythmias seem of greater importance to the pathophysiology of SUDEP.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 173,
                "text": "Sudden Unexpected Death in Epilepsy (SUDEP)"
            }
        },
        {
            "context": "Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine. Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r > 0.99. The assay demonstrated accuracy > 80% and precision < 20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 427,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 462,
                "text": "Stroke"
            }
        },
        {
            "context": "Targeting p53 for Novel Anticancer Therapy. Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the \"guardian of the genome,\" is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 330,
                "text": "p53"
            }
        },
        {
            "context": "[Molecular targeted treatment--new treatment strategy for patients with chronic myeloid leukemia]. Imatinib mesylate is a new drug that can inhibit the tyrosine kinase activity of Bcr-Abl, the receptors for platelet-derived growth factor receptor(PDGF) and stem cell factor, or c-kit. Chronic myeloid leukemia (CML) is distinguished by the presence of a reciprocal translocation between chromosomes 9 and 22 that results in a shortened chromosome 22, termed the Philadelphia(Ph) chromosome. As a result of the translocation, a fusion gene called the Bcr-Abl gene is created from two normal cellular genes, encoding a chimeric Bcr-Abl protein with a deregulated tyrosine kinase activity. The expression of Bcr-Abl tyrosine kinase has been shown to be necessary and sufficient for the transformed phenotype of CML cells. Imatinib can block the kinase activity of Bcr-Abl, thus inhibiting the proliferation of Ph-positive progenitors, and has shown activity against all phases of CML, though responses are most substantial and durable in patients in the chronic phase. An international phase III study which compared the efficacy of imatinib with that of interferon alpha combined with low-dose cytarabine in newly diagnosed chronic-phase CML showed the rate of major cytogenetic response at 24 months was 90%, including 82% of complete cytogenetic response. These results indicated that imatinib was superior to interferon-containing treatment as a first-line therapy. More than 10,000 patients worldwide, including those in Japan, have been treated with imatinib in clinical trials, and a lot of information has been accumulated on the use of this drug. The aim of this article is to review the use of this drug and the practical management of patients with chronic myeloid leukemia.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 180,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 334,
                "text": "MITF"
            }
        },
        {
            "context": "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.",
            "question": "How does increased GDF15 affect body weight?",
            "answers": {
                "answer_start": 474,
                "text": "reduces body weight"
            }
        },
        {
            "context": "[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. Hypo- and hyperpigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function and melanocytoses connected with melanocyte development. The article presents some hereditary hypomelanocytoses, which are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations. It has been demonstrated that mutations of the same gene may cause different hypopigmentation syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome. It has also been demonstrated that mutations of different genes may cause an identical syndrome. For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. In turn, mutation of the KIT gene and/or heterozygous deletion of the SNAI2 gene result in piebaldism disease. The knowledge of the exact mechanisms of pigmentary disorders may be useful in the development of new therapeutic approaches to their treatment.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1275,
                "text": "MITF"
            }
        },
        {
            "context": "Neonatal screening for cystic fibrosis in São Paulo State, Brazil: a pilot study. Cystic fibrosis is one of the most common autosomal recessive hereditary diseases in the Caucasian population, with an incidence of 1:2000 to 1:3500 liveborns. More than 1000 mutations have been described with the most common being F508del. It has a prevalence of 23-55% within the Brazilian population. The lack of population-based studies evaluating the incidence of cystic fibrosis in São Paulo State, Brazil, and an analysis concerning the costs of implantation of a screening program motivated the present study. A total of 60,000 dried blood samples from Guthrie cards obtained from April 2005 to January 2006 for neonatal screening at 4 reference centers in São Paulo State were analyzed. The immunoreactive trypsinogen (IRT)/IRT protocol was used with the cut-off value being 70 ng/mL. A total of 532 children (0.9%) showed IRT >70 ng/mL and a 2nd sample was collected from 418 (80.3%) of these patients. Four affected children were detected at two centers, corresponding to an incidence of 1:8403. The average age at diagnosis was 69 days, and 3 of the children already showed severe symptoms of the disease. The rate of false-positive results was 95.2% and the positive predictive value for the test was 8%. The cost of detecting an affected subject was approximately US$8,000.00 when this cystic fibrosis program was added to an existing neonatal screening program. The present study clearly shows the difficulties involved in cystic fibrosis screening using the IRT/IRT protocol, particularly in a population with no long-term tradition of neonatal screening.",
            "question": "What is the incidence of cystic fibrosis in the caucasian population?",
            "answers": {
                "answer_start": 214,
                "text": "1:2000"
            }
        },
        {
            "context": "Topoisomerase II regulates yeast genes with singular chromatin architectures. Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIα interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIβ regulates developmental genes in conjunction with chromatin remodeling and heterochromatin transitions. Here we show that in budding yeast, topo II regulates the expression of specific gene subsets. To uncover this, we carried out a genomic transcription run-on shortly after the thermal inactivation of topo II. We identified a modest number of genes not involved in the general stress response but strictly dependent on topo II. These genes present distinctive functional and structural traits in comparison with the genome average. Yeast topo II is a positive regulator of genes with well-defined promoter architecture that associates to chromatin remodeling complexes; it is a negative regulator of genes extremely hypo-acetylated with complex promoters and undefined nucleosome positioning, many of which are involved in polyamine transport. These findings indicate that yeast topo II operates on singular chromatin architectures to activate or repress DNA transcription and that this activity produces functional responses to ensure chromatin stability.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 107,
                "text": "topo II"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1093,
                "text": "53BP1"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 1510,
                "text": "larva"
            }
        },
        {
            "context": "Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif. Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the \"guardian of the genome.\"",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 1279,
                "text": "p53"
            }
        },
        {
            "context": "Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus. The proliferation and migration of vascular smooth muscle cells (VSMCs) in the intima of an artery, known as intimal hyperplasia, is an important component of cardiovascular diseases. This is seen most clearly in the case of in-stent restenosis, where drug eluting stents are used to deliver agents that prevent VSMC proliferation and migration. One class of agents that are highly effective in the prevention of in-stent restenosis is the mammalian Target of Rapamycin (mTOR) inhibitors. Inhibition of mTOR blocks protein synthesis, cell cycle progression, and cell migration. Key to the effects on cell cycle progression and cell migration is the inhibition of mTOR-mediated degradation of p27Kip1 protein. p27Kip1 is a cyclin dependent kinase inhibitor that is elevated in quiescent VSMCs and inhibits the G1 to S phase transition and cell migration. Under normal conditions, vascular injury promotes degradation of p27Kip1 protein in an mTOR dependent manner. Recent reports from our lab suggest that in the presence of diabetes mellitus, elevation of extracellular signal response kinase activity may promote decreased p27Kip1 mRNA and produce a relative resistance to mTOR inhibition. Here we review these findings and their relevance to designing treatments for cardiovascular disease in the presence of diabetes mellitus.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 554,
                "text": "mammalian Target of Rapamycin"
            }
        },
        {
            "context": "[Wilson's disease]. Wilson's disease is an inherited disorder leading to accumulation of copper in tissues, mainly in the liver and brain. Genetic defect is in the gene coding ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more then 500 mutations causing Wilson's disease were described. The most frequent mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's disease is usually hepatic or neurologic. Hepatic form is manifested by acute or chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested usually after 20 year of age by motor disturbances (tremor, disturbed speech, problems with writing), which could progress into severe extrapyramidal syndrome with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is based on clinical and laboratory examinations (neurologic symptoms, liver disease, low serum ceruloplasmin levels, elevated free copper concentration in serum, high urine copper excretion, and presence of Kayser-Fleischer rings). Confirmation of diagnosis is done by hepatic copper concentration in liver biopsy or by genetic examination. Untreated disease leads to the death of a patient. Treatment is based on chelating agents decreasing the copper content by excretion into urine (D-penicillamine, trientine) or on agents preventing absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with asymptomatic Wilson's disease have to be treated as well. In Czech Republic either penicillamine or zinc are used. Liver transplantation is indicated in patients with fulminant liver failure or decompensated cirrhosis. Screening in families of affected patients (all siblings) is obvious.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 218,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Estren is a selective estrogen receptor modulator with transcriptional activity. It was recently reported that the synthetic compound estren increases bone mass without affecting reproductive organs or classic transcription. The aim of the present study was to further characterize the in vivo and in vitro effects of estren. We demonstrate that estren is a selective estrogen receptor modulator (SERM) with a strong effect on thymus, a moderate effect on uterus and trabecular bone, but no major effect on fat or cortical bone in 11-month-old ovariectomized mice. The effect of estren on trabecular bone and uterus is mediated via estrogen receptors (ERs) because no effect is seen in ER double-inactivated mice. Furthermore, with the use of ERalpha- and ERbeta-expressing reporter cell lines, we demonstrate that estren displays an agonistic effect on transcriptional activity of an estrogen-responsive element-driven reporter gene with a degree of agonism similar to that of 17beta-estradiol for both ERalpha and ERbeta. Thus, estren has the capacity to exert genomic effects via both ERalpha and ERbeta. We conclude, in contrast to what was previously reported by others, that estren is a SERM with transcriptional activity.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 358,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study. BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.",
            "question": "Aleglitazar is agonist of which receptor?",
            "answers": {
                "answer_start": 524,
                "text": "peroxisome proliferator-activated receptor-α/γ"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 584,
                "text": "xa"
            }
        },
        {
            "context": "Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 104,
                "text": "Facioscapulohumeral dystrophy"
            }
        },
        {
            "context": "Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism. Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 199,
                "text": "tyrosinase"
            }
        },
        {
            "context": "The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. PURPOSE: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. EXPERIMENTAL DESIGN: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat. RESULTS: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC(50) 0.45 micromol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed approximately 70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth. CONCLUSION: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies.",
            "question": "Which enzyme is targeted by the drug Imetelstat?",
            "answers": {
                "answer_start": 279,
                "text": "human telomerase"
            }
        },
        {
            "context": "Role of agents for reversing the effects of target-specific oral anticoagulants. PURPOSE: The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed. SUMMARY: The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials. CONCLUSION: Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 881,
                "text": "xa"
            }
        },
        {
            "context": "Sudden death prevented in hypertrophic cardiomyopathy. The most common cause of sudden cardiac death in individuals aged less than 35 years, including competitive athletes, is the inherited disorder hypertrophic cardiomyopathy (HCM). Until recently, no therapeutic intervention had been identified to prevent sudden death in HCM. This case report highlights the role of the implantable cardioverter defibrillator (ICD) in preventing sudden death in patients with HCM. The report highlights the importance of risk stratification in patients with HCM in order to identify those individuals who would most likely benefit from ICD therapy. The ICD implantation is now the treatment of choice in preventing sudden death in selected (highest risk) populations with HCM. In the future, understanding the molecular basis of sudden death in HCM may identify potential new gene-based therapeutic strategies.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 199,
                "text": "hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure. Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the alphabeta fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 24,
                "text": "insulin receptor"
            }
        },
        {
            "context": "From animal models to human disease: a genetic approach for personalized medicine in ALS. Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 90,
                "text": "Amyotrophic Lateral Sclerosis"
            }
        },
        {
            "context": "Assessing serotonin receptor mRNA editing frequency by a novel ultra high-throughput sequencing method. RNA editing is a post-transcriptional modification of pre-mRNA that results in increased diversity in transcriptomes and proteomes. It occurs in a wide variety of eukaryotic organisms and in some viruses. One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation. This phenomenon has been observed in numerous transcripts, including the mammalian 5-HT(2C) receptor, which can be edited at five distinct sites. Methods used to date to quantify 5-HT(2C) receptor editing are labor-intensive, expensive and provide limited information regarding the relative abundance of 5-HT(2C) receptor editing variants. Here, we present a novel, ultra high-throughput method to quantify 5-HT(2C) receptor editing, compare it to a more conventional method, and use it to assess the effect of a range of genetic and pharmacologic manipulations on 5-HT(2C) editing. We conclude that this new method is powerful and economical, and we provide evidence that alterations in 5-HT(2C) editing appear to be a result of regional changes in brain activity, rather than a mechanism to normalize 5-HT(2C) signaling.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 361,
                "text": "A-to-I"
            }
        },
        {
            "context": "Stress granules as crucibles of ALS pathogenesis. Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.",
            "question": "Which domain allowing self-association do exist in TDP-43 and FUS proteins?",
            "answers": {
                "answer_start": 428,
                "text": "prion-like domain"
            }
        },
        {
            "context": "Role of agents for reversing the effects of target-specific oral anticoagulants. PURPOSE: The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed. SUMMARY: The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials. CONCLUSION: Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 855,
                "text": "factor Xa"
            }
        },
        {
            "context": "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in approximately 30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 0,
                "text": "Ribosomal protein genes"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 976,
                "text": "l-DOPA"
            }
        },
        {
            "context": "Structure-guided design of a methyl donor cofactor that controls a viral histone H3 lysine 27 methyltransferase activity. vSET (a viral SET domain protein) is an attractive polycomb repressive complex 2 (PRC2) surrogate to study the effect of histone H3 lysine 27 (H3K27) methylation on gene transcription, as both catalyze histone H3K27 trimethylation. To control the enzymatic activity of vSET in vivo with an engineered S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried out structure-guided design, synthesis, and characterization of orthogonal vSET methyltransferase mutant/SAM analogue pairs using a \"bump-and-hole\" strategy.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 448,
                "text": "SAM"
            }
        },
        {
            "context": "Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 156,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor. Phosphorylation-dependent ubiquitination and ensuing down-regulation and lysosomal degradation of the interferon alpha/beta receptor chain 1 (IFNAR1) of the receptor for Type I interferons play important roles in limiting the cellular responses to these cytokines. These events could be stimulated either by the ligands (in a Janus kinase-dependent manner) or by unfolded protein response (UPR) inducers including viral infection (in a manner dependent on the activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation. Casein kinase 1 alpha (CK1 alpha) was shown to directly phosphorylate Ser(535) within the ligand-independent pathway. Yet given the constitutive activity of CK1 alpha, it remained unclear how this pathway is stimulated by UPR. Here we report that induction of UPR promotes the phosphorylation of a proximal residue, Ser(532), in a pancreatic endoplasmic reticulum kinase-dependent manner. This serine serves as a priming site that promotes subsequent phosphorylation of IFNAR1 within its degron by CK1 alpha. These events play an important role in regulating ubiquitination and degradation of IFNAR1 as well as the extent of Type I interferon signaling.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 778,
                "text": "beta-Trcp"
            }
        },
        {
            "context": "Acoustic startle response is disrupted in iron-deficient rats. Diurnal effects on motor control are evident in the human disease of Restless Leg Syndrome (RLS), which is purported to be linked to brain iron deficiency as well as alterations in dopaminergic systems. Thus, we explored the relationship between daily rhythms, the onset of motor dysregulation and brain iron deficiency in an animal model of iron deficiency. Male and female weanling Sprague-Dawley rats consuming control (CN) or iron-deficient (ID) diets were examined weekly for acoustic startle response (ASR) and prepulse inhibition (PPI) for a 5-week period. Iron deficiency reduced the magnitude, but not timing, of the ASR at specific time points. ASR was elevated 60% at the onset of the dark cycle relative to the median of the light cycle in male CN and ID rats. The respective elevation was 400% and 150% in female CN and ID rats during the first 2 weeks of testing. The diurnal cycle of ASR response was attenuated by 3 weeks of testing in both dietary treatment groups. PPI was not affected by iron deficiency, sex, diurnal cycle or the interaction between these factors. These results thus demonstrate that iron deficiency moderately alters ASR signaling although the inhibitory pathways of ASR do not appear to be affected.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 202,
                "text": "iron"
            }
        },
        {
            "context": "Spinal muscular atrophy and therapeutic prospects. The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy. Both genes are ubiquitously expressed and encode identical proteins, but markedly differ in their splicing patterns: While SMN1 produces full-length (FL)-SMN transcripts only, the majority of SMN2 transcripts lacks exon 7. Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is believed to be clinically beneficial and therefore a crucial challenge in SMA research. Drugs such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA that mainly act as histone deacetylase inhibitors can mediate both: they stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby elevating the levels of FL-SMN2 protein. Preliminary phase II clinical trials and individual experimental curative approaches SMA patients show promising results. However, phase III double-blind placebo controlled clinical trials have to finally prove the efficacy of these drugs.",
            "question": "Which is the genetic basis of Spinal Muscular Atrophy (SMA)?",
            "answers": {
                "answer_start": 51,
                "text": "The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1)"
            }
        },
        {
            "context": "[Carpal tunnel syndrome: report of 3 cases]. The carpal tunnel syndrome is a neuropathy due to trapping (focal lesion of the peripheral nerve due to a local cause); in this case, the median nerve is the most commonly involved. Its presentation is characteristic in females about 40 years of age. The diagnosis is mainly based on clinical features and is confirmed by electrical criteria. In the anamnesis it is important to consider systemic diseases as causing the abnormality. Treatment depends on the etiology. It may be medical or surgical. In the present article we report three cases with different etiology and treatment. We also review the syndrome.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 183,
                "text": "median"
            }
        },
        {
            "context": "Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DeltaNp73 expression show enhanced resistance to chemotherapy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 225,
                "text": "7"
            }
        },
        {
            "context": "Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 243,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1052,
                "text": "Nox1"
            }
        },
        {
            "context": "High specific detection and near-infrared photothermal therapy of lung cancer cells with high SERS active aptamer-silver-gold shell-core nanostructures. Lung cancer is the leading cause of cancer death worldwide. Its early detection is of paramount importance for diagnosis, classification, treatment, and improvement of survivorship. However, current methods are not sensitive enough to detect lung cancer in its nascent stage. We reported an aptamer-Ag-Au shell-core nanostructure-based surface-enhanced Raman scattering (SERS) assay for sensitive and specific detection, and near-infrared (NIR) photothermal therapy of lung adenocarcinoma cells (A549 cells). The nanostructures target the cells with high affinity and specificity via the specific interaction between the aptamer (a 45-base oligonucleotide) and the cell, and distinguish A549 cells from other types of cancer cells (HeLa and MCF-7 cells) and subtypes of lung cancer cells (NCI-H157, NCI-H520, NCI-H1299, and NCI-H446 cells). The nanostructures have a high capability to absorb NIR irradiation and are able to perform photothermal therapy of the cells at a very low irradiation power density (0.20 W cm(-2)) without destroying the healthy cells and the surrounding normal tissues. In addition, the nanostructures exhibit a high SERS activity. Based on the SERS signal of the labeled Raman reporter (Rh6G molecules), we can specifically detect A549 cells at a very low abundance (~10 cells per mL) and monitor the therapy process of the cancer cells. Therefore, this nanostructure-based SERS assay has great potential in specific recognition, sensitive detection, and effective photothermal therapy of lung cancer.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 923,
                "text": "lung"
            }
        },
        {
            "context": "Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (deltaN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not deltaNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 451,
                "text": "7"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 489,
                "text": "xa"
            }
        },
        {
            "context": "A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 287,
                "text": "FBN1"
            }
        },
        {
            "context": "Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. Double bromodomain proteins bind to acetylated lysines in histones, bringing associated histone modification and nucleosome remodeling activity to chromatin. The ability of bromodomain regulators to alter chromatin status and control gene expression has long been appreciated to be important in the development of certain human cancers. However, bromodomain proteins have now been found also to be critical, non-redundant players in diverse, non-malignant phenotypes, directing transcriptional programs that control adipogenesis, energy metabolism and inflammation. The fact that such different processes are functionally linked by the same molecular machinery suggests a common epigenetic basis to understand and interpret the origins of several important co-morbidities, such as asthma or cancer that occurs in obesity, and complex inflammatory diseases like cardiovascular disease, systemic lupus erythematosus, rheumatoid arthritis and insulin resistance that may be built on a common pro-inflammatory foundation.",
            "question": "What histone modification is recognized by the bromodomain?",
            "answers": {
                "answer_start": 116,
                "text": "acetylated lysines"
            }
        },
        {
            "context": "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 1283,
                "text": "FOXP2"
            }
        },
        {
            "context": "Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy. Many recent studies have shown that DOX toxicity involves generation of reactive oxygen species (ROS). Although protection or alleviation of DOX toxicity can be achieved by administration of antioxidant vitamins such as ascorbic acid and vitamin E, their cardioprotective effect remains controversial. Thus alternative naturally occurring antioxidants may potentially be candidates for antioxidant therapy. In this study, we investigated the antioxidative and cytoprotective effects of Phyllanthus urinaria (PU) against DOX toxicity using H9c2 cardiac myoblasts. The total antioxidant capacity of PU (1 mg/ml) was 5306.75+/-461.62 FRAP value (microM). DOX IC50 values were used to evaluate the cytoprotective effects of PU ethanolic extract (1 or 10 microg/ml) in comparison with those of ascorbic acid (VIT C, 100 microM) and N-acetylcysteine (NAC, 100 microM). PU treatments (1 or 10 microg/ml) dose dependently caused rightward DOX IC50 shifts of 2.8- and 8.5-fold, respectively while treatments with VIT C and NAC increased DOX IC50 by 3.3- and 4.2-fold, respectively. Additionally, lipid peroxidation and caspase-3 activity were parameters used to evaluate cytoprotective effect. All antioxidants completely inhibited cellular lipid peroxidation and caspase-3 activation induced by DOX (1 microM). Endogenous antioxidant defense such as total glutathione (tGSH), catalase and superoxide dismutase (SOD) activity was also modulated by the antioxidants. PU treatment alone dose dependently increased tGSH, and this effect was retained in the presence of DOX. Similar effect was observed in the assessment of catalase and SOD enzyme activity. The nuclear factor kappaB (NFkappaB) transcription factor assay demonstrated that all antioxidants significantly inhibited DOX-induced NFkappaB activation. Our results suggest that PU protection against DOX cardiotoxicity was mediated through multiple pathways and this plant may serve as an alternative source of antioxidants for prevention of DOX cardiotoxicity.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 93,
                "text": "cardiotoxicity"
            }
        },
        {
            "context": "Functional variation of MC1R alleles from red-haired individuals. Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 314,
                "text": "Mc1r"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 272,
                "text": "methylKit"
            }
        },
        {
            "context": "Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. PURPOSE: To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis. DESIGN: Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE. PARTICIPANTS: A total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet's uveitis (ENDURE study) were enrolled. METHODS: After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study. MAIN OUTCOME MEASURES: Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes. RESULTS: After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies. CONCLUSIONS: The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 240,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "Calcium/calmodulin-dependent protein kinase IIalpha mediates activation of mitogen-activated protein kinase and cytosolic phospholipase A2 in norepinephrine-induced arachidonic acid release in rabbit aortic smooth muscle cells. We have investigated the contribution of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and mitogen-activated protein kinase (MAP kinase) in norepinephrine (NE)-induced arachidonic acid (AA) release in rabbit aortic vascular smooth muscle cells (VSMC). NE enhanced release of AA via activation of cytosolic phospholipase A2 (cPLA2) but not secretory PLA2 in VSMC prelabeled with [3H]AA. NE (10 microM) enhanced CaM kinase II and MAP kinase activity. In cells transiently transfected with antisense oligonucleotides complementary to the translation initiation sites of CaM kinase II and MAP kinase, NE-induced AA release was inhibited by 100 and 35% respectively. Treatment of cells with PD-098059, a MAP kinase kinase inhibitor, or with MAP kinase antisense oligonucleotide reduced NE-induced activation of MAP kinase and cPLA2. NE-induced MAP kinase and cPLA2 activation was also inhibited in cells treated with a CaM kinase II inhibitor, KN-93, or with CaM kinase II antisense oligonucleotide. On the other hand, inhibition of MAP kinase kinase with PD-098059 or of MAP kinase with antisense oligonucleotides did not alter the NE-induced increase in CaM kinase II activity. Phosphorylation of MAP kinase and CaM kinase II by NE, studied by 32P incorporation and immune complex kinase assays, was inhibited by KN-93. Collectively, these data suggest that CaM kinase II can activate MAP kinase, which in turn activates cPLA2 to release AA for prostacyclin synthesis in the rabbit VSMC. This novel pathway for activation of MAP kinase by CaM kinase II appears to be mediated through stimulation of MAP kinase kinase. Activation of adrenergic receptors with NE in VSMC caused translocation of CaM kinase II, MAP kinase, and cPLA2 to the nuclear envelope only in the presence of extracellular Ca2+. Okadaic acid, which increased phosphorylation and activity, did not translocate these enzymes. Therefore, it appears that in rabbit VSMC, NE, by promoting extracellular Ca2+ influx, increases CaM kinase II activity, leading to activation of MAP kinase and cPLA2 and translocation to the nuclear envelope, resulting in release of AA from the nuclear envelope for prostacyclin synthesis.",
            "question": "Which kinase is inhibited by the small molecule KN-93?",
            "answers": {
                "answer_start": 1196,
                "text": "CaM kinase II"
            }
        },
        {
            "context": "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this \"miracle herb\" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 420,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 2056,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Genomic context analysis reveals dense interaction network between vertebrate ultraconserved non-coding elements. MOTIVATION: Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic. RESULTS: In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online and at http://ccg.vital-it.ch/ucne/",
            "question": "How are ultraconserved elements called when they form clusters?",
            "answers": {
                "answer_start": 488,
                "text": "gene regulatory blocks (GRBs)"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 977,
                "text": "BRG1"
            }
        },
        {
            "context": "Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. PURPOSE: In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain. MATERIALS AND METHODS: Patients with interstitial cystitis received a single intravenous dose of 200 μg/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed. RESULTS: A total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was -1.4 [-2.2, -0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%). CONCLUSIONS: Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 267,
                "text": "nerve growth factor"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 1623,
                "text": "SMA"
            }
        },
        {
            "context": "Remission in post-traumatic stress disorder (PTSD): effects of sertraline as assessed by the Davidson Trauma Scale, Clinical Global Impressions and the Clinician-Administered PTSD scale. Rates of remission were examined in two controlled 12-week studies of sertraline and placebo for post-traumatic stress disorder (PTSD). The performance of three scales was evaluated: the self-rated Davidson Trauma Scale (DTS), and two interviewer scales: the Clinician Administered PTSD Scale (CAPS) and Clinical Global Impressions (CGI). Sertraline proved significantly superior to placebo with respect to remission on all three ratings. Rates of remission were very similar for all scales, ranging from 23.1-26.3% for sertraline and 13.9-14.9% for placebo. Traditional thresholds for the CAPS and DTS were tested relative to the CGI and to each other. The CAPS and DTS thresholds of < 20 and < 18 were found to be valid.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 45,
                "text": "PTSD"
            }
        },
        {
            "context": "hCINAP is an atypical mammalian nuclear adenylate kinase with an ATPase motif: structural and functional studies. Human coilin interacting nuclear ATPase protein (hCINAP) directly interacts with coilin, a marker protein of Cajal Bodies (CBs), nuclear organelles involved in the maturation of small nuclear ribonucleoproteins UsnRNPs and snoRNPs. hCINAP has previously been designated as an adenylate kinase (AK6), but is very atypical as it exhibits unusually broad substrate specificity, structural features characteristic of ATPase/GTPase proteins (Walker motifs A and B) and also intrinsic ATPase activity. Despite its intriguing structure, unique properties and cellular localization, the enzymatic mechanism and biological function of hCINAP have remained poorly characterized. Here, we offer the first high-resolution structure of hCINAP in complex with the substrate ADP (and dADP), the structure of hCINAP with a sulfate ion bound at the AMP binding site, and the structure of the ternary complex hCINAP-Mg(2+) ADP-Pi. Induced fit docking calculations are used to predict the structure of the hCINAP-Mg(2+) ATP-AMP ternary complex. Structural analysis suggested a functional role for His79 in the Walker B motif. Kinetic analysis of mutant hCINAP-H79G indicates that His79 affects both AK and ATPase catalytic efficiency and induces homodimer formation. Finally, we show that in vivo expression of hCINAP-H79G in human cells is toxic and drastically deregulates the number and appearance of CBs in the cell nucleus. Our findings suggest that hCINAP may not simply regulate nucleotide homeostasis, but may have broader functionality, including control of CB assembly and disassembly in the nucleus of human cells.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 195,
                "text": "coilin"
            }
        },
        {
            "context": "Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia. BACKGROUND: Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS: A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS: Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS: Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 199,
                "text": "telomerase"
            }
        },
        {
            "context": "Antiviral therapy for human rabies. Human rabies is virtually always fatal despite numerous attempts at aggressive therapy. Most survivors received one or more doses of rabies vaccine prior to the onset of the disease. The Milwaukee Protocol has proved to be ineffective for rabies and should no longer be used. New approaches are needed and an improved understanding of basic mechanisms responsible for the clinical disease in rabies may prove to be useful for the development of novel therapeutic approaches. Antiviral therapy is thought to be an important component of combination therapy for the management of human rabies, and immunotherapy and neuroprotective therapy should also be strongly considered. There are many important issues for consideration regarding drug delivery to the central nervous system in rabies, which are in part related to the presence of the blood-brain barrier and also the blood-spinal cord barrier. Ribavirin and interferon-α have proved to be disappointing agents for the therapy of rabies. There is insufficient evidence to support the continued use of ketamine or amantadine for the therapy of rabies. Minocycline or corticosteroids should not be used because of concerns about aggravating the disease. A variety of new antiviral agents are under development and evaluation, including favipiravir, RNA interference (for example, small interfering [si]RNAs) and novel targeted approaches, including interference with viral capsid assembly and viral egress.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 275,
                "text": "rabies"
            }
        },
        {
            "context": "Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients. The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewish patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS + 1 mutation constituted 2.26% of the disease alleles among Jewish patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated \"RecNciI\" and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations--D409H and R463C--was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, was 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 153,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Stabilities of folding of clustered, two-repeat fragments of spectrin reveal a potential hinge in the human erythroid spectrin tetramer. The large size of spectrin, the flexible protein promoting reversible deformation of red cells, has been an obstacle to elucidating the molecular mechanism of its function. By studying cloned fragments of the repeating unit domain, we have found a correspondence between positions of selected spectrin repeats in a tetramer with their stabilities of folding. Six fragments consisting of two spectrin repeats were selected for study primarily on the basis of the predicted secondary structures of their linker regions. Fragments with a putatively helical linker were more stable to urea- and heat-induced unfolding than those with a putatively nonhelical linker. Two of the less stably folded fragments, human erythroid alpha-spectrin repeats 13 and 14 (HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), are located opposite each other on antiparallel spectrin dimers. At least partial unfolding of these repeats under physiological conditions indicates that they may serve as a hinge. Also less stably folded, the fragment of human erythroid alpha-spectrin repeats 4 and 5 (HEalpha4,5) lies opposite the site of interaction between the partial repeats at the C- and N-terminal ends of beta- and alpha-spectrin, respectively, on the opposing dimer. More stably folded fragments, human erythroid alpha-spectrin repeats 1 and 2 (HEalpha1,2) and human erythroid alpha-spectrin repeats 2 and 3 (HEalpha2,3), lie nearly opposite each other on antiparallel spectrin dimers of a tetramer. These clusterings along the spectrin tetramer of repeats with similar stabilities of folding may have relevance for spectrin function, particularly for its well known flexibility.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 1002,
                "text": "antiparallel"
            }
        },
        {
            "context": "From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2. Zinc cluster proteins are a large family of transcriptional regulators with a wide range of biological functions. The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae. These proteins also control adaptations to anaerobic growth, sterol biosynthesis as well as filamentation and mating. Orthologs of these zinc cluster proteins have been identified in several species of Candida. Upc2 plays a critical role in antifungal resistance in these important human fungal pathogens. Upc2 is therefore an interesting potential target for novel antifungals. In this review we discuss the functions, mode of actions and regulation of Ecm22, Upc2, Sut1 and Sut2 in budding yeast and Candida.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 94,
                "text": "Ecm22"
            }
        },
        {
            "context": "Paramagnetic species in the plasma of dogs with lymphoma prior to and after treatment with doxorubicin. An ESR study. Doxorubicin is a potent cytostatic drug which is applied for the treatment of various kinds of malignant diseases. In spite of the routine use of this drug its major adverse effect, the dose-dependent cardiotoxicity, cannot be prevented yet. However, several clinical trials indicated that iron chelators are able to moderate the noxious effect more efficiently than radical scavenging antioxidants. This in turn supports the idea that doxorubicin-iron complexes are involved in triggering the cardiotoxicity of this drug by catalyzing the formation of oxygen radicals. However, both the mode of generation of doxorubicin-iron complexes and the consequences in vivo are not understood so far. In order to figure out whether or not doxorubicin can utilize iron from the transport protein transferrin for complex formation and prooxidative activities we studied the redox state of iron and its regulatory control by ceruloplasmin and ascorbate in the plasma of dogs suffering from malignant lymphoma by electron spin resonance spectroscopy. The respective electron spin resonance intensities prior to and after treatment with doxorubicin were compared with those from healthy controls. Our results revealed that dogs with lymphoma exhibit lower levels of paramagnetic copper in ceruloplasmin (-22%) and iron in transferrin (-33%) than healthy animals. Likewise the concentration of ascorbate radicals was lower in patients with lymphoma than in healthy subjects. The decreased cupric state of ceruloplasmin is equivalent to a diminished ferroxidase activity in plasma and therefore indicates indirectly an impaired antioxidant activity in these patients. Administration of doxorubicin in vivo further reduced the concentration of paramagnetic copper (-18%) and iron (-13%) while the concentration of ascorbate radicals remained unchanged. This decrease was also seen during the in vitro incubation of plasma with doxorubicin suggesting a direct interaction of the drug with the paramagnetic metal species. Model experiments revealed that the effect is based on a doxorubicin-induced release of iron from transferrin which is enhanced by ascorbate and the subsequent formation of doxorubicin-iron complexes. This mechanism was shown to trigger the formation of hydroxyl radicals from H(2)O(2) and to cause an oxidation of the antioxidant ceruloplasmin. Our data demonstrate that cardiotoxic doxorubicin-iron complexes are not only formed in cardiomyocytes itself as generally assumed, but are also present in the circulation. Therefore, these findings provide an additional rationale for potential benefit of iron chelators during doxorubicin chemotherapy.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 319,
                "text": "cardiotoxicity"
            }
        },
        {
            "context": "The pattern and evolution of looped gene bendability. Gene looping, defined as the physical interaction between the promoter and terminator regions of a RNA polymerase II-transcribed gene, is widespread in yeast and mammalian cells. Gene looping has been shown to play important roles in transcription. Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB. However, whether other factors contribute to gene looping remains to be elucidated. Here, we investigated the contribution of intrinsic DNA and chromatin structures to gene looping. We found that Saccharomyces cerevisiae looped genes show high DNA bendability around middle and 3/4 regions in open reading frames (ORFs). This bendability pattern is conserved between yeast species, whereas the position of bendability peak varies substantially among species. Looped genes in human cells also show high DNA bendability. Nucleosome positioning around looped ORF middle regions is unstable. We also present evidence indicating that this unstable nucleosome positioning is involved in gene looping. These results suggest a mechanism by which DNA bendability and unstable nucleosome positioning could assist in the formation of gene loops.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 409,
                "text": "TFIIB"
            }
        },
        {
            "context": "Jamaican vomiting sickness: a study of two adult cases. An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. Analyses of serum and urine samples were performed to compare the patterns of organic acidaemia and aciduria with those reported from childhood cases. The main conclusion from the comparison is that the toxic ackee constitutent, hypoglycin, produces essentially the same metabolic effects in adults as in children.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 148,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Progranulin (PGRN) is known to play a role in the pathogenesis of neurodegenerative diseases. Recently, it has been demonstrated that patients with the homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal function. In the present study, we investigated the possible role of PGRN in the lysosomes of activated microglia in the cerebral cortex after traumatic brain injury (TBI). We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes. PGRN was colocalized with Lamp1, a lysosomal marker, and Lamp1-positive areas in GRN-deficient (KO) mice were significantly expanded compared with wild-type (WT) mice after TBI. Expression of all the lysosome-related genes examined in KO mice was significantly higher than that in WT mice. The number of activated microglia with TFEB localized to the nucleus was also significantly increased in KO as compared with WT mice. Since the TFEB translocation is regulated by the mammalian target of rapamycin complex 1 (mTORC1) activity in the lysosome, we compared ribosomal S6 kinase 1 (S6K1) phosphorylation that reflects mTORC1 activity. S6K1 phosphorylation in KO mice was significantly lower than that in WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive cells around the injury was significantly decreased and increased, respectively, in KO as compared with WT mice. These results suggest that PGRN localized in the lysosome is involved in the activation of mTORC1, and its deficiency leads to increased TFEB nuclear translocation with a resultant increase in lysosomal biogenesis in activated microglia and exacerbated neuronal damage in the cerebral cortex after TBI.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 746,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8"
            }
        },
        {
            "context": "Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. INTRODUCTION: Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. METHODS: General clinical assessment, sural nerve biopsy, and genetic analysis were performed. RESULTS: Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular-like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. CONCLUSION: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 212,
                "text": "GAN gene"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder for which the exact pathophysiology remains unclear. Brain iron insufficiency and altered dopaminergic function appear to play important roles in the etiology of the disorder. This concept is based partly on extensive research studies using cerebrospinal fluid (CSF), autopsy material, and brain imaging indicating reduced regional brain iron and on the clinical efficacy of dopamine receptor agonists for alleviating RLS symptoms. Finding causal relations, linking low brain iron to altered dopaminergic function in RLS, has required however the use of animal models. These models have provided insights into how alterations in brain iron homeostasis and dopaminergic system may be involved in RLS. The results of animal models of RLS and biochemical, postmortem, and imaging studies in patients with the disease suggest that disruptions in brain iron trafficking lead to disturbances in striatal dopamine neurotransmission for at least some patients with RLS. This review examines the data supporting an iron deficiency-dopamine metabolic theory of RLS by relating the results from animal model investigations of the influence of brain iron deficiency on dopaminergic systems to data from clinical studies in patients with RLS.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 107,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Comprehensive analysis of the genes responsible for neuroacanthocytosis in mood disorder and schizophrenia. Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60-61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 545,
                "text": "XK"
            }
        },
        {
            "context": "Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis. BACKGROUND: Dermatitis herpetiformis (DH) is a specific dermatological manifestation of coeliac disease and 80% of DH patients have gluten sensitive enteropathy manifested by crypt hyperplasia and villous atrophy. Matrix degradation mediated by collagenase 1 (MMP-1) and stromelysin 1 (MMP-3) has previously been implicated in the pathobiology of coeliac intestine and cutaneous DH blisters. AIMS: To study expression of stromelysin 2, metalloelastase, collagenase 3, and matrilysin in the intestine and skin of DH patients. METHODS: In situ hybridisation using 35S labelled cRNA probes was performed on duodenal biopsies of 15 DH patients, three samples each of control duodenal or jejunal mucosa, fetal ileal explants, lesional DH skin, and 19 serial biopsies of experimental DH blisters. Immunostaining was used to examine type IV collagen, macrophages (CD68), and 92 kDa gelatinase (MMP-9) in the specimens. RESULTS: Metalloelastase (MMP-12) was abundantly expressed by subepithelial macrophages in both coeliac intestine and spontaneous and induced DH rash. It was also upregulated in the experimental model of coeliac disease (staphylococcal endotoxin B stimulated fetal explants). The only other MMP detected was MMP-9 which did not colocalise with MMP-12. CONCLUSIONS: Upregulation of metalloelastase is associated with T cell mediated immune responses both in the intestine and skin. In addition to modulating macrophage migration, it may contribute to degradation of proteoglycans or basement membrane components in the subepithelial mucosa.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 143,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Assessing post-traumatic stress symptoms in a Latino prison population. PURPOSE: The purpose of this paper is to assess the reliability and validity of the Spanish version of the Davidson trauma scale (DTS-S) and to determine the prevalence and correlates of post-traumatic stress disorder (PTSD) symptoms in a non-clinical random sample of prison inmates. DESIGN/METHODOLOGY/APPROACH: Probabilistic samples of 1,179 inmates from 26 penal institutions in Puerto Rico were selected using a multistage sampling design. Population estimates and correlations were obtained for PTSD, generalized anxiety and depression. The reliability, factor structure, and convergent validity of the DTS-S were assessed. Cross-validation was employed to confirm the results of the factor analyses. FINDINGS: Using the cut-offs adopted by the scale's author, 136 (13.4 percent) of the inmates are likely to have current PTSD and 117 (11.6 percent) reach the cut-off for sub-threshold PTSD. Confirmatory factor analysis generated two factors explaining 53 percent of the variance. High reliabilities were obtained for the total scale (α=0.95) and for the frequency and severity scales (α=0.90 and 0.91). Significantly higher DTS-S scores were found for females (t=2.26, p<0.025), for inmates diagnosed with depression or anxiety (t=2.02, p<0.05), and those reporting suicide attempts (t=4.47, p<0.0001). ORIGINALITY/VALUE: Findings support that the DTS-S is a reliable and valid measure to assess PTSD symptoms in Latino inmate populations and to identify individuals at risk for the disorder that require confirmatory diagnosis and clinical interventions.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 291,
                "text": "PTSD"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 692,
                "text": "7"
            }
        },
        {
            "context": "Familial hypercholesterolemia: etiology, diagnosis and new treatment options. Familial hypercholesterolemia (FH) is a common genetic disorder that presents with robust increases in low-density lipoprotein cholesterol (LDL-C) and can lead to premature cardiovascular disease. There are heterozygous and homozygous forms. The diagnosis is usually made based on blood cholesterol levels, clinical signs and family history. Genetic testing can be used to confirm the diagnosis. Effective lowering of LDL-C in FH can prevent cardiovascular morbidity and mortality, however, the disease remains greatly underdiagnosed. The mainstay of pharmacologic therapy in FH patients is high-dose statins, which are often combined with other lipid-lowering agents. The homozygous form is mainly treated with lipid apheresis. Guideline-recommended target levels of LDL-C are often not reached, making new treatment options desirable. Four classes of newer lipid-lowering drugs offer promising advances in treating FH, namely the apolipoprotein-B synthesis inhibitors (mipomersen), the microsomal transfer protein inhibitors (lomitapide), the cholesterol ester transfer protein inhibitors (anacetrapib, evacetrapib) and the proprotein convertase subtilisin/kexin type 9 inhibitors (evolocumab, alirocumab). In this review, the available evidence regarding the use of these drugs in patients with FH is discussed, with particular focus on their efficacy and safety.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 1204,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.",
            "question": "Which disease has been associated to a disruptive ALX1 protein?",
            "answers": {
                "answer_start": 135,
                "text": "frontonasal dysplasia"
            }
        },
        {
            "context": "RON-regulated innate immunity is protective in an animal model of multiple sclerosis. The tyrosine kinase receptor RON and its ligand, macrophage stimulating protein (MSP), exert inhibitory effects on systemic innate immunity, but their CNS expression and impact on human neuroinflammatory diseases are unknown were RON and MSP present in human brain perivascular macrophages and microglia, but RON mRNA and protein abundance in the CNS were diminished in both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE). Treatment of differentiated human monocytoid cells with MSP resulted in significant reduction of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and MMP-9 mRNA levels, whereas minimal effects were observed in human astrocytes. After induction of EAE, RON knockout and heterozygote animals exhibited significantly increased CNS proinflammatory gene (TNF-alpha, MMP-12) expression compared with wild-type littermate controls, although IL-4 levels were suppressed in both RON-deficient groups. Neurological disease in RON-deficient animals showed a more rapid onset with overall worsened severity, together with exacerbated demyelination, axonal injury, and neuroinflammation after EAE induction. The proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in glia in both MS brains and EAE spinal cords. Thus, the MSP-RON pathway represents a novel regulatory mechanism within the CNS by which innate immunity and its pathogenic effects could be targeted for future therapeutic interventions.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 498,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 48,
                "text": "aurora A"
            }
        },
        {
            "context": "Lewy body pathology in Alzheimer's disease. Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 1236,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor. Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1289,
                "text": "telomerase"
            }
        },
        {
            "context": "The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1079,
                "text": "NCX"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 279,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Cost-effectiveness of 5-aminolevulinic acid-induced fluorescence in malignant glioma surgery. OBJECTIVE: This study evaluates the cost-effectiveness of 5-aminolevulinic acid (5-ALA, Gliolan®) in patients undergoing surgery for malignant glioma, in standard clinical practice conditions in Spain. MATERIAL AND METHODS: Cost-effectiveness ratios were determined in terms of incremental cost per complete resection (CR) and incremental cost per additional quality-adjusted life year (QALY), based on data collected in the VISIONA observational study. RESULTS: Incremental cost with 5-ALA versus conventional surgery using white light only amounts to € 4550 per additional CR achieved and € 9021 per QALY gained. A sensitivity analysis shows these results to be robust. CONCLUSION: Malignant glioma surgery guided by 5-ALA fluorescence entails a moderate increase in hospital costs compared to current surgical practice and can be considered a cost-effective innovation.",
            "question": "What is the generic name of Gliolan?",
            "answers": {
                "answer_start": 152,
                "text": "5-aminolevulinic acid"
            }
        },
        {
            "context": "Partial lumbosacral transitional vertebra resection for contralateral facetogenic pain. STUDY DESIGN: Case report of surgically treated mechanical low back pain from the facet joint contralateral to a unilateral anomalous lumbosacral articulation (Bertolotti's syndrome). OBJECTIVES: To describe the clinical presentation, diagnostic evaluation, and management of facet-related low back pain in a 17-year-old cheerleader and its successful surgical treatment with resection of a contralateral anomalous articulation. SUMMARY OF BACKGROUND DATA: Lumbosacral transitional vertebrae are common in the general population. Bertolotti's syndrome is mechanical low back pain associated with these transitional segments. Little is known about the pathophysiology and mechanics of these vertebral segments and their propensity to be pain generators. Treatment of this syndrome is controversial, and surgical intervention has been infrequently reported. METHOD: A retrospective chart analysis and radiographic review were performed. RESULTS: Repeated fluoroscopically guided injections implicated a symptomatic L6-S1 facet joint contralateral to an anomalous lumbosacral articulation. Eventually, a successful surgical outcome was achieved with resection of the anomalous articulation. CONCLUSION: Clinicians should consider the possibility that mechanical low back pain may occur from a facet contralateral to a unilateral anomalous lumbosacral articulation, even in a young patient. Although reports of surgical treatment of Bertolotti's syndrome are infrequent, resection of the anomalous articulation provided excellent results in this patient, presumably because of reduced stresses on the symptomatic facet.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 222,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas. BACKGROUND: Gamma Knife radiosurgery (GKRS) is commonly used in treating small vestibular schwannomas; however, its use for larger vestibular schwannomas is still controversial. OBJECTIVE: To assess the long-term safety and efficacy of treating eligible Koos grade 4 vestibular schwannomas with GKRS. METHODS: We conducted a single-center, retrospective evaluation of patient undergoing GKRS for Koos grade 4 vestibular schwannomas. We evaluated clinical, imaging, and treatment characteristics and assessed treatment outcome. Inclusion criteria were tumor size of > 4 cm and follow-up of at least 6 months. Patients with neurofibromatosis type 2 were excluded. Primary outcomes measured were tumor control rate, hearing and facial function preservation rate, and complications. All possible factors were analyzed to assess clinical significance. RESULTS: Sixty-eight patients met inclusion criteria. Median follow-up was 47 months (range, 6-125 months). Baseline hearing was serviceable in 60%. Median tumor volume at radiosurgery was 7.4 cm (range, 4-19 cm). The median marginal dose used was 12 Gy at the 50% isodose line. Actuarial tumor control rates were 95% and 92% at 2 and 10 years, respectively. Actuarial serviceable hearing preservation rates were 89% and 49% at 2 and 5 years, respectively. Facial nerve preservation was 100%. Clinical complications included balance disturbance (11%), facial pain (10%), facial numbness (5%), and tinnitus (10%). Most complications were mild and transient. Hydrocephalus occurred in 3 patients, requiring ventriculoperitoneal shunt insertion. Larger tumor size was significantly associated with persisting symptoms post-treatment. CONCLUSION: Patients with Koos grade 4 vestibular schwannomas and minimal symptoms can be treated safely and effectively with GKRS.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 83,
                "text": "Vestibular Schwannoma"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1119,
                "text": "MARS"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 385,
                "text": "Xa"
            }
        },
        {
            "context": "The effects of proteasome inhibitors on bone remodeling in multiple myeloma. Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 857,
                "text": "proteasome"
            }
        },
        {
            "context": "[Current therapy of chronic myeloid leukemia]. Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and oncogenic BCR-ABL1 fusion gene. The first tyrosine-kinase inhibitor (TKI) imatinib was introduced to clinical practice 10 years ago, and it radically improved the outcome of CML patients. The rare patients that are imatinib resistant or intolerant can be treated with second generation TKIs such as dasatinib or nilotinib. As second generation TKIs appear to be more effective than imatinib and well tolerated, they may become standard first-line treatment for CML. The major future aim in CML is curative drug therapy.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 176,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 424,
                "text": "CD38"
            }
        },
        {
            "context": "Yeast Elc1 plays an important role in global genomic repair but not in transcription coupled repair. Transcription coupled repair (TCR) is a nucleotide excision repair (NER) pathway that is dedicated to repair in the transcribed strand of an active gene. The genome overall NER is called global genomic repair (GGR). Elc1, the yeast homolog of the mammalian elongation factor elongin C, has been shown to be a component of a ubiquitin ligase complex that contains Rad7 and Rad16, two factors that are specifically required for GGR. Elc1 has also been suggested to be present in another ubiquitin ligase complex that lacks Rad7 and Rad16 and is involved in UV-induced ubiquitylation and subsequent degradation of RNA polymerase II. Here we show that elc1 deletion increases UV sensitivity of TCR-deficient cells but does not affect the UV sensitivity of otherwise wild type and GGR-deficient cells. Cells deleted for elc1 show normal NER in the transcribed strand of an active gene but have no detectable NER in the non-transcribed strand. Elc1 does not affect UV-induced mutagenesis when TCR is operative, but plays an important role in preventing the mutagenesis if TCR is defective. Furthermore, the levels of Rad7 and Rad16 proteins are not significantly decreased in elc1 cells, and overexpression of Rad7 and Rad16 individually or simultaneously in elc1 cells does not restore repair in the non-transcribed strand of an active gene. Our results suggest that Elc1 has no function in TCR but plays an important role in GGR. Furthermore, the role of Elc1 in GGR may not be subsidiary to that of Rad7 and Rad16.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 213,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk. Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine's effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.",
            "question": "What alternate indication has Vanoxerine been repositioned for?",
            "answers": {
                "answer_start": 486,
                "text": "atrial fibrillation and flutter"
            }
        },
        {
            "context": "Diamond Blackfan anemia: ribosomal proteins going rogue. Within the decade following the demonstration that mutations in the RPS19 gene can lead to Diamond-Blackfan anemia (DBA), this disease has become a paradigm for an emerging group of pathologies linked to defects in ribosome biogenesis. DBA patients exhibit abnormal pre-rRNA maturation patterns and the majority bear mutations in one of several ribosomal protein genes that encode structural components of the ribosome essential for the correct assembly of the ribosomal subunits. Extensive study of the most frequently mutated gene, RPS19, has shown that mutations prevent the assembly of the ribosomal protein into forming pre-ribosomal particles. This defect in ribosome production triggers nucleolar stress pathways, the activation of which appears to be central to pathophysiological mechanisms. Why mutations in ribosomal protein genes so strongly and specifically affect erythropoiesis in DBA remains a challenging question, especially given the fact that defects in genes encoding nonstructural ribosome biogenesis factors have been shown to cause diseases other than DBA. A major problem in understanding the pathophysiological mechanisms in DBA remains the lack of a suitable animal model. Despite this, considerable strides have been made over that past few years demonstrating that several factors involved in the synthesis of ribosomes are targets of disease-causing mutations.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 402,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 1340,
                "text": "CisMapper"
            }
        },
        {
            "context": "Flumazenil in benzodiazepine antagonism. Actions and clinical use in intoxications and anaesthesiology. In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to 1.0mg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour). Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 2310,
                "text": "flumazenil"
            }
        },
        {
            "context": "Complex molecular epidemiology of methicillin-resistant staphylococcus aureus isolates from children with cystic fibrosis in the era of epidemic community-associated methicillin-resistant S aureus. BACKGROUND: Limited data exist about the molecular types of methicillin-resistant Staphylococcus aureus (MRSA) strains found in children with cystic fibrosis (CF). We sought to characterize MRSA strains from these patients and compare them with MRSA strains from non-CF pediatric patients. METHODS: All MRSA isolates were collected prospectively at Children's Medical Center in Dallas, TX, and the University of Chicago Comer Children's Hospital in 2004 to 2005. All CF MRSA isolates underwent susceptibility testing, multilocus sequence typing, Panton-Valentine leukocidin gene detection (pvl+), and staphylococcal chromosome cassette mec (SCCmec) typing. RESULTS: A total of 22 of 34 MRSA isolates (64.7%) from patients with CF belonged to clonal complex (CC) 5 and contained SCCmec II, so-called health-care associated MRSA (HA-MRSA) strains. Nine of 34 MRSA strains (26.5%) were CC 8, and contained SCCmec IV, so-called community-associated MRSA (CA-MRSA) strains. The CA-MRSA strains tended to be isolated from newly colonized CF patients. In contrast, CC8 isolates predominated among the non-CF patients (294 of 331 patients; 88.8%). MRSA isolates from children with CF were more likely to be resistant to clindamycin (65% vs 19%, respectively) and ciprofloxacin (62% vs 17%, respectively) compared with strains from non-CF patients (p < 0.001). There was no difference in the rate of pvl+ isolate recovery from children with CF undergoing a surveillance culture (7 of 23 children) compared with those with pulmonary exacerbation (3 of 11 children; p = 1.0). CONCLUSIONS: Both CA-MRSA (CC8) isolates and HA-MRSA (CC5) isolates populate the respiratory tracts of children with CF. HA-MRSA isolates predominated, but CA-MRSA strains predominated among CF patients with newly acquired MRSA strains and among the non-CF patients. The presence of CA-MRSA strains in children with CF was not associated with exacerbation or necrotizing pneumonia.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 303,
                "text": "MRSA"
            }
        },
        {
            "context": "Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen). The ficolins and mannose-binding lectin (MBL) are collagen-like defence proteins that serve as recognition molecules in lectin complement pathway. Differential features that may indicate diverse functions of these proteins are poorly understood. In this study we compared important biological features of the ficolins and MBL. We investigated the tissue distribution of the FCN1-3 and the MBL2 genes encoding the ficolins and MBL by quantitative PCR. Recombinant proteins were produced and structural and biological characteristics were investigated and compared. Our main findings were that FCN3 mRNA was highly expressed in the liver and lung compared with the other genes revealing the lung as the tissue with the highest FCN3 expression pattern. Ficolin-3 revealed higher complement activating capacity compared with Ficolin-2, MBL and Ficolin-1 and was highly resistant to bacterial collagenase treatment, which is different from the other ficolins and MBL. We discovered several unique properties of Ficolin-3 showing that FCN3 is the most highly expressed gene in liver and lung among the lectin complement pathway initiators. Moreover, Ficolin-3 has a high complement activating potential and is the only collagenase proteolytic resistant molecule among the lectin complement pathway initiators.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 1361,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. BACKGROUND: Eosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation. METHODS: In this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo. RESULTS: There were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events. CONCLUSIONS: Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 459,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 345,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Sudden death in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is regarded as the most common cause of sudden cardiac death in young people (including trained athletes). However, assessing sudden death (SD) risk and identifying the most appropriate candidates for prophylactic device therapy is a complex process compounded by the unpredictability of the underlying arrhythmogenic substrate, absence of a single dominant and quantitative risk maker for this heterogeneous disease, and also the difficulty encountered in assembling sufficiently powered prospective and randomized trials in large patient populations. Patients with multiple risk factors and most young patients with one strong and unequivocal risk marker can be considered candidates for primary prevention defibrillators. Despite certain limitations, the current risk factor algorithm (when combined with a measure of individual physician judgment) has proved to be an effective strategy for targeting high-risk status. This approach has served the HCM patient population well, as evidenced by the significant appropriate defibrillator intervention rates, although a very small proportion of patients without conventional risk factors may also be at risk for SD. Indeed, the introduction of implantable defibrillators to the HCM patient population represents a new paradigm for clinical practice, offering the only proven protection against SD by virtue of effectively terminating ventricular tachycardia/fibrillation. In the process, implantable defibrillators have altered the natural history of HCM, potentially providing the opportunity of normal or near-normal longevity for many patients. Prevention of SD is now an integral, albeit challenging, component of HCM management.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 45,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "A cascade of genes related to Waardenburg syndrome. On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 181,
                "text": "MITF"
            }
        },
        {
            "context": "Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex. The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 306,
                "text": "Swr1"
            }
        },
        {
            "context": "Dynamics of enzymatic interactions during short flap human Okazaki fragment processing by two forms of human DNA polymerase δ. Lagging strand DNA replication requires the concerted actions of DNA polymerase δ, Fen1 and DNA ligase I for the removal of the RNA/DNA primers before ligation of Okazaki fragments. To better understand this process in human cells, we have reconstituted Okazaki fragment processing by the short flap pathway in vitro with purified human proteins and oligonucleotide substrates. We systematically characterized the key events in Okazaki fragment processing: the strand displacement, Pol δ/Fen1 combined reactions for removal of the RNA/DNA primer, and the complete reaction with DNA ligase I. Two forms of human DNA polymerase δ were studied: Pol δ4 and Pol δ3, which represent the heterotetramer and the heterotrimer lacking the p12 subunit, respectively. Pol δ3 exhibits very limited strand displacement activity in contrast to Pol δ4, and stalls on encounter with a 5'-blocking oligonucleotide. Pol δ4 and Pol δ3 exhibit different characteristics in the Pol δ/Fen1 reactions. While Pol δ3 produces predominantly 1 and 2 nt cleavage products irrespective of Fen1 concentrations, Pol δ4 produces cleavage fragments of 1-10 nts at low Fen1 concentrations. Pol δ3 and Pol δ4 exhibit comparable formation of ligated products in the complete system. While both are capable of Okazaki fragment processing in vitro, Pol δ3 exhibits ideal characteristics for a role in Okazaki fragment processing. Pol δ3 readily idles and in combination with Fen1 produces primarily 1 nt cleavage products, so that nick translation predominates in the removal of the blocking strand, avoiding the production of longer flaps that require additional processing. These studies represent the first analysis of the two forms of human Pol δ in Okazaki fragment processing. The findings provide evidence for the novel concept that Pol δ3 has a role in lagging strand synthesis, and that both forms of Pol δ may participate in DNA replication in higher eukaryotic cells.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 142,
                "text": "DNA replication"
            }
        },
        {
            "context": "The importance of IgG4 in the predictive model of thyroiditis. UNLABELLED: Immunoglobulin (Ig)G4-related sclerosing disease (IgG4-RSD) is a new disease entity first proposed with regard to autoimmune pancreatitis. A 67-year-old male patient was examined because of weight loss and an abdominal pain. Based on the clinical characteristics, laboratory parameters and ultrasound features, we identified the diagnosis of the IgG4-related systemic disease (IgG4-RSD), that was confirmed by the histopathological analysis after the biopsy of the head of pancreas. After confirmation, we started with the corticosteroid therapy with a good clinical, biochemical and morphological response. During the previous therapy, the disturbance of glucoregulation appeared, so we had to change the modality of treatment. We decided to add Azathioprine to the therapy in a dose of 150 mg/day. We achieved a stable phase of the disease with IgG 4.37 g/l and IgG4 0.179 g/l, and with no side effects from the therapy. LEARNING POINTS: There are potential clinical applications of identifying subsets of patients with IgG4 thyroiditis (FVHT and Riedel thyroiditis).A trial of immunosuppressive therapy should be included if a resection is deemed inadvisable.In particular, cases of FVHT that mimic malignancy, tissue and serum IgG4 may provide supportive diagnostic information.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 1097,
                "text": "IgG4"
            }
        },
        {
            "context": "Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta. In the CNS, astrocytes are significant sources of RANTES/CCL5 (regulated upon activation, normal T cell expressed and secreted), a CC-chemokine with important biological function. Astrocyte RANTES/CCL5 has been shown to be induced by interleukin-1 (IL-1), with interferon-gamma (IFNgamma) as a primer, but whether type I interferons play any role in the expression of RANTES/CCL5 is not known. In this report, we studied the detailed mechanism of RANTES/CCL5 induction in primary human astrocytes activated with IL-1 and IFNbeta. Ribonuclease protection assay and ELISA showed that IFNbeta, although not effective alone, increased IL-1-induced RANTES/CCL5 expression, but did not antagonize IFNgamma. IL-1 or IL-1/IFNbeta-induced RANTES/CCL5 expression was inhibited by the super-repressor IkappaBalpha or inhibitors of p38 or c-Jun N-terminal kinase (JNK) MAPKs (mitogen-activated protein kinases), but not by extracellular signal regulated kinases (ERK) inhibitors. IFNbeta enhanced IL-1-induced phosphorylation of p38 MAPK, but was not effective alone. Transfection with mutated RANTES/CCL5 promoter-reporter constructs revealed that kappaB, interferon-stimulated response element (ISRE) and CAATT-enhancer binding protein-beta (C/EBPbeta) sites all contributed to IL-1/IFNbeta-induced RANTES/CCL5 transcription. IFNbeta synergized with IL-1 to induce nuclear accumulation of C/EBPbeta protein. They also synergized to form nuclear ISRE complexes with Stat1, Stat2 and interferon regulatory factor-1 (IRF-1) proteins. Together, our results demonstrate that IFNbeta plays a positive regulatory role in the expression of RANTES/CCL5 in human astrocytes through several distinct mechanisms.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 947,
                "text": "JNK"
            }
        },
        {
            "context": "psygenet2r: a R/Bioconductor package for the analysis of psychiatric disease genes. Motivation: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. Results: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. Availability and implementation: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html). Contact: juanr.gonzalez@isglobal.org or laura.furlong@upf.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for the analysis of psychiatric disease genes?",
            "answers": {
                "answer_start": 850,
                "text": "Psygenet2r"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1010,
                "text": "xa"
            }
        },
        {
            "context": "The atxA gene product activates transcription of the anthrax toxin genes and is essential for virulence. Bacillus anthracis plasmid pXO1 carries the structural genes for the three anthrax toxin proteins, cya (edema factor), lef (lethal factor), and pag (protective antigen). Expression of the toxin genes by B. anthracis is enhanced during growth under elevated levels of CO2. This CO2 effect is observed only in the presence of another pXO1 gene, atxA, which encodes a transactivator of anthrax toxin synthesis. Here we show that transcription of atxA does not appear to differ in cells grown in 5% CO2 compared with cells grown in air. Using a new efficient method for gene replacement in B. anthracis, we constructed an atxA-null mutant in which the atxA-coding sequence on pXO1 is replaced with an omega km-2 cassette. Transcription of all three toxin genes is decreased in the absence of atxA. The pag gene possesses two apparent transcription start sites, P1 and P2; only transcripts with 5' ends mapping to P1 are decreased in the atxA-null mutant. Deletion analysis of the pag promoter region indicates that the 111 bp region upstream of the P1 site is sufficient for atxA-mediated activation of this transcript. The cya and lef genes each have one apparent start site for transcription. Transcripts with 5' ends mapping to these sites are not detected in the atxA-null mutant. The atxA-null mutant is avirulent in mice. Moreover, the antibody response to all three toxin proteins is decreased significantly in atxA-null mutant-infected mice. These data suggest that the atxA gene product also regulates toxin gene expression during infection.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 600,
                "text": "CO2"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1851,
                "text": "Xa"
            }
        },
        {
            "context": "NOTCH3 gene mutations in subjects clinically suspected of CADASIL. BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of relatives at risk is critical in mutation carriers. METHODS: Mutation analysis of the NOTCH3 gene was performed through direct sequencing in 140 patients with clinical suspicion of CADASIL. Patients underwent genetic counselling pre and post testing. The 2-23 exons containing all EGF-like domains were screened. RESULTS: 14 familial forms of the disease have been identified with 14 different causative mutations in exons 2, 3, 4, 5, 7, 10, 14, 19, 20 and 22 of the NOTCH3 gene; no pathogenetic mutations have been identified in exons 6 and 8; several genetic variations both in coding as well as in intronic regions were identified too. CONCLUSIONS: Our data confirm the importance of screening the whole EGF-like domains region of NOTCH3 gene for the molecular diagnosis of CADASIL among the Italian population too. Moreover genetic variants different from loss or gain of a cysteine residue are identified and presented.",
            "question": "Which amino acid residue appears mutated in most of the cases reported with  cadasil syndrome?",
            "answers": {
                "answer_start": 265,
                "text": "cysteine"
            }
        },
        {
            "context": "CTCF Binding Polarity Determines Chromatin Looping. CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional (3D) organization of chromatin. In this study, we assayed the 3D genomic contact profiles of a large number of CTCF binding sites with high-resolution 4C-seq. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR/Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal, convergent CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher-order chromatin structure.",
            "question": "What is the preferred orientation of CTCF binding sites for chromatin looping?",
            "answers": {
                "answer_start": 427,
                "text": "convergent"
            }
        },
        {
            "context": "Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 296,
                "text": "iron"
            }
        },
        {
            "context": "[Analysis of the small supernumerary marker chromosome in Turner syndrome with 45, X/46, X, + mar karyotype]. OBJECTIVE: To identify the origin and study the morphology of small supernumerary marker chromosome (sSMC) in Turner syndrome with 45, X/46, X, + mar karyotype. METHODS: Using the conventional chromosome G-banding technique, 10 cases of Turner syndrome with 45, X/46, X, + mar chromosome karyotype were obtained, dual-color fluorescence in situ hybridization was applied to study the origin and morphology of the sSMC. RESULTS: In the 10 cases of Turner syndrome with 45, X/46, X, + mar karyotype, the sSMC of 7 cases was derived from X chromosome [sSMC(X)], the sSMC of 2 cases was derived from Y chromosome [sSMC(Y)] and the remaining 1 case was derived from the autosome. There were 4 cases of ring(r) chromosomes and 3 of centric minutes (min) in the 7 sSMC (X) cases. In the 2 sSMC(Y), one case was dicentric (dic) and the other was centric minute (min). The sSMC originated from the autosome was a centric minute (min). CONCLUSION: The origin of sSMC of Turner syndrome with 45, X/46, X, + mar karyotype was almost all from sex chromosomes, and rarely from autosomes. sSMC can exist as isodicentric, ring, or centric minute. The molecular cytogenetic features of the sSMC can provide useful information for genetic counseling, prenatal diagnosis and treatment of the Turner syndrome patients with a 45, X/46, X, + mar karyotype.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 245,
                "text": "X"
            }
        },
        {
            "context": "The role of SMARCAL1 in replication fork stability and telomere maintenance. SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.",
            "question": "Mutations in which gene cause Schimke immune-osseous dysplasia?",
            "answers": {
                "answer_start": 198,
                "text": "HARP"
            }
        },
        {
            "context": "Infantile hemophagocytic lymphohistiocytosis in a case of chediak-higashi syndrome caused by a mutation in the LYST/CHS1 gene presenting with delayed umbilical cord detachment and diarrhea. A 2-month-old female infant, born to consanguineous parents, presented with infections in skin and upper respiratory tract. She was notable for delayed umbilical cord detachment, partial albinism, and neurological irritability. Giant granules were present in white blood cells. The intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient with 82% and 8% perforin-containing CD8 T cells at active and nonactive hemophagocytic lymphohistiocytosis (HLH) disease, respectively. HLH was confirmed by hemophagocytosis in bone marrow and absent natural killer cell activity. The patient carried a homozygous G>A mutation in the 3' splice site of intron 24 of the LYST/CHS1 gene, leading to the use of an alternative YAG splice site located in exon 25, introducing a premature STOP codon (L2355fsX2370; NP_000072.2). The early-onset accelerated phase in this severe phenotype of Chediak-Higashi syndrome was probably induced by rotaviral infection. Interestingly, the intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient. Late separation of the umbilical cord in concordance with clinical symptoms should lead to evaluation of a possible neutrophil dysfunction including Chediak-Higashi syndrome before onset of HLH.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 58,
                "text": "chediak-higashi syndrome"
            }
        },
        {
            "context": "Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation. BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 39,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes. The let-7 microRNA (miRNA) plays important roles in human liver development and diseases such as hepatocellular carcinoma, liver fibrosis and hepatitis wherein oxidative stress accelerates the progression of these diseases. To date, the role of the let-7 miRNA family in modulation of heme oxygenase 1 (HMOX1), a key cytoprotective enzyme, remains unknown. Our aims were to determine whether let-7 miRNA directly regulates Bach1, a transcriptional repressor of the HMOX1 gene, and whether indirect up-regulation of HMOX1 by let-7 miRNA attenuates oxidant injury in human hepatocytes. The effects of let-7 miRNA on Bach1 and HMOX1 gene expression in Huh-7 and HepG2 cells were determined by real-time qRT-PCR, Western blot, and luciferase reporter assays. Dual luciferase reporter assays revealed that let-7b, let-7c, or miR-98 significantly decreased Bach1 3'-untranslated region (3'-UTR)-dependent luciferase activity but not mutant Bach1 3'-UTR-dependent luciferase activity, whereas mutant let-7 miRNA containing base complementarity with mutant Bach1 3'-UTR restored its effect on mutant reporter activity. let-7b, let-7c, or miR-98 down-regulated Bach1 protein levels by 50-70%, and subsequently up-regulated HMOX1 gene expression by 3-4 fold, compared with non-specific controls. Furthermore, Huh-7 cells transfected with let-7b, let-7c or miR-98 mimic showed increased resistance against oxidant injury induced by tert-butyl-hydroperoxide (tBuOOH), whereas the protection was abrogated by over-expression of Bach1. In conclusion, let-7 miRNA directly acts on the 3'-UTR of Bach1 and negatively regulates expression of this protein, and thereby up-regulates HMOX1 gene expression. Over-expression of the let-7 miRNA family members may represent a novel approach to protecting human hepatocytes from oxidant injury.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 566,
                "text": "repressor"
            }
        },
        {
            "context": "Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. AIM: Fostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHOD: Three clinical studies were conducted in healthy subjects: (A) A single ascending dose study for R406 with doses ranging from 80-600 mg, (B) a single- and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg twice daily and (C) a study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS: These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension and steady-state was achieved after 3-4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change. CONCLUSION: Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once daily or twice daily oral administration of fostamatinib.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 36,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 214,
                "text": "chordomas"
            }
        },
        {
            "context": "Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. BACKGROUND: Screening medullary thyroid carcinomas (MTCs) for rearranged during transfection (RET) mutations becomes increasingly important for clinical assessment of the disease. The role of mutations in other genes including RAS (i.e. HRAS, KRAS, and NRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-akt murine thymoma viral oncogene homolog 1 (AKT1), and CTNNB1 (β-catenin) is unknown or not fully explored yet for this disease. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded (FFPE) material was the primary source for screening 13 sporadic and inherited MTCs and matched non-tumor specimens. Multiplex PCR was included in the PCR protocol. Sequence analysis encompassed mutational hotspot regions in RET exons 5, 8, 10, 11, and 13 to 16; HRAS exons 1 and 2; KRAS exons 1 and 2; NRAS exons 1 and 2; BRAF exon 15; AKT1 exon 2, and CTNNB1 exon 3. RESULTS: We identified RET mutations in seven of 13 MTCs: five RET-positive cases revealed a mutation in exon 16 (M918T) and two a mutation in exon 10 (C618S and C620S). In four of the RET-positive cases, the mutation was inherited, out of which three were reportedly associated with a multiple endocrine neoplasia type 2 (MEN2) syndrome, i.e. MEN2A (C618S), MEN2A/familial MTC (FMTC) (C620S), and MEN2B (M918T). These cases reflect the known MEN2 genotype-phenotype correlation. Three of the five stage IVc MTCs were inherited RET-positive cases. Mutational screening in HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 disclosed one sporadic RET-negative MTC (stage III) with mutation in HRAS codon 13 (G13R). CONCLUSION: Our study supports the clinical relevance of screening MTC patients for RET mutations. The role of RAS mutations, in particular HRAS mutations, in sporadic RET-negative MTC has not been fully explored yet. Mutations in BRAF, AKT1, and CTNNB1 are likely not to play a role in MTC.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1163,
                "text": "RET"
            }
        },
        {
            "context": "Human monoamine oxidase gene (MAOA): chromosome position (Xp21-p11) and DNA polymorphism. An essentially full-length cDNA clone for the human enzyme monoamine oxidase type A (MAO-A) has been used to determine the chromosomal location of a gene encoding it. This enzyme is important in the degradative metabolism of biogenic amines throughout the body and is located in the outer mitochondrial membrane of many cell types. Southern blot analysis of PstI-digested human DNA revealed multiple fragments that hybridized to this probe. Using rodent-human somatic cell hybrids containing all or part of the human X chromosome, we have mapped these fragments to the region Xp21-p11. A restriction fragment length polymorphism (RFLP) for this MAOA gene was identified and used to evaluate linkage distances between this locus and several other loci on Xp. The MAOA locus lies between DXS14 and OTC, about 29 cM from the former.",
            "question": "Which is the chromosomal location of the gene MAOA?",
            "answers": {
                "answer_start": 666,
                "text": "Xp21-p11"
            }
        },
        {
            "context": "Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. BACKGROUND: Homozygous familial hypercholesterolaemia is a rare, serious disorder caused by very low or absent plasma clearance of LDL, substantially raised LDL cholesterol, and accelerated development of cardiovascular disease. Conventional lipid-lowering treatments are modestly effective. Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. We now report results with evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial. METHODS: This randomised, double-blind, placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America, Europe, the Middle East, and South Africa. 50 eligible patients (aged > 12 years) with homozygous familial hypercholesterolaemia, on stable lipid-regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a computer-generated randomisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was stratified by LDL cholesterol at screening (<11 mmol/L or > 11 mmol/L) and implemented by a computerised interactive voice-response system. Patients, study personnel, and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit. The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01588496. FINDINGS: Of the 50 eligible patients randomly assigned to the two treatment groups, 49 actually received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI -43·9% to -18·0%; p<0·0001). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study. INTERPRETATION: In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo. FUNDING: Amgen Inc.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 480,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 958,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "Tyrosinase"
            }
        },
        {
            "context": "Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as \"rufous/red albinism,\" is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed \"OCA4.\" The encoded protein, MATP (for \"membrane-associated transporter protein\") is predicted to span the membrane 12 times and likely functions as a transporter.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 623,
                "text": "tyr"
            }
        },
        {
            "context": "Restless leg syndrome manifested by iron deficiency from chronic hemoptysis in cystic fibrosis. Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be a continuum of a neurological sleep disorder associated with abnormal iron metabolism or deficiency. I describe a case of RLS and PLMD in a cystic fibrosis patient with iron deficiency from chronic hemoptysis. This is the first case that reports RLS and PLMD manifesting from iron deficiency caused by chronic hemoptysis in advanced cystic fibrosis lung disease.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 258,
                "text": "iron"
            }
        },
        {
            "context": "Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. The human melanocortin-1 receptor gene (MC1R) encodes a G-protein coupled receptor that is primarily expressed on melanocytes, where it plays a key role in pigmentation regulation. Variant alleles are associated with red hair colour and fair skin, known as the RHC phenotype, as well as skin cancer risk. The R151C, R160W and D294H alleles, designated 'R', are strongly associated with the RHC phenotype and have been proposed to result in loss of function receptors due to impaired G-protein coupling. We recently provided evidence that the R151C and R160W variants can efficiently couple to G-proteins in response to alpha-melanocyte stimulating hormone. The possibility that altered cellular localization of the R151C and R160W variant receptors could underlie their association with RHC was therefore considered. Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors. In additional exogenous expression studies, the R variant D84E and the rare I155T variant, also demonstrated a significant reduction in plasma membrane receptor numbers. The V60L, V92M and R163Q weakly associated RHC alleles, designated 'r', were expressed with normal or intermediate cell surface receptor levels. These results indicate that reduced receptor coupling activity may not be the only contributing factor to the genetic association between the MC1R variants and the RHC phenotype, with MC1R polymorphisms now linked to a change in receptor localization.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 158,
                "text": "MC1R"
            }
        },
        {
            "context": "Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the \"Mowat-Wilson\" syndrome. ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway. ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 325,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination. This strategy led to complete regression of established tumors in a significant percentage of treated animals, with survival prolongation. We show for the first time that combining CT-011 and CPM significantly increases the number of vaccine-induced tumor-infiltrating CD8(+) T cells, with simultaneous decrease in infiltrating Treg cells. Interestingly, we find that CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable significant synergistic decrease of splenic and tumor-infiltrated Treg cells. Surprisingly, we find that the anti-tumor effect elicited by the combination of CT-011 and CPM is dependent on both CD8(+) and CD4(+) T-cell responses, although the antigen we used is a class I MHC-restricted peptide. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 433,
                "text": "PD-1"
            }
        },
        {
            "context": "Long-term control of endemic hospital-wide methicillin-resistant Staphylococcus aureus (MRSA): the impact of targeted active surveillance for MRSA in patients and healthcare workers. OBJECTIVE: To evaluate the long-term impact of successive interventions on rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection and MRSA bacteremia in an endemic hospital-wide situation. DESIGN: Quasi-experimental, interrupted time-series analysis. The impact of the interventions was analyzed by use of segmented regression. Representative MRSA isolates were typed by use of pulsed-field gel electrophoresis. SETTING: A 950-bed teaching hospital in Seville, Spain. PATIENTS: All patients admitted to the hospital during the period from 1995 through 2008. METHODS: Three successive interventions were studied: (1) contact precautions, with no active surveillance for MRSA; (2) targeted active surveillance for MRSA in patients and healthcare workers in specific wards, prioritized according to clinical epidemiology data; and (3) targeted active surveillance for MRSA in patients admitted from other medical centers. RESULTS: Neither the preintervention rate of MRSA colonization or infection (0.56 cases per 1,000 patient-days [95% confidence interval {CI}, 0.49-0.62 cases per 1,000 patient-days]) nor the slope for the rate of MRSA colonization or infection changed significantly after the first intervention. The rate decreased significantly to 0.28 cases per 1,000 patient-days (95% CI, 0.17-0.40 cases per 1,000 patient-days) after the second intervention and to 0.07 cases per 1,000 patient-days (95% CI, 0.06-0.08 cases per 1,000 patient-days) after the third intervention, and the rate remained at a similar level for 8 years. The MRSA bacteremia rate decreased by 80%, whereas the rate of bacteremia due to methicillin-susceptible S. aureus did not change. Eighty-three percent of the MRSA isolates identified were clonally related. All MRSA isolates obtained from healthcare workers were clonally related to those recovered from patients who were in their care. CONCLUSION: Our data indicate that long-term control of endemic MRSA is feasible in tertiary care centers. The use of targeted active surveillance for MRSA in patients and healthcare workers in specific wards (identified by means of analysis of clinical epidemiology data) and the use of decolonization were key to the success of the program.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 142,
                "text": "MRSA"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 324,
                "text": "beta-Trcp"
            }
        },
        {
            "context": "Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 157,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "A Korean family with the Muenke syndrome. The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members.",
            "question": "Which gene is associated with Muenke syndrome?",
            "answers": {
                "answer_start": 244,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "Widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protracted clinical course. Hallervorden-Spatz syndrome (HSS) is a rare autosomal recessive disorder clinically characterized by extrapyramidal signs and progressive dementia. In a typical case, the clinical symptoms become apparent during late childhood, and usually the course is protracted over a decade or more. We recently had an opportunity to study the brains of two cases of HSS with a clinical course of over 30 years. Case 1 was a 44-year-old female and case 2 was a 37-year-old male. Grossly, the brains showed severe fronto-temporal lobar atrophy with abundant spheroids and mild iron deposits in the globus pallidus, associated with features of motor neuron disease. In addition, there was diffuse sponginess in the atrophic cortex as well as widespread Alzheimer's neurofibrillary tangles (NFTs) and Lewy bodies (LBs) in the cortical and subcortical regions, including the spinal cord. Ultrastructurally, NFTs were composed of paired helical filaments, and LBs of central dense cores with radiating fibrils. Discrete immunostaining was demonstrated in NFTs and neuropil threads with various antibodies against phosphorylated tau, and in LBs with antibody against alpha-synuclein. In addition, diffuse, overlapping immunoreactivity of alpha-synuclein and phosphorylated tau was seen within the cytoplasm of many neurons. However, when LBs and NFTs coexisted within the same neurons, they were clearly segregated. The findings of our present cases as well as those reported in the literature may indicate that simultaneous and extensive occurrence of abnormal phosphorylation of tau and accumulation of alpha-synuclein may constitute cardinal pathological features of HSS with protracted clinical course.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 1279,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers. OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0-∞) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-∞ and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope β of the regression lines being slightly less than 1 (slope β for AUC0-∞: 0.94, 95% CI: 0.90 - 0.97; slope β for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 298,
                "text": "SGLT2"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyr"
            }
        },
        {
            "context": "Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells. The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellular model of regulated human frataxin overexpression. We identified, by differential display technique, the mitogen activated protein kinase kinase 4 mRNA down regulation in frataxin overexpressing cells. We studied the stress kinases pathway in this cellular model and in fibroblasts from FRDA patients. Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. Furthermore, exposure of FRDA fibroblasts to several forms of environmental stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand if this susceptibility results in cell death, we have investigated the involvement of caspases. A significantly higher activation of caspase-9 was observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling pathway. The role of frataxin in FRDA pathogenesis could be explained, at least in part, by this hyperactivity.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 156,
                "text": "frataxin"
            }
        },
        {
            "context": "Use of dialectical behavior therapy in borderline personality disorder: a view from residency. OBJECTIVE: The authors describe the use of dialectical behavior therapy (DBT) in treating borderline personality disorder during psychiatry residency, and assess the status of DBT education within psychiatry residencies in the United States. METHOD: The authors present a patient with borderline personality disorder treated by a resident using DBT, along with perspectives from the resident's supervisors. Additionally, self-report surveys inquiring about the attitudes and experiences of residency directors and PGY-4 residents regarding DBT were sent to program directors with available e-mail addresses on FREIDA online. RESULTS: The DBT method employed by the resident had to be modified to fit the constraints of a residency program. The patient in therapy had a tumultuous course, ultimately resulting in the discontinuation of treatment. Survey results suggested an underemphasis on the education and use of DBT during residency, though the strength of this conclusion is limited by the small proportion of surveys returned. CONCLUSIONS: Achieving the efficacy of DBT-based treatment of borderline personality disorder reported in the literature in the setting of a residency program is challenging. Greater exposure to DBT during residency may increase residents' skills in using the technique and the likelihood that they will use it after residency.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 39,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Depolarization induces downregulation of DNMT1 and DNMT3a in primary cortical cultures. DNA methylation in post-mitotic neurons is reported to serve a variety of functions from survival during development to the consolidation of memory. Of particular interest with regards neuronal functioning is the change in site-specific methylation of a variety of gene promoters in the context of neuronal depolarization and the coding of new information. We examined the expression of DNMT1 and DNMT3a, representative of a maintenance and de novo methyltransferase respectively, in response to in-vitro depolarization of cortical neurons, using standard techniques such as high potassium (KCl) or the sodium channel agonist veratridine. KCl and veratridine mediated depolarization caused a modest but significant and replicable reduction in the mRNA and protein expression of both DNMTs that was time and dose dependent. These effects were supported by parallel increases in the mRNA expression of BDNF exon-1 and exon-4 as a typical response of neurons to depolarization and to rule out the possibility of impaired transcriptional activity as a trivial explanation. In addition to effects on mRNA and protein expression, functional DNA methyltransferase activity was reduced in nuclear protein extracts from cells exposed to a depolarization condition. Also, these changes could not be explained by differential neuronal loss as measured by cell viability cytochemistry. Our results support the idea that a reduction in DNA methyltransferase activity in the activated and depolarized neuron could contribute to the enhanced intensity and multiplicity of gene expression frequently reported.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 475,
                "text": "DNMT1"
            }
        },
        {
            "context": "Novel Abl kinase inhibitors in chronic myeloid leukemia in blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia. Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib being the first and most successful of these. Resistance to imatinib results in some patients from Abl kinase point mutations. Overcoming imatinib resistance represents one of the biggest challenges facing clinicians in the modern management of CML. In this review, we discuss the current understanding of CML pathophysiology and mechanisms of imatinib resistance and how advancing this knowledge has led to the design of novel therapies in the area of blastic phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia with previous imatinib failure.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 343,
                "text": "bcr-abl"
            }
        },
        {
            "context": "Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development. BACKGROUND: zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies. MATERIALS AND METHODS: We identified a patient with Mowat-Wilson syndrome who also developed cholestasis and histopathologic features consistent with biliary atresia, suggesting that mutations involving zfhz1b may lead to biliary developmental anomalies or injury to the biliary tract. We used the zebrafish model system to determine whether zfhx1b has a role in vertebrate biliary development. RESULTS: Using zebrafish we determined that zfhx1b was expressed in the developing liver during biliary growth and remodeling, and that morpholino antisense oligonucleotide-mediated knockdown of zfhx1b led to defects in biliary development. These findings were associated with decreased expression of vhnf1, a transcription factor known to be important in biliary development in zebrafish and in mammals. CONCLUSIONS: Our studies underscore the importance of genetic contributions in the etiology of infantile hepatobiliary disorders, including biliary atresia.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 676,
                "text": "zfhx1b"
            }
        },
        {
            "context": "Valbenazine granted breakthrough drug status for treating tardive dyskinesia. The chronic use and high dosing of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics predispose patients to the onset of tardive syndromes. One particular subtype, tardive dyskinesia, is characterized by rapid, repetitive, stereotypic, involuntary movements of the face, limbs or trunk. The inhibition of the vesicular monoamine transporter system, using tetrabenazine therapy, improves the severity of tardive dyskinesia. But there are also drawbacks to tetrabenazine treatment, such as a fluctuating response and the need for frequent intake due to its rapid metabolism. Clinical research on the potentially more efficacious and easier to use tetrabenazine analogs is already under way. One of them is valbenazine, the purified parent drug of the (+)-α-isomer of tetrabenazine. The FDA lowered approval hurdles for valbenazine due to a successful Phase II trial, which showed a distinctive improvement in tardive dyskinesia symptoms during valbenazine administration. This resurgence in the clinical research of tardive syndrome therapy is most welcome. This author notes that the putative long-term side effects of valbenazine should carefully be investigated in the future via naturalistic observational trials. Furthermore, valbenazine may also support the onset of symptoms, such as Parkinsonism and depression, with chronic administration, as it, to a certain extent, shares the mode of action of tetrabenazine.",
            "question": "What is the indication for valbenazine?",
            "answers": {
                "answer_start": 0,
                "text": "Valbenazine granted breakthrough drug status for treating tardive dyskinesia."
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 0,
                "text": "LARVA"
            }
        },
        {
            "context": "The Gcn5 bromodomain co-ordinates nucleosome remodelling. The access of transcription factors to eukaryotic promoters often requires modification of their chromatin structure, which is accomplished by the action of two general classes of multiprotein complexes. One class contains histone acetyltransferases (HATs), such as Gcn5 in the SAGA complex, which acetylate nucleosomal histones. The second class contains ATPases, such as Swi2 in the Swi/Snf complex, which provide the energy for nucleosome remodelling. In several promoters these two complexes cooperate but their functional linkage is unknown. A protein module that is present in all nuclear HATs, the bromodomain, could provide such a link. The recently reported in vitro binding of a HAT bromodomain with acetylated lysines within H3 and H4 amino-terminal peptides indicates that this interaction may constitute a targeting step for events that follow histone acetylation. Here we use a suitable promoter to show that bromodomain residues essential for acetyl-lysine binding are not required in vivo for Gcn5-mediated histone acetylation but are fundamental for the subsequent Swi2-dependent nucleosome remodelling and consequent transcriptional activation. We show that the Gcn5 bromodomain stabilizes the Swi/Snf complex on this promoter.",
            "question": "What histone modification is recognized by the bromodomain?",
            "answers": {
                "answer_start": 768,
                "text": "acetylated lysines"
            }
        },
        {
            "context": "The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Ten years after Fire and Melo's Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.",
            "question": "In November 2017,  in what phase  was  the clinical trial for the drug SYL040012?",
            "answers": {
                "answer_start": 790,
                "text": "phase 3"
            }
        },
        {
            "context": "Analysis of the genetic distribution among members of Clostridium botulinum group I using a novel multilocus sequence typing (MLST) assay. Clostridium botulinum is the etiological agent of botulism. Due to food-borne poisoning and the potential use of the extremely toxic botulinum neurotoxin (BoNT) from C. botulinum in bioterror or biocrime related actions, reliable high resolution typing methods for discriminating C. botulinum strains are needed. Partial sequencing of the adk, atpH, gyrB, proC, rpoD and spo0A genes from 51 various C. botulinum/sporogenes isolates was performed, resulting in 37 different sequence types (STs). Analysis of the sequence data revealed a genetic distribution in five larger clusters with a loose correlation to the BoNT serotypes. The developed MLST assay had a slightly lower resolution ability when compared to the MLVA (multilocus variable number of tandem repeat analysis), but the two methods resulted in similar subclusters of the strains possessing the BoNT serotypes A, B and F. The current work presents the development of a novel MLST assay useful for genotyping C. botulinum related to basic phylogenetic research and trace-back analysis in microbial forensic studies.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 139,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "JTV-519, a novel cardioprotective agent, improves the contractile recovery after ischaemia-reperfusion in coronary perfused guinea-pig ventricular muscles. A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective. However, the precise mechanism underlying the cardioprotective effect of this drug is unknown. Coronary-perfused guinea-pig ventricular muscles were subjected to 20-min no-flow ischaemia followed by 60-min reperfusion (I/R). I/R significantly decreased the contraction in untreated preparations (control group, 34+/-4% of baseline value, n=6). Brief administration of JT (1.0 microM) prior to ischaemia significantly improved the postischaemic contractile recovery (63+/-5% of baseline value, n=4), as compared to the control group. JT (1.0 microM) slightly prolonged action potential duration before ischaemia and induced conduction disturbance (2 : 1 block) after the initiation of ischaemia. The cardioprotective effect of JT was antagonized by chelerythrine (CH, 5.0 microM), an inhibitor of protein kinase C (PKC) or by 5-hydroxydecanoic acid (5-HD, 400 microM), an inhibitor of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. These results suggest that the protective effect of JT is due to the opening of mitochondrial K(ATP) channels, which, in turn, is linked to PKC activation.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 176,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "A selective inhibitor of Na+/Ca2+ exchanger, SEA0400, preserves cardiac function and high-energy phosphates against ischemia/reperfusion injury. The Ca2+ overload by Ca2+ influx via Na+/Ca2+ exchanger (NCX) is a critical mechanism in myocardial ischemia/reperfusion injury. We investigated protective effects of a novel selective inhibitor of NCX, SEA0400, on cardiac function and energy metabolism during ischemia and reperfusion. Langendorff-perfused rat hearts were exposed to 35 minutes global ischemia and 40 minutes reperfusion. Using 31P nuclear magnetic resonance spectroscopy, cardiac phosphocreatine (PCr), ATP, and pHi were monitored. SEA0400 did not change the basic cardiac function, but improved the recovery of left ventricular developed pressure (LVDP) after reperfusion (27.6 +/- 4.9 mm Hg in control, 101.2 +/- 19.3 mm Hg in 0.1 microM, and 115.5 +/- 13.3 mm Hg in 1 microM SEA0400, means +/- SE, n = 6, P < 0.05). SEA0400 reduced left ventricular end-diastolic pressure and increased coronary flow after reperfusion. SEA0400 improved the recoveries of cardiac phosphocreatine and ATP after reperfusion, but did not affect pHi. There were significant linear correlations between left ventricular developed pressure and cardiac phosphocreatine (r = 0.79, P < 0.05), and left ventricular developed pressure and ATP (r = 0.80, P < 0.05). However, SEA0400 increased the incidence and duration of reperfusion ventricular arrhythmias. SEA0400 added only after reperfusion also improved both the contractile function and energy metabolism. It is concluded that the selective inhibition of NCX may be effective to preserve high-energy phosphates and to improve cardiac function after reperfusion, but may not be able to prevent fatal arrhythmias.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 343,
                "text": "NCX"
            }
        },
        {
            "context": "Inhibition of calcium currents and exocytosis by Lambert-Eaton syndrome antibodies in human lung cancer cells. 1. Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired. Whole-cell patch-clamp techniques were used to study the voltage-dependent Ca2+ channels expressed by H146 SCLC cells and the effects of LES antibodies on these channels. The types of Ca2+ channels were determined using biophysical properties and pharmacological sensitivity to several antagonists. 2. Whole-cell Ca2+ currents (ICa) in SCLC cells are sensitive to the dihydropyridine (DHP) nicardipine, omega-conotoxin GVIA (omega-CgTX GVIA) and omega-agatoxin IVA (omega-AgTX IVA). Nicardipine at 100 nM and 10 microM reduced ICa by 35 and 45% (n = 38 cells), respectively, while omega-CgTX GVIA (1 microM) inhibited ICa by 32% (n = 31). Application of omega-AgTX IVA at 50 and 100 nM to the cancer cells decreased ICa by 41 and 42%, respectively (n = 22). 3. Measurement of cell membrane capacitance (Cm) revealed that Ca(2+)-dependent exocytosis underlies the secretory activity of SCLC cells. Exocytosis, when induced by step depolarizing pulses and measured by increases in Cm, was markedly inhibited by nicardipine (10 microM) and omega-AgTX IVA (100 nM). In contrast, omega-CgTX GVIA (1 microM) was not as effective in altering increases in Cm. 4. From negative (-80 mV) and depolarized (-40 mV) holding potentials, both peak and plateau ICa were inhibited by the presence of LES antibodies (1 mg ml-1 IgG). LES serum also reduced depolarization-induced increases in Cm by 48% (n = 15). 5. To determine whether the LES antibodies are downregulating a specific type(s) of Ca2+ channel, nicardipine (10 microM), omega-CgTX GVIA (1 microM) or omega-AgTX IVA (100 nM) was applied to tumour cells that had been previously exposed to LES serum for 24 h. The most pronounced change was that omega-AgTX IVA was 38-84% less effective at reducing ICa after the IgG treatment. The effectiveness of nicardipine was diminished by 18% after incubation with the LES antibodies, whereas the omega-CgTX GVIA was seen to be more effective. These results suggest that LES IgG downregulates P-type Ca2+ channels and, possibly, to a lesser extent L-type channels. 6. In view of recent evidence that P-type Ca2+ channels mediate cholinergic transmitter release at the mammalian neuromuscular junction (NMJ), the expression of P-type Ca2+ channels in the SCLC cells and the reactivity of LES IgG with these channels support the hypothesis that P-type Ca2+ channels in these cancer cells may trigger the autoantibody production in this disorder. The antibodies so produced are implicated in the functional impairment of the Ca2+ channels characteristic of LES.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 120,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "The SF-36 Offers a Strong Measure of Mental Health Symptoms in Survivors of Acute Respiratory Failure. A Tri-National Analysis. RATIONALE: Survivors of acute respiratory failure commonly experience long-term psychological sequelae and impaired quality of life. For researchers interested in general mental health, using multiple condition-specific instruments may be unnecessary and inefficient when using the Medical Outcomes Study Short Form (SF)-36, a recommended outcome measure, may suffice. However, relationships between the SF-36 scores and commonly used measures of psychological symptoms in acute survivors of respiratory failure are unknown. OBJECTIVES: Our objective is to examine the relationship of the SF-36 mental health domain (MH) and mental health component summary (MCS) scores with symptoms of depression, anxiety, and post-traumatic stress disorder (PTSD) evaluated using validated psychological instruments. METHODS: We conducted a cross-sectional analysis of 1,229 participants at 6- and 12-month follow-up assessment using data from five studies from the United States, the United Kingdom, and Australia. MEASUREMENTS AND MAIN RESULTS: Symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), Depression Anxiety Stress Scales, the Davidson Trauma Scale, Impact of Event Scale (IES), and IES-Revised (IES-R). At 6-month assessment there were moderate to strong correlations of the SF-36 MH scores with HADS depression and anxiety symptoms (r = -0.74 and -0.79) and with IES-R PTSD symptoms (r = -0.60) in the pooled analyses. Using the normalized population mean of 50 on the SF-36 MH domain score as a cut-off, positive predictive values were 16 and 55% for substantial depression; 20 and 68% for substantial anxiety (Depression Anxiety Stress Scales and HADS, respectively); and 40, 44, and 67% for substantial PTSD symptoms (IES-R, IES, and Davidson Trauma Scale, respectively). Negative predictive values were high. The area under the receiver operating characteristics curve of the SF-36 MH score was high for depression, anxiety, and PTSD symptoms (0.88, 0.91, and 0.84, respectively). All results were consistent for the MCS, across the individual studies, and for the 12-month assessment. CONCLUSIONS: For researchers interested in general mental health status, the SF-36 MH or MCS offers a strong measure of psychological symptoms prevalent among survivors of acute respiratory failure. For researchers interested in specific conditions, validated psychological instruments should be considered.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 1859,
                "text": "PTSD"
            }
        },
        {
            "context": "Topoisomerase II regulates yeast genes with singular chromatin architectures. Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIα interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIβ regulates developmental genes in conjunction with chromatin remodeling and heterochromatin transitions. Here we show that in budding yeast, topo II regulates the expression of specific gene subsets. To uncover this, we carried out a genomic transcription run-on shortly after the thermal inactivation of topo II. We identified a modest number of genes not involved in the general stress response but strictly dependent on topo II. These genes present distinctive functional and structural traits in comparison with the genome average. Yeast topo II is a positive regulator of genes with well-defined promoter architecture that associates to chromatin remodeling complexes; it is a negative regulator of genes extremely hypo-acetylated with complex promoters and undefined nucleosome positioning, many of which are involved in polyamine transport. These findings indicate that yeast topo II operates on singular chromatin architectures to activate or repress DNA transcription and that this activity produces functional responses to ensure chromatin stability.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 89,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Human monoamine oxidase gene (MAOA): chromosome position (Xp21-p11) and DNA polymorphism. An essentially full-length cDNA clone for the human enzyme monoamine oxidase type A (MAO-A) has been used to determine the chromosomal location of a gene encoding it. This enzyme is important in the degradative metabolism of biogenic amines throughout the body and is located in the outer mitochondrial membrane of many cell types. Southern blot analysis of PstI-digested human DNA revealed multiple fragments that hybridized to this probe. Using rodent-human somatic cell hybrids containing all or part of the human X chromosome, we have mapped these fragments to the region Xp21-p11. A restriction fragment length polymorphism (RFLP) for this MAOA gene was identified and used to evaluate linkage distances between this locus and several other loci on Xp. The MAOA locus lies between DXS14 and OTC, about 29 cM from the former.",
            "question": "Which is the chromosomal location of the gene MAOA?",
            "answers": {
                "answer_start": 58,
                "text": "Xp21-p11"
            }
        },
        {
            "context": "SeqArray-a storage-efficient high-performance data format for WGS variant calls. Motivation: Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Results: Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. Availability and Implementation: http://www.bioconductor.org/packages/SeqArray. Contact: zhengx@u.washington.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm has been proposed for efficient storage of WGS variant calls?",
            "answers": {
                "answer_start": 0,
                "text": "SeqArray"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 438,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend. Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 633,
                "text": "PLN"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 223,
                "text": "NCX"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 1600,
                "text": "Malaria"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 794,
                "text": "telomerase"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 103,
                "text": "MRSA"
            }
        },
        {
            "context": "European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 359,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 757,
                "text": "53BP1"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 778,
                "text": "LARVA"
            }
        },
        {
            "context": "Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged > 18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 171,
                "text": "poly(ADP-ribose) polymerase"
            }
        },
        {
            "context": "Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich ataxia. Friedreich ataxia is a human neurodegenerative and myocardial disease caused by decreased expression of the mitochondrial protein frataxin. Proteomic analysis of the mutant yeast model of Friedreich ataxia presented in this paper reveals that these cells display increased amounts of proteins involved in antioxidant defenses, including manganese-superoxide dismutase. This enzyme shows, however, lower activity than that found in wild type cells. Our results indicate that this lack of activity is a consequence of cellular manganese deficiency, because in manganese-supplemented cultures, cell manganese content, and manganese-superoxide dismutase activity were restored. One of the hallmarks of Friedreich ataxia is the decreased activity of iron/sulfur-containing enzymes. The activities of four enzymes of this group (aconitase, glutamate synthase, succinate dehydrogenase, and isopropylmalate dehydratase) have been analyzed for the effects of manganese supplementation. Enzyme activities were recovered by manganese treatment, except for aconitase, for which, a specific interaction with frataxin has been demonstrated previously. Similar results were obtained when cells were grown in iron-limited media suggesting that manganese-superoxide dismutase deficiency is a consequence of iron overload. In conclusion, these data indicate that generalized deficiency of iron-sulfur protein activity could be a consequence of manganese-superoxide dismutase deficiency, and consequently, it opens new strategies for Friedreich ataxia treatment.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 237,
                "text": "frataxin"
            }
        },
        {
            "context": "Rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) in diverse clinical specimens by the BD GeneOhm MRSA assay and comparison with culture. The efficacy of the BD GeneOhm methicillin-resistant Staphylococcus aureus (MRSA) assay was assessed by analyzing nasal swabs and swabs from other body sites for the presence of MRSA in a low-prevalence area. From 681 patients with a high risk for MRSA carriage, 1,601 specimens were collected and transported in Amies agar. After discordant analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of the BD GeneOhm MRSA assay were 84.3%, 99.2%, 88.4%, and 98.9%, respectively, compared to culture.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 64,
                "text": "MRSA"
            }
        },
        {
            "context": "The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes. Nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase (JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured astrocytes. In view of the previous observation that NO stimulates the activity of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 685,
                "text": "NCX"
            }
        },
        {
            "context": "Leptin attenuates lipopolysaccharide-induced apoptosis of thymocytes partially via down-regulation of cPLA2 and p38 MAPK activation. Leptin, a 16-kDa protein that is mainly secreted by adipocytes, plays a protective role in many cell types. It has been shown that leptin acts in the central and peripheral immune system to protect thymocytes. Cytosolic phospholipase A(2) (cPLA(2)) is an enzyme that can specifically initiate the release of arachidonic acid (AA) to produce eicosanoids, which regulate inflammation and immune responses. Our previous work has shown that leptin is important to prevent apoptosis of thymocytes. However, the role of cPLA(2) is still unclear, and the precise mechanism also remains to be elucidated. In this work, we demonstrated that leptin inhibited the LPS-induced toxicity and apoptosis of thymocytes. Western blot and RT-PCR showed that leptin led to a reduction of cPLA(2) activity and mRNA level, as well as caspase-3 cleavage. Moreover, we found that leptin could decrease the activation of p38 MAPK. Accordingly, we pre-treated apoptotic thymocytes with the p38 MAPK inhibitor, SB203580 and observed an effect similar to the leptin alone treated group. SB203580 also suppressed expression of cPLA(2) and cleavage of caspase-3. Based on these results, we suggest that leptin could attenuate LPS-induced apoptotic injury in mouse thymocyte cells, mainly through the p38/cPLA(2) signalling pathway. The study of the regulatory role of leptin in LPS-induced thymocyte apoptosis can help to explain the role of leptin in the immune system and may provide a novel treatment option in cases of severe trauma, infection, shock, organ failure and autoimmune disease caused by thymic atrophy.",
            "question": "From which cell type is leptin secreted?",
            "answers": {
                "answer_start": 185,
                "text": "adipocytes"
            }
        },
        {
            "context": "The DnaJ-related factor Mrj interacts with nuclear factor of activated T cells c3 and mediates transcriptional repression through class II histone deacetylase recruitment. The calcium-regulated protein phosphatase calcineurin (PP2B) functions as a regulator of gene expression in diverse tissues through the dephosphorylation and activation of a family of transcription factors known as nuclear factor of activated T cells (NFAT). Here we show that NFATc3, in addition to being calcium responsive, is regulated through an indirect recruitment of class II histone deacetylases (HDACs). Specifically, yeast two-hybrid screening with the rel homology domain of NFATc3 identified the chaperone mammalian relative of DnaJ (Mrj) as a specific interacting factor. Mrj and NFATc3 were shown to directly associate with one another in mammalian cells and in vitro. Mrj served as a potent inhibitor of NFAT transcriptional activity within the nucleus through a mechanism involving histone deacetylase recruitment in conjunction with heat shock stimulation. Indeed, Mrj was determined to interact with class II histone deacetylases, each of which translocated to the nucleus following heat shock stimulation. Mrj also decreased NFATc3 occupancy of the tumor necrosis factor-alpha promoter in cardiomyocytes in an HDAC-dependent manner, and Mrj blocked calcineurin-induced cardiomyocyte hypertrophic growth. Conversely, small-interfering-RNA-mediated reduction of Mrj augmented NFAT transcriptional activity and spontaneously induced cardiac myocyte growth. Collectively, our results define a novel response pathway whereby NFATc3 is negatively regulated by class II histone deacetylases through the DnaJ (heat shock protein-40) superfamily member Mrj.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 214,
                "text": "calcineurin"
            }
        },
        {
            "context": "A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence. Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells were also activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 121,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Early onset HER2-positive breast cancer is associated with germline TP53 mutations. BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 17,
                "text": "positive"
            }
        },
        {
            "context": "Disease progression and treatment responses in a prospective DMARD-naive seropositive early rheumatoid arthritis cohort: does gender matter? OBJECTIVE: To assess gender differences in disease characteristics and treatment responses over time in a disease-modifying antirheumatic drug (DMARD)-naive seropositive early rheumatoid arthritis (RA) cohort. METHODS: Patients with polyarticular disease who were DMARD-naive and had seropositive early RA (< 14 months) were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using chi-squared, Mann-Whitney U, and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation was significantly influenced by gender. RESULTS: At baseline, men (n = 67) and women (n = 225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year followup, as assessed by trends in Disease Activity Score 28/erythrocyte sedimentation rate (DAS28-ESR4), physician global scores, and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28-ESR4 scores (p = 0.009), although not independently associated with disease activity. Self-reported measures (Health Assessment Questionnaire-Disability Index, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission. CONCLUSION: At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 2029,
                "text": "women"
            }
        },
        {
            "context": "Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up. Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 693,
                "text": "IgG4"
            }
        },
        {
            "context": "The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.",
            "question": "How is OCT3 associated with serotonin?",
            "answers": {
                "answer_start": 367,
                "text": "serotonin clearance"
            }
        },
        {
            "context": "Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome. PURPOSE OF REVIEW: A major challenge for understanding neurodevelopmental disorders, including autism spectrum disorders (ASDs), is to advance the findings from gene discovery to an exposition of neurobiological mechanisms that underlie these disorders and subsequently translate this knowledge into mechanism-based therapeutics. A promising way to proceed is revealed by the recent studies of rare subsets of ASDs. In this review, we summarize the latest advances in the mechanisms and emerging therapeutics for a rare single-gene ASD, Rett syndrome. RECENT FINDINGS: Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Although MeCP2 has diverse functions, examination of MeCP2 mutant mice suggests the hypothesis that MeCP2 deficiency leads to aberrant maturation and maintenance of synapses and circuits in multiple brain systems. Some of the deficits arise from alterations in specific intracellular pathways such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially rescued in MeCP2 mutant mice by treatment with therapeutic agents. SUMMARY: Mechanism-based therapeutics are emerging for single-gene neurodevelopmental disorders such as Rett syndrome. Given the complexity of MeCP2 function, future directions include combination therapeutics that target multiple molecules and pathways. Such approaches will likely be applicable to other ASDs as well.",
            "question": "Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2?",
            "answers": {
                "answer_start": 666,
                "text": "Rett syndrome"
            }
        },
        {
            "context": "PU.1 positively regulates GATA-1 expression in mast cells. Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1(-/-) fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages.",
            "question": "Which gene controls the expression of GATA-1 isoforms?",
            "answers": {
                "answer_start": 977,
                "text": "PU.1"
            }
        },
        {
            "context": "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs \"facing\" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.",
            "question": "What is the preferred orientation of CTCF binding sites for chromatin looping?",
            "answers": {
                "answer_start": 787,
                "text": "convergent"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 433,
                "text": "xa"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyrosinase"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1620,
                "text": "XK"
            }
        },
        {
            "context": "The evolutionary chromosome translocation 4;19 in Gorilla gorilla is associated with microduplication of the chromosome fragment syntenic to sequences surrounding the human proximal CMT1A-REP. Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 634,
                "text": "chromosome 2"
            }
        },
        {
            "context": "HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia. Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 189,
                "text": "neural crest cells"
            }
        },
        {
            "context": "Bazex syndrome: acrokeratosis paraneoplastica. The focus of this article is acrokeratosis paraneoplastica, one of two disorders that have acquired the eponym Bazex syndrome. To date, all of the patients reported in the literature have had an underlying neoplasm, most commonly squamous cell carcinoma of the upper aerodigestive tract. In this review of 113 cases of acrokeratosis paraneoplastica (mean age, 61 years; 105 males, 8 females), the psoriasiform lesions preceded the diagnosis of the associated malignancy in 73 (67%) of 109 patients, whereas the cutaneous manifestations followed the diagnosis of the neoplasm in only 16 (15%) of 109; in the remainder, the onset of the skin lesions and the diagnosis of the tumor occurred simultaneously. Therefore, awareness of the cutaneous signs of Bazex syndrome is of obvious importance to dermatologists. Evidence in favor of the paraneoplastic nature of this disease is as follows: in 81 (93%) of 87 patients with adequate clinical descriptions, the skin lesions either improved significantly (or resolved) when the underlying neoplasm was treated or they remained unchanged in the setting of persistent disease. Occasionally, the reappearance of skin lesions has signaled a recurrence of the tumor.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 0,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "To screen or not to screen for methicillin-resistant Staphylococcus aureus. There are few more compelling questions in clinical microbiology today than the issue of whether or not to screen for the presence of methicillin-resistant Staphylococcus aureus (MRSA), with the results being used to institute infection control interventions aimed at preventing transmission of MRSA in health care environments. Numerous different matters must be addressed when considering a screening program. Who is to be screened, what method is to be employed to detect MRSA, and what sites should be sampled? When and how often should the screening be performed? Who is going to pay for the screening, and, finally and perhaps most importantly, how are screening results to be communicated to health care providers and what kind of interventions are best undertaken based on the results? Numerous governmental agencies have mandated MRSA screening programs, and yet several authorities in infection control organizations have questioned the appropriateness of mandated screening. In this Point-Counterpoint feature, Dr. Lance Peterson of Evanston Hospital (Evanston, IL) offers his perspective on why screening for MRSA is to be encouraged. Dr. Daniel Diekema of the University of Iowa Carver College of Medicine (Iowa City, IA) offers an opposing view.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 371,
                "text": "MRSA"
            }
        },
        {
            "context": "Poly(A) tail length is controlled by the nuclear poly(A)-binding protein regulating the interaction between poly(A) polymerase and the cleavage and polyadenylation specificity factor. Poly(A) tails of mRNAs are synthesized in the cell nucleus with a defined length, approximately 250 nucleotides in mammalian cells. The same type of length control is seen in an in vitro polyadenylation system reconstituted from three proteins: poly(A) polymerase, cleavage and polyadenylation specificity factor (CPSF), and the nuclear poly(A)-binding protein (PABPN1). CPSF, binding the polyadenylation signal AAUAAA, and PABPN1, binding the growing poly(A) tail, cooperatively stimulate poly(A) polymerase such that a complete poly(A) tail is synthesized in one processive event, which terminates at a length of approximately 250 nucleotides. We report that PABPN1 is required to restrict CPSF binding to the AAUAAA sequence and to permit the stimulation of poly(A) polymerase by AAUAAA-bound CPSF to be maintained throughout the elongation reaction. The stimulation by CPSF is disrupted when the poly(A) tail has reached a length of approximately 250 nucleotides, and this terminates processive elongation. PABPN1 measures the length of the tail and is responsible for disrupting the CPSF-poly(A) polymerase interaction.",
            "question": "Which is the RNA sequence of the canonical polyadenylation signal?",
            "answers": {
                "answer_start": 596,
                "text": "AAUAAA"
            }
        },
        {
            "context": "New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome. The authors report a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, \"coarse\" face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high (>50 microU/ml; normal value 0.2-4 microU/ml), while serum free T(3) (FT3) and free T(4) (FT4) levels were normal (FT3 3.6 pg/ml, normal value 2.8-5.6 pg/ml; FT4 11.6 pg/ml, normal value 6.6-14 pg/ml); antithyroid autoantibodies were absent. Thyroid scintigraphy with sodium 99m Tc pertechnetate showed a small ectopic thyroid located in sublingual position, so treatment with L-thyroxine 37.5 microg/24 hr was started with rapid improvement of the clinical picture. At 17 months of age the patient developed the complete characteristic phenotype of Williams syndrome (WS); the clinical diagnosis was proven by fluorescent in situ hybridization (FISH) analysis which showed hemizygous deletion of the elastin gene on chromosome 7. Recently a case of thyroid hemiagenesis in a child with WS has been reported; our patient underscores the association of hypothyroidism and WS. Moreover, our case shows that clinical manifestations of hypothyroidism may be present and the treatment may be necessary as it is in isolated congenital hypothyroidism.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1295,
                "text": "thyroid"
            }
        },
        {
            "context": "Phthiriasis palpebrarum misdiagnosed as allergic blepharoconjunctivitis in a 6-year-old girl. Phthiriasis palpebrarum is an infestation of the eyelashes caused by the louse Pthirus pubis (Linnaeus, 1758). We report a case of phthiriasis palpebrarum in a 6-year-old girl, which was initially misdiagnosed as allergic blepharoconjunctivitis. Parasites and their nits were found adhering to the eyelashes and eyelids of her right eye as well as scalp hairs. No abnormality was found in the left eye. The histopathology exam revealed the presence of adults and eggs of Pthirus pubis. We mechanically removed all the eyelashes of the right eye at their base, with lice and nits. The scalp was shaved and washed with phenothrin shampoo. No recurrence was found during 3 months of follow-up. Removal of the eyelashes, cutting of scalp hairs, and phenothrin shampoo may be effective in treating phthiriasis palpebrarum. In cases of blepharoconjunctivitis, eyelids and eyelashes should be carefully examined by slit lamp to avoid misdiagnosis.",
            "question": "What is the cause of Phthiriasis Palpebrarum?",
            "answers": {
                "answer_start": 173,
                "text": "Pthirus pubis"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Transcriptional regulator PRDM12 is essential for human pain perception. Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.",
            "question": "What is the phenotype of people carrying mutations in the gene PRDM12?",
            "answers": {
                "answer_start": 620,
                "text": "CIP"
            }
        },
        {
            "context": "No aberrant methylation of neurofibromatosis 1 gene (NF1) promoter in pilocytic astrocytoma in childhood. Tumors of the central nervous system are the most frequent solid tumors in childhood. With 30-40% of this heterogenous group, low-grade astrocytomas represent the most common subtype. Neurofibromatosis type 1 (NF1) is strongly associated with the development of pilocytic astrocytoma (PA), frequently appearing as optic glioma. Neurofibromatosis 1 gene (NF1 ) fulfills the criteria of a tumor suppressor gene and is deleted or mutated heterozygously in patients with NF1. This suggests an involvement in the development of PA. To clarify whether silencing of NF1 by promoter methylation plays a role in PA and especially in optic glioma, the authors investigated the methylation status in 30 PA, 6 of which had optic glioma. However, no methylation was found at the NF1 promoter region in PA. To rule out that silencing of NF1 by promoter methylation is restricted to higher-grade astrocytomas, 15 pediatric WHO II degree and IV degree astrocytomas were analyzed: 12 astrocytomas II and 3 glioblastomas displayed no NF1 promoter methylation. The authors conclude that NF1 silencing by methylation plays no role in low-grade astrocytoma.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 460,
                "text": "NF1"
            }
        },
        {
            "context": "Stable carbon isotopes and the study of prehistoric human diet. Mass spectrometric analysis of the stable carbon isotope composition (13C/12C or delta 13C) of bone collagen from human remains recovered at archaeological sites provides a direct chemical method for investigating dietary patterns of prehistoric human populations. This methodology is based on the facts that (1) different food items within the human diet have distinct delta 13C values, and (2) the delta 13C value of human bone collagen is determined by the delta 13C value of the diet. Studies of the development of subsistence patterns based on corn agriculture, one of the most significant developments in North American prehistory, can benefit from the use of stable carbon isotope techniques because corn has a high delta 13C value relative to other components of the human diet. Measurements of delta 13C of bone collagen from prehistoric human skeletal remains from southeastern Missouri and northeastern Arkansas indicate that intensive corn agriculture began in this region around A.D. 1000, that the incorporation of corn into the human diet was a rapid phenomenon, and that 35 to 77% of the human diet from A.D. 1000 to A.D. 1600 consisted of corn. Results from an isochronous population in southeastern South Dakota (A.D. 1400) suggest that 78 to 90% of the diet of this group consisted of corn, with no difference between males and females. Coupled with more traditional archaeological methods, stable carbon isotope analysis of bone collagen can significantly enhance reconstruction of dietary patterns of prehistoric humans.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 1513,
                "text": "collagen"
            }
        },
        {
            "context": "Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate. Oxidative stress activates the c-Jun N-terminal kinase (JNK) pathway. However, the exact mechanisms by which reactive oxygen species (ROS) activate JNK are unclear. We found that the ability of hydrogen peroxide (H(2)O(2)) to induce JNK activation varied in different cell types. Pyrrolidine dithiocarbamate (PDTC), a presumed antioxidant, induced JNK activation on its own and enhanced JNK activation by H(2)O(2) in many cell types, including Jurkat, HEK293, and LNCaP and Tsu-Pr1 prostate cancer cells. The activation of JNK by PDTC, in the presence or absence of exogenous H(2)O(2), was dependent on its chelating ability to metal ions, most likely copper ions. Despite the strong JNK-activating ability, H(2)O(2) plus PDTC did not induce significant activation of the upstream kinases, SEK1/MKK4 and MKK7. However, the JNK inactivation rate was slower in cells treated with H(2)O(2) plus PDTC compared with the rate in cells treated with ultraviolet C (UV-C). Treatment of H(2)O(2) plus PDTC significantly decreased the expression levels of a JNK phosphatase, M3/6 (also named hVH-5), but not the levels of other phosphatases (PP2A and PP4). In contrast, UV-C irradiation did not cause the down-regulation of M3/6. These results suggest that JNK activation by H(2)O(2) plus PDTC resulted from the down-regulation of JNK phosphatases. Our data also reveal a necessity to carefully evaluate the pharmacological and biochemical properties of PDTC.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 1392,
                "text": "JNK"
            }
        },
        {
            "context": "A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China. BACKGROUND: The mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. METHODS: Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. RESULTS: A novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. CONCLUSION: This study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 136,
                "text": "tyr"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 1005,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Stepwise histone replacement by SWR1 requires dual activation with histone H2A.Z and canonical nucleosome. Histone variant H2A.Z-containing nucleosomes are incorporated at most eukaryotic promoters. This incorporation is mediated by the conserved SWR1 complex, which replaces histone H2A in canonical nucleosomes with H2A.Z in an ATP-dependent manner. Here, we show that promoter-proximal nucleosomes are highly heterogeneous for H2A.Z in Saccharomyces cerevisiae, with substantial representation of nucleosomes containing one, two, or zero H2A.Z molecules. SWR1-catalyzed H2A.Z replacement in vitro occurs in a stepwise and unidirectional fashion, one H2A.Z-H2B dimer at a time, producing heterotypic nucleosomes as intermediates and homotypic H2A.Z nucleosomes as end products. The ATPase activity of SWR1 is specifically stimulated by H2A-containing nucleosomes without ensuing histone H2A eviction. Remarkably, further addition of free H2A.Z-H2B dimer leads to hyperstimulation of ATPase activity, eviction of nucleosomal H2A-H2B, and deposition of H2A.Z-H2B. These results suggest that the combination of H2A-containing nucleosome and free H2A.Z-H2B dimer acting as both effector and substrate for SWR1 governs the specificity and outcome of the replacement reaction.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 247,
                "text": "SWR1"
            }
        },
        {
            "context": "Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab-A Case Report. INTRODUCTION: Idarucizumab is a reversal agent for dabigatran etexilate. By reversing the anticoagulating effect of dabigatran etexilate with idarucizumab (Praxbind), patients presenting with an acute ischemic stroke can now be eligible for thrombolysis. PATIENT: We describe our experience with idarucizumab in a 71-year-old male patient pretreated with dabigatran etexilate. The patient arrived with a hemiparesis, central facial palsy, and dysarthria. METHOD: Dabigatran etexilate was antagonized with idarucizumab, approximately 2.5 hours after the patient's last dose. Immediately after the infusion of idarucizumab, the patient received thrombolytic therapy. RESULTS: The hemiparesis and the central facial palsy were fully remitted 3 days after the onset of symptoms, and the dysarthria was remitted 2 days afterwards. DISCUSSION: Non-vitamin K oral anticoagulants (NOACs) are widely used for the prevention of embolic stroke in patients with atrial fibrillation. Dabigatran etexilate is an oral thrombin inhibitor that can be reversed by idarucizumab. Idarucizumab, a monoclonal antibody fragment, directly binds dabigatran etexilate and neutralizes its activity. CONCLUSION: Reversal of dabigatran etexilate using idarucizumab was safe and successful with no recombinant tissue plasminogen activator interactions.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1237,
                "text": "dabigatran"
            }
        },
        {
            "context": "Spermidine protects against α-synuclein neurotoxicity. As our society ages, neurodegenerative disorders like Parkinson`s disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human α-synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued α-synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.",
            "question": "What is the association of spermidine with α-synuclein neurotoxicity?",
            "answers": {
                "answer_start": 0,
                "text": "Spermidine protects against α-synuclein neurotoxicity"
            }
        },
        {
            "context": "Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study. OBJECTIVE: The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. BACKGROUND: Triptans are effective acute anti-migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene-related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300-mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12-lead ambulatory electrocardiographic (Holter) monitoring was performed. RESULTS: Twenty-eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment-related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. CONCLUSIONS: Two doses of 300-mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 425,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Assessing manganese efflux using SEA0400 and cardiac T1-mapping manganese-enhanced MRI in a murine model. The sodium-calcium exchanger (NCX) is one of the transporters contributing to the control of intracellular calcium (Ca(2+)) concentration by normally mediating net Ca(2+) efflux. However, the reverse mode of the NCX can cause intracellular Ca(2+) concentration overload, which exacerbates the myocardial tissue injury resulting from ischemia. Although the NCX inhibitor SEA0400 has been shown to therapeutically reduce myocardial injury, no in vivo technique exists to monitor intracellular Ca(2+) fluctuations produced by this drug. Cardiac manganese-enhanced MRI (MEMRI) may indirectly assess Ca(2+) efflux by estimating changes in manganese (Mn(2+)) content in vivo, since Mn(2+) has been suggested as a surrogate marker for Ca(2+). This study used the MEMRI technique to examine the temporal features of cardiac Mn(2+) efflux by implementing a T(1)-mapping method and inhibiting the NCX with SEA0400. The change in (1)H(2)O longitudinal relaxation rate, Delta R(1), in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl(2)) in healthy adult male mice. The results showed 50% MEMRI signal attenuation at 3.4 +/- 0.6 h post-MnCl(2) infusion without drug intervention. Furthermore, treatment with 50 +/- 0.2 mg/kg of SEA0400 significantly reduced the rate of decrease in Delta R(1). At 4.9-5.9 h post-MnCl(2) infusion, the average Delta R(1) values for the two groups treated with SEA0400 were 2.46 +/- 0.29 and 1.72 +/- 0.24 s(-1) for 50 and 20 mg/kg doses, respectively, as compared to the value of 1.27 +/- 0.28 s(-1) for the control group. When this in vivo data were compared to ex vivo absolute manganese content data, the MEMRI T(1)-mapping technique was shown to effectively quantify Mn(2+) efflux rates in the myocardium. Therefore, combining an NCX inhibitor with MEMRI may be a useful technique for assessing Mn(2+) transport mechanisms and rates in vivo, which may reflect changes in Ca(2+) transport.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 462,
                "text": "NCX"
            }
        },
        {
            "context": "Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene. The Apert syndrome is characterized by craniosynostosis and syndactyly of hands and feet. Although most cases are sporadic, an autosomal dominant mode of inheritance is well documented. Two mutations in the FGFR2 gene (Ser252Trp and Pro253Arg) account for most of the cases. We report a patient with a rare form of Apert syndrome with polydactyly. The proposita has turribrachycephaly. complete syndactyly of 2nd to 5th digits (\"mitten hands\" and cutaneous fusion of all toes). The X-rays revealed craniosynostosis of the coronal suture and preaxial polydactyly of hands and feet with distal bony fusion. Molecular analysis found a C755G transversion (Ser252Trp) in the FGFR2 gene. Only eight patients with Apert syndrome and preaxial polydactyly have been reported and this is the first case in which molecular diagnosis is available. On the basis of the molecular findings in this patient, polydactyly should be considered part of the spectrum of abnormalities in the Apert syndrome. This assertion would establish the need for a new molecular classification of the acrocephalopolysyndactylies.",
            "question": "What is the inheritance pattern of Apert syndrome?",
            "answers": {
                "answer_start": 226,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Different mechanisms may generate sustained hypertonic and rhythmic bursting muscle activity in idiopathic dystonia. Despite that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favored intervention for patients with medically intractable dystonia, the pathophysiological mechanisms of dystonia are largely unclear. In eight patients with primary dystonia who were treated with bilateral chronic pallidal stimulation, we correlated symptom-related electromyogram (EMG) activity of the most affected muscles with the local field potentials (LFPs) recorded from the globus pallidus electrodes. In 5 dystonic patients with mobile involuntary movements, rhythmic EMG bursts in the contralateral muscles were coherent with the oscillations in the pallidal LFPs at the burst frequency. In contrast, no significant coherence was seen between EMG and LFPs either for the sustained activity separated out from the compound EMGs in those 5 cases, or in the EMGs in 3 other cases without mobile involuntary movements and rhythmic EMG bursts. In comparison with the resting condition, in both active and passive movements, significant modulation in the GPi LFPs was seen in the range of 8-16 Hz. The finding of significant coherence between GPi oscillations and rhythmic EMG bursts but not sustained tonic EMG activity suggests that the synchronized pallidal activity may be directly related to the rhythmic involuntary movements. In contrast, the sustained hypertonic muscle activity may be represented by less synchronized activity in the pallidum. Thus, the pallidum may play different roles in generating different components of the dystonic symptom complex.",
            "question": "Neurostimulation of which nucleus is used for treatment of dystonia?",
            "answers": {
                "answer_start": 166,
                "text": "globus pallidus internus"
            }
        },
        {
            "context": "Unifying the definitions of sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy (SUDEP) is a category of death in people with epilepsy occurring in the absence of a known structural cause of death and is most likely heterogeneous with regard to mechanisms and circumstances. SUDEP is particularly difficult to investigate in research studies for several reasons, including its relatively low incidence, its unpredictable occurrence often in unwitnessed settings, and its low rate of complete autopsy examinations. Over the past two decades, two complementary definitions have been used in most SUDEP studies, but often with variations. We propose here a unified SUDEP definition and classification to resolve current ambiguities and to retrieve cases that would not have been further studied if the previous definitions were used. The proposed Unified SUDEP Definition and Classification contains, in addition to concepts inherent in the previous definitions, nine main recommendations. (1) The word \"unexpected,\" and not the word \"unexplained,\" should be uniformly used in the term SUDEP. (2) The SUDEP category should be applied when appropriate, whether or not a terminal seizure is known to have occurred. (3) The \"Possible SUDEP\" category should be used only for cases with competing causes of death, with cases left unclassified when data are insufficient to reasonably permit their classification. (4) Cases that would otherwise fulfill the definition of SUDEP should be designated as \"SUDEP Plus\" when evidence indicates that a preexisting condition, known before or after autopsy, could have contributed to the death, which otherwise is classified as SUDEP (e.g., coronary insufficiency with no evidence of myocardial infarction or long-QT syndrome with no documented primary ventricular arrhythmia leading to death). (5) To be considered SUDEP, the death should have occurred within 1 h from the onset of a known terminal event. (6) For status epilepticus as an exclusion criterion for SUDEP, the duration of seizure activity should be 30 min or more. (7) A specific category of SUDEP due to asphyxia should not be designated, the distinction being largely impractical on circumstantial or autopsy evidence, with more than one mechanism likely to be contributory in many cases. (8) Death occurring in water but without circumstantial or autopsy evidence of submersion should be classified as \"Possible SUDEP.\" If any evidence of submersion is present, the death should not be classified as SUDEP. (9) A category of \"Near-SUDEP\" should be agreed to include cases in which cardiorespiratory arrest was reversed by resuscitation efforts with subsequent survival for more than 1 h. Scenarios that demonstrate the basis for each SUDEP category are described. If disagreement exists about which category fits a particular case, we suggest the use of consensus decision by a panel of informed reviewers to adjudicate the classification of the case.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 65,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 178,
                "text": "TFIIS"
            }
        },
        {
            "context": "A spontaneous novel XK gene mutation in a patient with McLeod syndrome. A 29-year-old man with a history of elevated creatine kinase and necrotizing myopathy was reviewed. Prominent red cell acanthocytosis in association with reduced Kell antigen expression was present, findings consistent with the McLeod syndrome. Investigation of the patient's XK gene revealed a novel TGG- to-TAG transition at position 1023 in exon 3. This point mutation creates an in-frame stop codon (W314X), and predicts a truncated XK protein of 313 amino acids, compared with 444 amino acids in the normal XK protein. The mutation was not identified in the patient's mother or sister indicating that this mutation was spontaneous.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 348,
                "text": "XK"
            }
        },
        {
            "context": "A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke. INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence. METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance. RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2). CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 251,
                "text": "Acute ischemic stroke"
            }
        },
        {
            "context": "CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes. The CRISPR-Cas (clustered regularly interspaced short palindromic repeats, CRISPR-associated genes) is an adaptive immunity system in bacteria and archaea that functions via a distinct self-non-self recognition mechanism that is partially analogous to the mechanism of eukaryotic RNA interference (RNAi). The CRISPR-Cas system incorporates fragments of virus or plasmid DNA into the CRISPR repeat cassettes and employs the processed transcripts of these spacers as guide RNAs to cleave the cognate foreign DNA or RNA. The Cas proteins, however, are not homologous to the proteins involved in RNAi and comprise numerous, highly diverged families. The majority of the Cas proteins contain diverse variants of the RNA recognition motif (RRM), a widespread RNA-binding domain. Despite the fast evolution that is typical of the cas genes, the presence of diverse versions of the RRM in most Cas proteins provides for a simple scenario for the evolution of the three distinct types of CRISPR-cas systems. In addition to several proteins that are directly implicated in the immune response, the cas genes encode a variety of proteins that are homologous to prokaryotic toxins that typically possess nuclease activity. The predicted toxins associated with CRISPR-Cas systems include the essential Cas2 protein, proteins of COG1517 that, in addition to a ligand-binding domain and a helix-turn-helix domain, typically contain different nuclease domains and several other predicted nucleases. The tight association of the CRISPR-Cas immunity systems with predicted toxins that, upon activation, would induce dormancy or cell death suggests that adaptive immunity and dormancy/suicide response are functionally coupled. Such coupling could manifest in the persistence state being induced and potentially providing conditions for more effective action of the immune system or in cell death being triggered when immunity fails.",
            "question": "Gene silencing can be achieved by RNA interference (RNAi) in eukaryotic organisms. What is the name of the analogous process in prokaryotic organisms?",
            "answers": {
                "answer_start": 83,
                "text": "CRISPR-Cas"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1467,
                "text": "Nox1"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 817,
                "text": "MethPed"
            }
        },
        {
            "context": "Two cases of Sotos syndrome with novel mutations of the NSD1 gene. Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome. Fluorescent in situ hybridization analysis (FISH), MLPA or multiplex quantitative PCR allow detection of total/partial NSD1 deletions and direct sequencing allows detection of NSD1 mutations. We describe two boys with Sotos syndrome in whom PCR amplification and direct sequencing of the NSD1 gene identified two novel mutations not previously described: c.4736dupG in exon 12 and c.3938_3939insT in exon 7. In addition to the cardinal and major features of the syndrome (abnormal facial appearance, overgrowth, cardiac anomalies, renal anomalies, hypotonia, neonatal jaundice, seizures and brain MRI abnormalities) in both patients, one boy also had cryptorchidism and vertebral anomalies, features considered not common. Despite the wide range of possible combinations of phenotypic features, molecular analysis can correctly identify Sotos syndrome.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 56,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 527,
                "text": "7"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "External Validation of Three Prediction Tools for Patients at Risk of a Complicated Course of Clostridium difficile Infection: Disappointing in an Outbreak Setting. OBJECTIVE Estimating the risk of a complicated course of Clostridium difficile infection (CDI) might help doctors guide treatment. We aimed to validate 3 published prediction models: Hensgens (2014), Na (2015), and Welfare (2011). METHODS The validation cohort comprised 148 patients diagnosed with CDI between May 2013 and March 2014. During this period, 70 endemic cases of CDI occurred as well as 78 cases of CDI related to an outbreak of C. difficile ribotype 027. Model calibration and discrimination were assessed for the 3 prediction rules. RESULTS A complicated course (ie, death, colectomy, or ICU admission due to CDI) was observed in 31 patients (21%), and 23 patients (16%) died within 30 days of CDI diagnosis. The performance of all 3 prediction models was poor when applied to the total validation cohort with an estimated area under the curve (AUC) of 0.68 for the Hensgens model, 0.54 for the Na model, and 0.61 for the Welfare model. For those patients diagnosed with CDI due to non-outbreak strains, the prediction model developed by Hensgens performed the best, with an AUC of 0.78. CONCLUSION All 3 prediction models performed poorly when using our total cohort, which included CDI cases from an outbreak as well as endemic cases. The prediction model of Hensgens performed relatively well for patients diagnosed with CDI due to non-outbreak strains, and this model may be useful in endemic settings. Infect Control Hosp Epidemiol 2017;38:897-905.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 620,
                "text": "ribotype 027"
            }
        },
        {
            "context": "Selexipag for the treatment of pulmonary arterial hypertension. INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 279,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Base excision repair and nucleotide excision repair contribute to the removal of N-methylpurines from active genes. Many different cellular pathways have evolved to protect the genome from the deleterious effects of DNA damage that result from exposure to chemical and physical agents. Among these is a process called transcription-coupled repair (TCR) that catalyzes the removal of DNA lesions from the transcribed strand of expressed genes, often resulting in a preferential bias of damage clearance from this strand relative to its non-transcribed counterpart. Lesions subject to this type of repair include cyclobutane pyrimidine dimers that are normally repaired by nucleotide excision repair (NER) and thymine glycols (TGs) that are removed primarily by base excision repair (BER). While the mechanism underlying TCR is not completely clear, it is known that its facilitation requires proteins used by other repair pathways like NER. It is also believed that the signal for TCR is the stalled RNA polymerase that results when DNA damage prevents its translocation during transcription elongation. While there is a clear role for some NER proteins in TCR, the involvement of BER proteins is less clear. To explore this further, we studied the removal of 7-methylguanine (7MeG) and 3-methyladenine (3MeA) from the dihydrofolate reductase (dhfr) gene of murine cell lines that vary in their repair phenotypes. 7MeG and 3MeA constitute the two principal N-methylpurines formed in DNA following exposure to methylating agents. In mammalian cells, alkyladenine DNA alkyladenine glycosylase (Aag) is the major enzyme required for the repair of these lesions via BER, and their removal from the total genome is quite rapid. There is no observable TCR of these lesions in specific genes in DNA repair proficient cells; however, it is possible that the rapid repair of these adducts by BER masks any TCR. The repair of 3MeA and 7MeG was examined in cells lacking Aag, NER, or both Aag and NER to determine if rapid overall repair masks TCR. The results show that both 3MeA and 7MeG are removed without strand bias from the dhfr gene of BER deficient (Aag deficient) and NER deficient murine cell lines. Furthermore, repair of 3MeA in this region is highly dependent on Aag, but repair of 7MeG is equally efficient in the repair proficient, BER deficient, and NER deficient cell lines. Strikingly, in the absence of both BER and NER, neither 7MeG nor 3MeA is repaired. These results demonstrate that NER, but not TCR, contributes to the repair of 7MeG, and to a lesser extent 3MeA.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 400,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 931,
                "text": "factor Xa"
            }
        },
        {
            "context": "Daratumumab granted breakthrough drug status. Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 586,
                "text": "CD38"
            }
        },
        {
            "context": "alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse \"cloud-like\" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 131,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Treatment of Phthiriasis Palpebrarum and Crab Louse: Petrolatum Jelly and 1% Permethrin Shampoo. Phthiriasis palpebrarum is an uncommon cause of blepharoconjunctivitis in which Pthirus pubis infest the eyelashes. We report a case of unilateral phthiriasis palpebrarum with crab louse. A 45-year-old man presented with conjunctival hyperaemia and moderate itching associated with irritation, and crusty excretions of the eyelashes in the left eye. Careful slit-lamp examination revealed many lice and nits in left eye and mild conjunctival hyperaemia. No abnormality was found in the right eye. On dermatologic examination, only one louse was found at the pubic area. The patient was treated effectively with petrolatum jelly (Vaseline) and 1% permethrin shampoo (Kwellada 1% shampoo). At the end of the first week no louse or nit was present on eyelashes and pubic area.",
            "question": "What is the cause of Phthiriasis Palpebrarum?",
            "answers": {
                "answer_start": 177,
                "text": "Pthirus pubis"
            }
        },
        {
            "context": "Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family? AIM: to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. METHODS: this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. RESULTS: during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. CONCLUSION: the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 99,
                "text": "MRSA"
            }
        },
        {
            "context": "The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review. INTRODUCTION: Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. AREAS COVERED: SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1481,
                "text": "xa"
            }
        },
        {
            "context": "Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6. Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5' splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.",
            "question": "Which gene is associated with the Mitchell-Riley syndrome?",
            "answers": {
                "answer_start": 192,
                "text": "RFX6"
            }
        },
        {
            "context": "RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex. Compelling evidence indicates that the CRISPR-Cas system protects prokaryotes from viruses and other potential genome invaders. This adaptive prokaryotic immune system arises from the clustered regularly interspaced short palindromic repeats (CRISPRs) found in prokaryotic genomes, which harbor short invader-derived sequences, and the CRISPR-associated (Cas) protein-coding genes. Here, we have identified a CRISPR-Cas effector complex that is comprised of small invader-targeting RNAs from the CRISPR loci (termed prokaryotic silencing (psi)RNAs) and the RAMP module (or Cmr) Cas proteins. The psiRNA-Cmr protein complexes cleave complementary target RNAs at a fixed distance from the 3' end of the integral psiRNAs. In Pyrococcus furiosus, psiRNAs occur in two size forms that share a common 5' sequence tag but have distinct 3' ends that direct cleavage of a given target RNA at two distinct sites. Our results indicate that prokaryotes possess a unique RNA silencing system that functions by homology-dependent cleavage of invader RNAs.",
            "question": "Gene silencing can be achieved by RNA interference (RNAi) in eukaryotic organisms. What is the name of the analogous process in prokaryotic organisms?",
            "answers": {
                "answer_start": 100,
                "text": "CRISPR-Cas"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 363,
                "text": "stroke"
            }
        },
        {
            "context": "Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series. Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 315,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "The development of dasatinib as a treatment for chronic myeloid leukemia (CML): from initial studies to application in newly diagnosed patients. PURPOSE: Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI) designed as a prototypic short-acting BCR-ABL-targeted TKI that inhibits BCR-ABL with greater potency compared with imatinib, nilotinib, bosutinib, and ponatinib and has been shown to have potential immunomodulatory effects. Dasatinib is approved for the treatment of all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to prior imatinib treatment and first-line treatment for CML in chronic phase. In this article, the development of dasatinib as a treatment for patients with CML is reviewed. METHODS: This is a review of the relevant literature regarding dasatinib development in CML (2003-2013). RESULTS: Dasatinib demonstrates efficacy against most BCR-ABL mutations arising during imatinib therapy and is effective in treating patients with imatinib resistance due to other mechanisms. Randomized trial data show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. Dasatinib has a generally acceptable safety profile, with most adverse events (AEs) proving manageable and reversible. Cytopenias are commonly observed with dasatinib, and some nonhematologic AEs including pleural effusion have been consistently reported. CONCLUSION: Dasatinib is an effective treatment option for patients with CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 287,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. Patients with Tietz syndrome have congenital profound deafness and generalised hypopigmentation, inherited in a fully penetrant autosomal dominant fashion. The pigmentary features and complete penetrance make this syndrome distinct among syndromes with pigmentary anomalies and deafness, which characteristically have patchy depigmentation and variable penetrance. Only one family has been reported with the exact features described in the original report of this syndrome. This family was reascertained and a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome. Mutations in other regions of this gene have been found to produce Waardenburg syndrome type 2 (WS2), which also includes pigmentary changes and hearing loss, but in contrast to Tietz syndrome, depigmentation is patchy and hearing loss is variable in WS2.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 636,
                "text": "MITF"
            }
        },
        {
            "context": "In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first 'outside to in' signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of interleukin 17 (IL-17) and interferon γ production and proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA animal model using SCID mice implanted with synovium and cartilage from patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice and also reduced synovial inflammation and invasion into the implanted cartilage. A phase 2 double-blind study using tofacitinib was carried out in Japanese patients with active RA and inadequate response to methotrexate (MTX). A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1668,
                "text": "tofacitinib"
            }
        },
        {
            "context": "TYK2 activity promotes ligand-induced IFNAR1 proteolysis. The type I IFNR (interferon receptor) is a heterodimer composed of two transmembrane chains, IFNAR1 (interferon-alpha receptor 1 subunit) and IFNAR2, which are associated with the tyrosine kinases Tyk2 and Jak1 (Janus kinase 1) respectively. Ligand-induced down-regulation of the type I IFNR is a major mechanism of negative regulation of cellular signalling and involves the internalization and lysosomal degradation of IFNAR1. IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. The non-catalytic role of Tyk2 in sustaining the steady-state IFNAR1 level at the plasma membrane is well documented; however, little is known about the function of Tyk2 in the steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to ligand binding. In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 598,
                "text": "beta-TrCP"
            }
        },
        {
            "context": "Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. The human dopamine transporter (DAT1) gene is localized to chromosome 5p15.3 by in situ hybridization and PCR amplification of rodent somatic cell hybrid DNA. Analysis of a 40-bp repeat in the 3' untranslated region of the message revealed variable numbers of the repeat ranging from 3 to 11 copies. These results will aid in the investigation of a role for this gene in genetic disorders of the dopaminergic system in humans.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 58,
                "text": "5p15.3"
            }
        },
        {
            "context": "Altered composition and secretion of lysosome-derived compartments in Dictyostelium AP-3 mutant cells. Genetic alteration of the adaptor protein (AP)-3 complex is responsible for the type 2 Hermansky-Pudlak syndrome, a lysosomal storage disease similar to the Chediak-Higashi syndrome (CHS). AP-3 presumably participates in the biogenesis of late endosomal compartments and may also be critical for the regulated secretion of lysosomes by specialized cells. Here, Dictyostelium discoideum cells defective for the mu3 subunit of the AP-3 complex were used and their phenotype analyzed. In mu3 mutant cells, endosomal maturation and lysosome secretion were markedly slower than that in wild-type cells. This phenotype is similar to that reported previously in lvsB mutant cells where the ortholog of the LYST gene, involved in CHS, is mutated. Detailed analysis revealed however significant differences between these two isogenic mutant cells: in lvsB mutant cells, the primary defect is an inefficient biogenesis of otherwise normal secretory lysosomes, while in mu3 mutant cells, the biogenesis and also the composition and the fusion properties of secretory lysosomes are affected. These results suggest that in D. discoideum, AP-3 controls both the efficiency and the specificity of postlysosome maturation, which represent two critical elements in the control of lysosome secretion.",
            "question": "Which mutated gene causes the Chédiak–Higashi Syndrome?",
            "answers": {
                "answer_start": 802,
                "text": "LYST gene"
            }
        },
        {
            "context": "Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [(3)H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [(3)H]S107 per RyR1 tetramer with EC(50) ∼52 µM and Hillslope ∼2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 µM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 532,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 2123,
                "text": "fungi"
            }
        },
        {
            "context": "Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 864,
                "text": "Xa"
            }
        },
        {
            "context": "A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. BACKGROUND: Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase. METHODS: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions. RESULTS: A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P=0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P=0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P=0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%). CONCLUSIONS: Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression. (Funded by Geron; ClinicalTrials.gov number, NCT01731951.).",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 338,
                "text": "telomerase"
            }
        },
        {
            "context": "Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. This article discusses the infection control and public health measures taken whilst managing a case of laboratory-confirmed rabies, and the challenges faced in implementing these measures. Case management requires intensive multi-disciplinary co-ordination. The Milwaukee protocol, which to date has five reported human rabies survivors associated with its use, has been suggested as a potential management pathway for human rabies. Consensus among hospital and public health clinicians would aid future deployment of this approach in selected cases.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 549,
                "text": "rabies"
            }
        },
        {
            "context": "Two-site interaction of nuclear factor of activated T cells with activated calcineurin. Transcription factors belonging to the nuclear factor of activated T cells (NFAT) family regulate the expression of cytokine genes and other inducible genes during the immune response. The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin. Here we show that the binding of calcineurin to NFAT is substantially increased when calcineurin is activated with calmodulin and calcium. FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of NFAT with activated calcineurin much more effectively than they inhibited the interaction with inactive calcineurin, suggesting that part of the interaction with activated calcineurin involved the enzyme active site. We have previously shown that NFAT is targeted to inactive calcineurin at a region distinct from the calcineurin active site (Aramburu, J., Garcia-Cozar, F. J., Raghavan, A., Okamura, H., Rao, A., and Hogan, P. G. (1998) Mol. Cell 1, 627-637); this region is also involved in NFAT binding to activated calcineurin, since binding is inhibited by an NFAT peptide spanning the calcineurin docking site on NFAT. The interacting surfaces are located on the catalytic domain of the calcineurin A chain and on an 86-amino acid fragment of the NFAT regulatory domain. NFAT binding to the calcineurin catalytic domain was inhibited by the calcineurin autoinhibitory domain and the RII substrate peptide, which bind in the calcineurin active site, as well as by the NFAT docking site peptide, which binds to a region of calcineurin distinct from the active site. We propose that, in resting cells, NFAT is targeted to a region of the calcineurin catalytic domain that does not overlap the calcineurin active site. Upon cell activation, displacement of the autoinhibitory domain by calmodulin binding allows NFAT to bind additionally to the calcineurin active site, thus positioning NFAT for immediate dephosphorylation at functional phosphoserine residues.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 381,
                "text": "calcineurin"
            }
        },
        {
            "context": "Inter-observer reproducibility of diagnosis of diabetic foot osteomyelitis based on a combination of probe-to-bone test and simple radiography. Probe-to-bone test and simple X-rays are both standard tests for the diagnosis of diabetic foot osteomyelitis. This study demonstrates the importance of considering jointly clinical information (probe-to-bone test) and diagnostic tests (simple radiography) to increase agreement among clinicians on diagnosis of diabetic foot osteomyelitis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 47,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "subSeq: determining appropriate sequencing depth through efficient read subsampling. MOTIVATION: Next-generation sequencing experiments, such as RNA-Seq, play an increasingly important role in biological research. One complication is that the power and accuracy of such experiments depend substantially on the number of reads sequenced, so it is important and challenging to determine the optimal read depth for an experiment or to verify whether one has adequate depth in an existing experiment. RESULTS: By randomly sampling lower depths from a sequencing experiment and determining where the saturation of power and accuracy occurs, one can determine what the most useful depth should be for future experiments, and furthermore, confirm whether an existing experiment had sufficient depth to justify its conclusions. We introduce the subSeq R package, which uses a novel efficient approach to perform this subsampling and to calculate informative metrics at each depth. AVAILABILITY AND IMPLEMENTATION: The subSeq R package is available at http://github.com/StoreyLab/subSeq/.",
            "question": "Which method for subsampling of NGS reads requires only gene counts?",
            "answers": {
                "answer_start": 0,
                "text": "subSeq"
            }
        },
        {
            "context": "Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 128,
                "text": "SGLT2"
            }
        },
        {
            "context": "c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 94,
                "text": "JNK"
            }
        },
        {
            "context": "Effects of BCR-ABL inhibitors on anti-tumor immunity. In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple in vitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on different immune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as important cellular components of anti-tumor immunity.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 89,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Non-transcribed strand repair revealed in quiescent cells. Stem cells, one of the progenitors of cancer, exist predominately in a quiescent state. Thus, understanding the mechanisms of DNA repair and mutagenesis in such arrested cells may help unravel the complex process of tumorigenesis. Two major nucleotide excision repair (NER) pathways are known to remove bulky physical or chemical lesions from DNA. Transcription-coupled repair (TCR) acts solely on the transcribed strand of expressed genes, while global genomic repair (GGR) is responsible for the ubiquitous repair of the genome. Indirectly, it has been shown that while TCR functions in quiescent cells GGR does not. To explicitly elucidate this phenomenon, we adapted a quantitative PCR (QPCR) assay to study UV-damage repair via TCR and GGR in quiescent and proliferating cells. We present evidence that repair of untranscribed silent regions of the genome and repair of the non-transcribed strand of active genes proceeds by two discrete mechanisms in quiescent cells; rather than by GGR, which was believed to encompass both. Thus, our findings suggest the existence of an alternate NER pathway in quiescent cells. The proposed subcategories of NER are as follows: (i) TCR, responsible for maintenance of transcribed strands; (ii) GGR, responsible for ubiquitous genome repair; and (iii) non-transcribed strand repair (NTSR), predominantly responsible for the repair of the NTS in arrested cells. In quiescent cells, it is evident that TCR and NTSR function and GGR are arrested. As a consequence, mutation accumulation at temporally silent genes and incomplete or imperfect repair of transcribed genes, in quiescent stem cells, may provide a source of cancer causing mutations.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 457,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "The cellular story of dishevelleds. Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVL-AXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer.",
            "question": "Which signaling pathway is activating the dishevelled proteins?",
            "answers": {
                "answer_start": 173,
                "text": "Wnt signaling"
            }
        },
        {
            "context": "Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 3625,
                "text": "malaria"
            }
        },
        {
            "context": "The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. PURPOSE: Imatinib mesylate is a tyrosine kinase inhibitor with high affinity for the BCR-ABL fusion protein expressed by the hematopoietic cells in chronic myelogenous leukemia (CML). Some patients with chronic-phase or accelerated-phase CML either relapse after an initial response or are refractory to imatinib, prompting us to evaluate the efficacy of dose increase in such patients. EXPERIMENTAL DESIGN: Twelve chronic-phase patients initially receiving 400 mg/day and 4 patients with accelerated phase initially receiving either 400 mg/day (two patients) or 600 mg/day (two patients) had their dose increased (14 to 800 mg/day and 2 to 600 mg/day) because of progressive disease (usually clonal evolution) or inadequate cytogenetic response after at least 1 year of therapy. RESULTS: Six patients had major cytogenetic responses after dose increase (3 complete and 3 partial). Two others had minor cytogenetic responses. Two patients with clonal evolution transiently lost the additional clonal aberrations. Almost all of the responses occurred within 6 months, and were typically 3-6 months in duration. However, 3 patients have continuing major cytogenetic responses of >18 months duration. Dose increase was well tolerated, with thrombocytopenia, mild leukopenia, and exacerbation of prior edema being the most common adverse events. CONCLUSIONS: Although increasing the dose of imatinib can benefit a subgroup of patients with CML with either an inadequate cytogenetic response or disease progression, our results suggest the majority will not have a sustained meaningful response, and that other options, such as allogeneic stem cell transplant or investigational therapies, also need to be considered at the time of dose increase.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 283,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study. BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.",
            "question": "Aleglitazar is agonist of which receptor?",
            "answers": {
                "answer_start": 524,
                "text": "peroxisome proliferator-activated receptor-α/γ"
            }
        },
        {
            "context": "The immunopathogenesis of chronic autoimmune thyroiditis one century after hashimoto. Hakaru Hashimoto described 4 patients with a hitherto unknown cause for goitre, struma lymphomatosa, a century ago. He was careful to distinguish this from Riedel thyroiditis but it has become clear that fibrosis and atrophy of the thyroid are indeed components of Hashimoto thyroiditis, and in rare cases IgG4-related sclerosing disease may be an outcome. Although the cause of the lymphocytic infiltration was unknown to Hashimoto, we now know through the pioneering studies of N.R. Rose and E. Witebsky [J Immunol 1956;76:417-427] that this condition is the archetype for autoimmune destruction as a disease mechanism. In the last two decades in particular, there has been huge interest in unravelling the genetic basis for this and related autoimmune disorders. The list of polymorphisms associated with autoimmune thyroid disease grows each year, and in the case of vitiligo, which is frequently found in association with thyroid autoimmunity, we know that 27 separate susceptibility loci account for less than 20% of the heritability of this condition. Environmental and existential factors may turn out to be just as complex in number and in interactions. We can thus imagine a 'Swiss cheese' model for the causation of autoimmune thyroid disease, in which the effects of cumulative weaknesses line up - like the holes in slices of cheese - to allow the catastrophic event of autoimmune destruction to occur.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 392,
                "text": "IgG4"
            }
        },
        {
            "context": "A human polymorphism of protein phosphatase-1 inhibitor-1 is associated with attenuated contractile response of cardiomyocytes to beta-adrenergic stimulation. Aberrant beta-adrenergic signaling and depressed calcium homeostasis, associated with an imbalance of protein kinase A and phosphatase-1 activities, are hallmarks of heart failure. Phosphatase-1 is restrained by its endogenous inhibitor, protein phosphatase inhibitor-1 (PPI-1). We assessed 352 normal subjects, along with 959 patients with heart failure and identified a polymorphism in PPI-1 (G147D) exclusively in black subjects. To determine whether the G147D variant could affect cardiac function, we infected adult cardiomyocytes with adenoviruses expressing D147 or wild-type (G147) PPI-1. Under basal conditions, there were no significant differences in fractional shortening or contraction or relaxation rates. However, the enhancement of contractile parameters after isoproterenol stimulation was significantly blunted in D147 compared with G147 and control myocytes. Similar findings were observed in calcium kinetics. The attenuated beta-agonist response was associated with decreased (50%) phosphorylation of phospholamban (PLN) at serine 16, whereas phosphorylation of troponin I and ryanodine receptor was unaltered. These findings suggest that the human G147D PPI-1 can attenuate responses of cardiomyocytes to beta-adrenergic agonists by decreasing PLN phosphorylation and therefore may contribute to deteriorated function in heart failure.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 430,
                "text": "PPI-1"
            }
        },
        {
            "context": "A novel RNA structural motif in the selenocysteine insertion element of eukaryotic selenoprotein mRNAs. In eukaryotes, co-translational insertion of selenocysteine into selenoproteins necessitates the participation of the selenocysteine insertion sequence (SECIS), an element lying in the 3'-untranslated region of selenoprotein mRNAs. We report a detailed experimental study of the secondary structures of the SECIS elements of three selenoprotein mRNAs, the rat and human type I iodothyronine deiodinase (5'DI) and rat glutathione peroxidase (GPx). Based on RNase and chemical probing, a new secondary structure model is established. It is characterized by a stem-loop structure, comprising two helices (I and II) separated by an internal loop, with an apical loop surmounting helix II. Sequence comparisons of 20 SECIS elements, arising from 2 5'DI, 13 GPx, 2 selenoprotein P, and 1 selenoprotein W mRNAs, confirm the secondary structure model. The most striking finding of the experimental study concerns a set of conserved sequences in helix II that interact to form a novel RNA structural motif consisting of a quartet composed of non-Watson-Crick base pairs 5'UGAY3': 5'UGAU3'. The potential for forming the quartet is preserved in 15 SECIS elements, but three consecutive non-Watson-Crick base pairs can nevertheless form in the other five SECIS, the central G.A tandem being invariant in all cases. A 3D model, derived by computer modeling with the use of the solution data, suggests that the base pairing interactions in the G.A tandem are of the type found in GNRA loops. The 3D model displays the quartet lying in an accessible position at the foot of helix II, which is bent at the internal loop, suggesting that the non-Watson-Crick base pair arrangement provides an unusual pattern of chemical groups for putative ligand interaction.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 411,
                "text": "SECIS"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 0,
                "text": "Chromosome XII"
            }
        },
        {
            "context": "Estrogen attenuates lipopolysaccharide-induced nitric oxide production in macrophages partially via the nongenomic pathway. Steroid hormones exert genotropic effects through members of the nuclear hormone receptor family. In the present study, we examined the effects of 17β-estradiol (E2) on nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation and investigated the mechanisms in mouse bone marrow-derived macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2 inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen, we found that the increase in NO production induced by LPS was also attenuated. In addition, the intracellular estrogen receptor blocker, ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated NO production capacity. E2 also attenuated the LPS activation of p38 mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB 203580, greatly reduced the LPS-induced NO production, and the remaining NO levels were no longer regulated by E2. Additionally, E2-BSA inhibited LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover, E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially antagonized by ICI 182780. Taken together, these results suggest that E2 has an inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects are mediated at least in part via a nongenomic pathway.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1107,
                "text": "JNK"
            }
        },
        {
            "context": "Second-generation tyrosine kinase inhibitors as therapy for chronic myeloid leukemia. Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a single genetic abnormality, characterized by a reciprocal translocation involving chromosomes 9 and 22 (the Philadelphia chromosome). The fusion gene that results (BCR-ABL) produces a constitutively activated tyrosine kinase that exists in different isoforms depending on BCR break-points. Imatinib mesylate is a highly selective inhibitor of this kinase, producing normal blood-counts in 98% of patients in chronic phase CML and disappearance of the Philadelphia chromosome in 86%. However, 17% of patients in the chronic phase will either relapse or develop resistance resulting mainly from one or more point mutations affecting at least 30 amino acids within the Abl kinase protein. This review focuses on the relevant biology of CML, imatinib mesylate resistance mechanisms, and the current status of the next generation of Bcr-Abl inhibitors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 336,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "RET mutation Tyr791Phe: the genetic cause of different diseases derived from neural crest. Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 111,
                "text": "RET"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 0,
                "text": "CAGEr"
            }
        },
        {
            "context": "Delamanid for multidrug-resistant pulmonary tuberculosis. BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 2253,
                "text": "tuberculosis"
            }
        },
        {
            "context": "The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 220,
                "text": "MC1R"
            }
        },
        {
            "context": "Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 789,
                "text": "p16Ink4"
            }
        },
        {
            "context": "Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. BACKGROUND & AIMS: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 303,
                "text": "liver"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 0,
                "text": "webSDA"
            }
        },
        {
            "context": "Disease Development Following Infection of Tomato and Basil Foliage by Airborne Conidia of the Soilborne Pathogens Fusarium oxysporum f. sp. radicis-lycopersici and F. oxysporum f. sp. basilici. ABSTRACT Fusarium oxysporum f. sp. radicis-lycopersici, the causal agent of Fusarium crown and root rot of tomato, and F. oxysporum f. sp. basilici, the causal agent of Fusarium wilt in basil, are soilborne pathogens capable of producing conspicuous masses of macroconidia along the stem. The role of the airborne propagules in the epidemics of the disease in tomato plants was studied. In the field, airborne propagules of F. oxysporum f. sp. radicis-lycopersici were trapped with a selective medium and their prevalence was determined. Plants grown in both covered and uncovered pots, detached from the field soil, and exposed to natural aerial inoculum developed typical symptoms (82 to 87% diseased plants). The distribution of inoculum in the growth medium in the pots also indicated the occurrence of foliage infection. In greenhouse, foliage and root inoculations were carried out with both tomato and basil and their respective pathogens. Temperature and duration of high relative humidity affected rate of colonization of tomato, but not of basil, by the respective pathogens. Disease incidence in foliage-inoculated plants reached 75 to 100%. In these plants, downward movement of the pathogens from the foliage to the crown and roots was observed. Wounding enhanced pathogen invasion and establishment in the foliage-inoculated plants. The sporulation of the two pathogens on stems, aerial dissemination, and foliage infection raise the need for foliage protection in addition to soil disinfestation, in the framework of an integrated disease management program.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 302,
                "text": "tomato"
            }
        },
        {
            "context": "Lack of prognostic significance of survivin in pediatric medulloblastoma. Medulloblastoma (MDB) is the most common malignant cerebellar tumor in children. Because of the significant rate of mortality and treatment-related morbidity, the identification of prognostic factors could lead to a more accurate selection of patients who can benefit from a less aggressive therapy and improve risk stratification. Survivin is an inhibitor of apoptosis protein (IAP), the expression of which has been associated with worse prognosis in MDB. However, both of its subcellular localizations may contribute to tumor progression, and ultimately, survivin subcellular localization prognostic value depends on tumor type biological features. The goal of this study was to analyze these survivin features in the pediatric MDB tumor samples and its impact on clinical outcome. Survivin expression and subcellular localization were accessed by immunohistochemistry in a series of 41 tumor samples. Kaplan-Meier survival curves were compared using the log-rank test. Survivin expression ranged from completely absent to fully present in a notably higher pattern of nuclear localization than cytoplasmic (19 of 41 versus 4 of 41, respectively). However, survivin expression and subcellular localization were not associated with five-year overall survival or metastasis status at diagnosis, which was the only statistically significant prognostic factor in our series (p = 0.008). Taken together, our results suggest that survivin expression should be further studied in large, multicenter series to determine its accurate impact on prognosis and pathobiology of pediatric MDB.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 74,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "Mepolizumab: 240563, anti-IL-5 monoclonal antibody - GlaxoSmithKline, anti-interleukin-5 monoclonal antibody - GlaxoSmithKline, SB 240563. Mepolizumab is an anti-interleukin-5 monoclonal antibody that is in clinical trials with GlaxoSmithKline (GSK) for the treatment of severe asthma, nasal polyposis and hypereosinophilic syndrome and eosinophilic oesophagitis (the latter two indications are classed as eosinophilia in the phase table). Interleukin-5 stimulates the production, activation and maturation of eosinophils. Since mepolizumab inhibits interleukin-5 and has a long terminal half-life, treatment with mepolizumab causes a sustained reduction in the numbers of circulating eosinophils. Thus, mepolizumab may be a useful therapeutic agent for the treatment of conditions characterized by increased levels of eosinophils. Hypereosinophilic syndrome is a rare idiopathic disease with broad clinical signs and symptoms that is diagnosed based on a persistent blood eosinophil count of >1500 cells, various end-organ damages (including skin, heart, lung, nervous system and digestive system), and with exclusion of known secondary causes of hypereosinophilia. Mepolizumab is in clinical trials for the treatment of hypereosinophilic syndrome, eosinophilc oesophagitis, severe asthma (in patients with airway eosinophilia) and nasal polyposis. GlaxoSmithKline (GSK) has completed enrolment in a phase II study of mepolizumab in 20 patients with symptomatic eosinophilic bronchitis with or without asthma in Canada. The randomized, double-blind, placebo-controlled study is evaluating the effects of intravenous mepolizumab on asthma control, airway eosinophilia and the degree to which concomitant corticosteroid treatment can be reduced (NCT00292877). In previous clinical studies, including trials in the EU and US, mepolizumab has shown a lack of effect on allergen-induced airway responses and inflammation despite a significant reduction in blood and sputum eosinophil levels.A randomized, double-blind, placebo-controlled, multicentre, phase III study of mepolizumab over 9 months in 85 patients with hypereosinophilic syndrome was completed in 2006. All patients have been offered, and continued in, a phase III, open-label, long-term extension study of mepolizumab. Enrolment in this study was completed in September 2006.A phase III, compassionate use trial of mepalizumab (NCT00244686) in patients with hypereosinophilic syndrome was ongoing in October 2007 in the US. Patients who have significant clinical disease but are unresponsive to traditional treatment and those who have demonstrated clinical benefit from previous anti-IL-5 treatment are eligible to take part in the trial. Mepolizumab received orphan drug status for first-line treatment in patients with hypereosinophilic syndrome in the US and the EU in 2004. Mepolizumab is also in phase I/II clinical development for the treatment of eosinophilic oesophagitis. A phase I/II trial (NCT00358449) began in August 2006 in the US, Australia, the UK and Canada, and will enrol approximately 72 paediatric patients with eosinophilic oesophagitis. The randomized, parallel-group clinical trial will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous mepolizumab for 12 weeks. In September 2006, GSK completed enrolment in a phase I/II study of mepolizumab for the treatment of eosinophilic oesophagitis in ten adult patients in Switzerland (NCT00274703). The randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of IV mepolizumab.A phase I/II trial of mepolizumab in four patients with eosinophilic oesophagitis conducted by Cincinnati Children's hospital found the monoclonal antibody was safe and effective. Brigham and Women's Hospital in association with GSK is conducting a phase I/II trial of mepolizumab in patients with Churg-Strauss Syndrome (CSS) in the US. The trial, which started in September 2007, will evaluate the potential of mepolizumab to reduce the need for corticosteroid therapy in patients with CSS (NCT00527566). CSS, otherwise known as allergic granulomatosis, is defined by patients with asthma, eosinophilia and vasculitis.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 162,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletions in exon 19 or point mutations that result in substitution of arginine for leucine at amino acid 858 (L858R). To study further the role of these mutations in the initiation and maintenance of lung cancer, we have developed transgenic mice that express an exon 19 deletion mutant (EGFR(DeltaL747-S752)) or the L858R mutant (EGFR(L858R)) in type II pneumocytes under the control of doxycycline. Expression of either EGFR mutant leads to the development of lung adenocarcinomas. Two weeks after induction with doxycycline, mice that express the EGFR(L858R) allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFR(DeltaL747-S752) develop multifocal tumors embedded in normal lung parenchyma with a longer latency. With mice carrying either EGFR allele, withdrawal of doxycycline (to reduce expression of the transgene) or treatment with erlotinib (to inhibit kinase activity) causes rapid tumor regression, as assessed by magnetic resonance imaging and histopathology, demonstrating that mutant EGFR is required for tumor maintenance. These models may be useful for developing improved therapies for patients with lung cancers bearing EGFR mutations.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 238,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "p73 plays a role in erythroid differentiation through GATA1 induction. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. Although TAp73alpha and -beta proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, DeltaNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or DeltaN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73alpha. Furthermore, TAp73alpha induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and DeltaNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 161,
                "text": "7"
            }
        },
        {
            "context": "Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. Heme oxygenase-1 (HO-1) protects cells from various insults including oxidative stress. Transcriptional activators, including the Nrf2/Maf heterodimer, have been the focus of studies on the inducible expression of ho-1. Here we show that a heme-binding factor, Bach1, is a critical physiological repressor of ho-1. Bach1 bound to the multiple Maf recognition elements (MAREs) of ho-1 enhancers with MafK in vitro and repressed their activity in vivo, while heme abrogated this repressor function of Bach1 by inhibiting its binding to the ho-1 enhancers. Gene targeting experiments in mice revealed that, in the absence of Bach1, ho-1 became expressed constitutively at high levels in various tissues under normal physiological conditions. By analyzing bach1/nrf2 compound-deficient mice, we documented antagonistic activities of Bach1 and Nrf2 in several tissues. Chromatin immunoprecipitation revealed that small Maf proteins participate in both repression and activation of ho-1. Thus, regulation of ho-1 involves a direct sensing of heme levels by Bach1 (by analogy to lac repressor sensitivity to lactose), generating a simple feedback loop whereby the substrate effects repressor-activator antagonism.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 372,
                "text": "repressor"
            }
        },
        {
            "context": "Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. STUDY OBJECTIVE: The literature suggests that the d -dimer is useful in patients suspected of having pulmonary embolism and who have a low pretest probability of disease. A previously defined clinical decision rule, the Wells Criteria, may provide a reliable and reproducible means of determining this pretest probability. We evaluate the interrater agreement and external validity of Wells Criteria in determining pretest probability in patients suspected of having pulmonary embolism. METHODS: This was a prospective observational study. Trained research assistants enrolled patients during 120 random 8-hour shifts. Patients who underwent imaging for pulmonary embolism after a medical history, physical examination, and chest radiograph were enrolled. Treating providers and research assistants determined pretest probability according to Wells Criteria in a blinded fashion. Two d -dimer assays were run. Three-month follow-up for the diagnosis of pulmonary embolism was performed. Interrater agreement tables were created. kappa Values, sensitivities, and specificities were determined. RESULTS: Of the 153 eligible patients, 3 patients were missed, 16 patients declined, and 134 (88%) patients were enrolled. Sixteen (12%) patients were diagnosed with pulmonary embolism. The kappa values for Wells Criteria were 0.54 and 0.72 for the trichotomized and dichotomized scorings, respectively. When Wells Criteria were trichotomized into low pretest probability (n=59, 44%), moderate pretest probability (n=61, 46%), or high pretest probability (n=14, 10%), the pulmonary embolism prevalence was 2%, 15%, and 43%, respectively. When Wells Criteria were dichotomized into pulmonary embolism-unlikely (n=88, 66%) or pulmonary embolism-likely (n=46, 34%), the prevalence was 3% and 28%, respectively. The immunoturbidimetric and rapid enzyme-linked immunosorbent assay d -dimer assays had similar sensitivities (94%) and specificities (45% versus 46%). CONCLUSION: Wells Criteria have a moderate to substantial interrater agreement and reliably risk stratify pretest probability in patients with suspected pulmonary embolism.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 86,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. PURPOSE: Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD. METHODS: We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria. RESULTS: Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days). CONCLUSION: These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 25,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 94,
                "text": "2"
            }
        },
        {
            "context": "p73 expression is regulated by RNPC1, a target of the p53 family, via mRNA stability. p73, a p53 family tumor suppressor, is expressed as TA and ΔN isoforms. Due to the role of p73 in tumor suppression and neural development, its expression and activity are tightly regulated by multiple mechanisms, including transcription and posttranslational modifications. Here, we found that p73 mRNA stability is regulated by RNPC1, an RNA binding protein and a target of the p53 family. We also showed that a CU-rich element in the 3' untranslated region of p73 is recognized by and responsive to RNPC1. To explore the physiological significance of RNPC1-regulated p73 expression, we showed that the loss of RNPC1 in p53-null mouse embryonic fibroblasts leads to reduced expression of p73, along with decreased expression of p21, p130, and γ-H2A.X, and consequently a decreased number of senescent cells. Furthermore, we observed that knockdown of TAp73 or p21, another target of RNPC1, attenuates the inhibitory effect of RNPC1 on cell proliferation and premature senescence, whereas combined knockdown of TAp73 and p21 completely abolishes it. Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 87,
                "text": "7"
            }
        },
        {
            "context": "Diverse molecular pattern in a bihemispheric glioblastoma (butterfly glioma) in a 16-year-old boy. Glioblastoma multiforme (GBM), the most common malignant brain tumor of adults, is relatively rare in children. In a GBM affecting a 16-year-old boy, the tumor spread across the corpus callosum (butterfly glioma). This type of bilateral hemispheric growth has previously been thought to result from spread along the white matter tracts. Two samples obtained from opposite sides of the same tumor were analyzed comprehensively for loss of heterozygosity (LOH) and microsatellite instability (MSI). Amplification of EGFR and MDM2 was studied by means of multiplex polymerase chain reaction. Exons 5, 6, 7, and 8 of TP53 were screened for mutations by sequencing. In neither specimen were molecular alterations found in the EGFR, MDM2, or TP53 genes. The specimen obtained from the right hemisphere exhibited a high level of MSI and LOH in chromosome arms 5q, 9p, and 13q. The specimen from the left hemisphere exhibited LOH in chromosome arms 3p, 5q, 9p, 9q, 10p, 10q, and 13q. Here we propose four plausible hypothetical scenarios underlying the tumorigenesis of this GBM.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 99,
                "text": "Glioblastoma multiforme"
            }
        },
        {
            "context": "Fam118B, a newly identified component of Cajal bodies, is required for Cajal body formation, snRNP biogenesis and cell viability. Cajal bodies are specialized and dynamic compartments in the nucleus that are involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs). Because of the dynamic and varied roles of Cajal bodies, it is of great interest to identify the components of Cajal bodies to better understand their functions. We performed a genome-wide screen to identify proteins that colocalize with coilin, the marker protein of Cajal bodies. In this study, we identified and characterized Fam118B as a newly discovered component of Cajal bodies. Fam118B is widely expressed in a variety of cell lines derived from various origins. Overexpression of Fam118B changes the canonical morphology of Cajal bodies, whereas depletion of Fam118B disrupts the localization of components of Cajal bodies, including coilin, the survival of motor neuron protein (SMN) and the Sm protein D1 (SmD1, also known as SNRPD1). Moreover, depletion of Fam118B reduces splicing capacity and inhibits cell proliferation. In addition, Fam118B associates with coilin and SMN proteins. Fam118B depletion reduces symmetric dimethylarginine modification of SmD1, which in turn diminishes the binding of SMN to this Sm protein. Taken together, these data indicate that Fam118B, by regulating SmD1 symmetric dimethylarginine modification, plays an important role in Cajal body formation, snRNP biogenesis and cell viability.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 519,
                "text": "coilin"
            }
        },
        {
            "context": "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy. RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase. SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1183,
                "text": "Xa"
            }
        },
        {
            "context": "Erythema multiforme-like lesions in the course of infectious mononucleosis. BACKGROUND: The rash in infectious mononucleosis is usually diffusely macular. MAIN OBSERVATIONS: A 15-year-old boy presented to us with high grade fever, sore throat, malaise, body aches, and polyarthralgia. He developed annular, erythematous, and non-scaly eruptions on chest and right arm. Blanching erythema was noted on his trunk. He had bilateral tender cervical lymph nodes, severe pharyngeal congestion, petechiae on soft palate, uvular edema, infraorbital edema, and marginal tender hepatomegaly. Investigations revealed lymphocytosis and activated atypical lymphocytes in the peripheral smear, and positive monospot test. The boy subsequently recovered in one week with total disappearance of his rash. Epstein-Barr virus-related infectious mononucleosis was considered the most likely diagnosis for our patient. CONCLUSIONS: To our knowledge, this atypical case is the third reported case of annular lesions in infectious mononucleosis. Dermatologists and other clinicians should be alerted to this special presentation of primary EBV infection.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 789,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "tyr"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 485,
                "text": "malaria"
            }
        },
        {
            "context": "Cytosine methylation: remaining faithful. DNA methyltransferase-1 (DNMT1) has a higher specific activity on hemimethylated DNA than on unmethylated DNA, but this preference is too small to explain the faithful mitotic inheritance of genomic methylation patterns. New genetic studies in plants and mammals have identified a novel factor that increases the fidelity of maintenance methylation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 67,
                "text": "DNMT1"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2234,
                "text": "stroke"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 1952,
                "text": "libFLASM"
            }
        },
        {
            "context": "New evidence on the relationship between Microsporidia and Fungi: a genome-wide analysis by DarkHorse software. Microsporidia are a group of obligate intracellular eukaryotic parasites that infect a wide variety of species, including humans. Phylogenetic analysis indicates a relationship between the Microsporidia and the Fungi. However, most results are based on the analysis of relatively few genes. DarkHorse analysis involves the transformation of BLAST results into a lineage probability index (LPI) value and allows for the comparison of genes for an entire genome with those of other genomes. Thus, we can see which genes from the microsporidia score most closely based on the LPI with other eukaryotic organisms. In this analysis, we calculated the LPI for each gene from the genomes of 7 Microsporidia, Antonospora locustae, Enterocytozoon bieneusi, Encephalitozoon cuniculi, Encephalitozoon intestinalis, Nosema bombycis, Nosema ceranae, and Nematocida parisii, to analyze the genetic relationships between Microsporidia and other species. It was found that many (91%) genes were most closely correlated with genes from other microsporidial genomes and had the highest mean LPI (0.985), indicating a monophyletic origin of the Microsporidia. In a subsequent analysis, we excluded the other Microsporidia from the analysis to look for relationships before the divergence of Microsporidia, and found that 43% of the microsporidial genes scored highest with fungal genes, and a higher mean LPI was found with Fungi than with other kingdoms, suggesting that Microsporidia is closely related to Fungi at the genomic level. Microsporidial genes were functionally clustered based on the KOG (Eukaryotic COG) database, and the possible lineages for each gene family were discussed in concert with the DarkHorse results.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1601,
                "text": "Fungi"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 1207,
                "text": "ZEB2"
            }
        },
        {
            "context": "Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. We used [18F]altanserin and positron emission tomography (PET) to image serotonin 5-HT2A receptors in humans. The highest [18F]altanserin uptake is found in the cerebral cortex, with specific-to-nonspecific binding ratios varying from 0.53 to 1.91 in humans between 24 and 48 years of age. In all neocortical regions studied, [18F]altanserin uptake correlates negatively with age. No correlations were found between age and uptake in the cerebellum, the regional cerebral blood flow, or the time course of metabolization of [18F]altanserin. The reduction in cerebral 5-HT2A receptor binding thus directly reflects the loss of specific 5-HT2A receptors with age.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 220,
                "text": "5-HT2A"
            }
        },
        {
            "context": "JAMM: a peak finder for joint analysis of NGS replicates. MOTIVATION: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets. RESULTS: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy. AVAILABILITY AND IMPLEMENTATION: JAMM is available for free and can run on Linux machines through the command line: http://code.google.com/p/jamm-peak-finder.",
            "question": "Which peak calling algorithm employs mixture model clustering under the hood?",
            "answers": {
                "answer_start": 424,
                "text": "JAMM"
            }
        },
        {
            "context": "Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 228,
                "text": "XK"
            }
        },
        {
            "context": "Non-invasive prenatal testing for fetal sex determination: is ultrasound still relevant? Early prenatal diagnosis of fetal sex is necessary to optimize pregnancy management in families known to be at risk of some heritable disorders. The demonstration of cell-free fetal DNA (cffDNA) in the mother's blood has made it possible to identify Y chromosome sequences in maternal blood and to determine fetal sex noninvasively, during the first trimester. This procedure can significantly reduce the number of invasive procedures for women with fetuses at risk of sex-linked diseases and optimize the management of these pregnancies. Fetal sex can be diagnosed by ultrasound with the same sensitivity and specificity, but later in pregnancy. We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy. We present the feasibility of the two methods and their impact on clinical practice. We applied a sensitive search of multiple bibliographic databases including Pubmed (MEDLINE), EMBASE, the Cochrane Library and Web of science between 1998 and 2013. Sixteen reports of the determination of fetal sex in maternal blood and 13 reports of the determination by ultrasound met our inclusion criteria. We found a sensitivity and specificity of nearly 100% from 8 weeks of gestation for cffDNA and from 13 weeks of gestation for ultrasound respectively. Based on this review, we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA and at an earlier gestation than ultrasound. Ten years after the first feasibility study, the French National Authority for Health (HAS) released a technological assessment report on the determination of fetal sex in maternal blood, which has resulted in validating this test for reimbursement by the national health insurance fund for the following indications: X-linked recessive disease and congenital adrenal hyperplasia.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 881,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. In yeast, the macromolecular complex Set1/COMPASS is capable of methylating H3K4, a posttranslational modification associated with actively transcribed genes. There is only one Set1 in yeast; yet in mammalian cells there are multiple H3K4 methylases, including Set1A/B, forming human COMPASS complexes, and MLL1-4, forming human COMPASS-like complexes. We have shown that Wdr82, which associates with chromatin in a histone H2B ubiquitination-dependent manner, is a specific component of Set1 complexes but not that of MLL1-4 complexes. RNA interference-mediated knockdown of Wdr82 results in a reduction in the H3K4 trimethylation levels, although these cells still possess active MLL complexes. Comprehensive in vitro enzymatic studies with Set1 and MLL complexes demonstrated that the Set1 complex is a more robust H3K4 trimethylase in vitro than the MLL complexes. Given our in vivo and in vitro observations, it appears that the human Set1 complex plays a more widespread role in H3K4 trimethylation than do the MLL complexes in mammalian cells.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 323,
                "text": "H3K4"
            }
        },
        {
            "context": "CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package is used for the detection of chromosomal abnormalities from microarray data?",
            "answers": {
                "answer_start": 252,
                "text": "CAFE"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 666,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Vanoxerine, a new drug for terminating atrial fibrillation and flutter. BACKGROUND: Vanoxerine produces potent block of cardiac hERG, sodium, and L-type calcium channels. Block is strongly frequency dependent, is unassociated with transmural dispersion of repolarization, and occurs at concentrations safe in humans. Therefore, we proposed that vanoxerine might be antiarrhythmic. In these studies, we tested the hypothesis that vanoxerine would terminate induced atrial fibrillation (AF) and atrial flutter (AFL) in dogs with sterile pericarditis (SP). METHODS AND RESULTS: In 9 SP dogs, 11 episodes each of sustained (>10 minutes) AF and AFL were induced. Electrophysiological studies were performed before and after infusion of vanoxerine, which effectively terminated AF and AFL in 19 of 22 episodes. Simultaneous multisite mapping during 3 AF and 3 AFL episodes demonstrated that termination of each arrhythmia occurred with termination of the driver (a reentrant circuit) following an increase in tachycardia CL. Except for conduction in an area of slow conduction in the driver's reentrant circuit, vanoxerine did not significantly affect intraatrial or atrioventricular conduction time, QRS duration, or QT/QTc intervals. Ventricular refractoriness prolonged minimally during ventricular pacing at 400 and 333 ms (176 +/- 16 ms to 182 +/- 16 ms; 173 +/- 11 ms to 178 +/- 18 ms, respectively). Vanoxerine minimally increased (mean 0.7 mA) atrial stimulus threshold for capture. CONCLUSIONS: Vanoxerine effectively terminated induced, sustained AF and AFL in the canine SP model, and produced insignificant or minimal changes in refractoriness, conduction time, or stimulus threshold, consistent with little proarrhythmic risk.",
            "question": "What alternate indication has Vanoxerine been repositioned for?",
            "answers": {
                "answer_start": 39,
                "text": "atrial fibrillation and flutter"
            }
        },
        {
            "context": "Genetic variation within coat color genes of MC1R and ASIP in Chinese brownish red Tibetan pigs. Melanocortin receptor 1 (MC1R) and agouti signaling protein (ASIP) are two major genes affecting coat color phenotypes in mammals, and inactivation mutations in the MC1R gene are responsible for red coat color in European pig breeds. Conversely, the gain-of-function ASIP mutations block MC1R signaling and lead to the production of red pheomelanin. Chinese Tibetan pigs have three types of coat color phenotypes, including brownish red, solid black and black with patches of brownish red and white. Herein, we investigated variations of the MC1R and ASIP genes in Tibetan pigs. The results showed that the brownish red Tibet pig had the dominant black MC1R allele (E(D1)). No loss-of-function mutation in MC1R responsible for red coat color in European breeds was observed in this breed. No causal mutation for the red coat color phenotype was found in the coding sequence of the ASIP gene. A novel missense mutation c.157G > A was firstly identified in exon 2 of ASIP, which was further genotyped in 285 pigs from five Chinese breeds and three Western breeds having different coat color phenotypes. Nearly all pigs were GG homozygotes. In conclusion, no functional variant responsible for brownish red coloration was found in the coding region of MC1R and ASIP in Tibetan pigs.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 262,
                "text": "MC1R"
            }
        },
        {
            "context": "Transnasal endoscopic approach to expose the medial rectus from the annulus of Zinn to the penetration of Tenon's capsule. Conventional strabismus surgery employs a conjunctival incision to gain access to Tenon's space where a wide variety of procedures are routinely performed on the tendon and anterior aspect of the extraocular muscles. Recently, transnasal endoscopic surgical techniques have gained acceptance as effective means of decompressing the medial wall and floor of the orbit in patients with thyroid-related orbitopathy. The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenon's capsule. In theory, this technique also provides the exposure necessary to locate and retrieve a \"lost\" medial rectus when the usual sub-Tenon's approach fails to recover the muscle. Cadaver studies demonstrate the feasibility of exposure and suture placement in the stump of a lost medial rectus with passage of the suture through Tenon's capsule to transmit the force of the muscle to the globe, provided that the lost muscle is retrieved before severe contracture develops.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 540,
                "text": "orbit"
            }
        },
        {
            "context": "CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package is used for the detection of chromosomal abnormalities from microarray data?",
            "answers": {
                "answer_start": 0,
                "text": "CAFE"
            }
        },
        {
            "context": "Comprehensive analysis of the genes responsible for neuroacanthocytosis in mood disorder and schizophrenia. Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60-61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 635,
                "text": "XK"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 374,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 529,
                "text": "INCA"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 369,
                "text": "INCA"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 218,
                "text": "tyr"
            }
        },
        {
            "context": "Cognitive abilities of Alzheimer's disease transgenic mice are modulated by social context and circadian rhythm. In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer's disease mouse model.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 161,
                "text": "ad"
            }
        },
        {
            "context": "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 344,
                "text": "Transcription Factor EB (TFEB)"
            }
        },
        {
            "context": "Comparative FISH mapping of the ancestral fusion point of human chromosome 2. It is known that human chromosome 2 originated from the fusion of two ancestral primate chromosomes. This has been confirmed by chromosome banding and fluorescence in-situ hybridization (FISH) with human chromosome-2-specific DNA libraries. In this study, the order of 38 cosmid clones derived from the human chromosome region 2q12-q14 was exactly determined by high-resolution FISH in human chromosome 2 and its homologous chromosomes in chimpanzees (Pan trogrodydes, 2n=48) and cynomolgus monkeys (Macacafascicularis, 2n = 42). This region includes the telomere-to-telomere fusion point of two ancestral ape-type chromosomes. As a result of comparative mapping, human chromosome region 2q12-q14 was found to correspond to the short arms of chimpanzee chromosomes 12 and 13 and cynomolgus monkey chromosomes 9 and 15. It is noted that no difference was detected in the relative order of the cosmid clones between human and chimpanzee chromosomes. This suggests that two ancestral ape-type chromosomes fused tandemly at telomeres to form human chromosome 2, and the genomic organization of this region is thought to be considerably conserved. In the cynomolgus monkey, however, the order of clones in each homologue was inverted. In addition to cosmid mapping, two chromosome-2-specific yeast artificial chromosome (YAC) clones containing the fusion point were identified by FISH.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 112,
                "text": "2"
            }
        },
        {
            "context": "Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria. Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 2525,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Hereditary conjugated hyperbilirubinaemia: 37 years later. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 382,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica (Bazex syndrome): report of a case associated with small cell lung carcinoma and review of the literature. Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 31,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene. Mutations in SCN1A gene, encoding the voltage-gated sodium channel α1-subunit, are found to be associated with severe myoclonic epilepsy in infancy or Dravet syndrome (DS), but only rarely with the myoclonic astatic epilepsy (MAE, or Doose syndrome). We report on two patients with SCN1A mutations and severe epilepsy within the spectrum of generalized epilepsy with febrile seizures plus syndrome (GEFS+), the phenotypes being consistent with DS and MAE, respectively. Analysis of SCN1A revealed a heterozygous de novo frameshift mutation (c.4205_4208delGAAA) in the patient with DS, and a recurrent missense mutation (c.3521C>G) in that suffering from MAE. The missense mutation has been reported in patients with neurological diseases of various manifestations, which suggests that this variability is likely to result from the modifying effects of other genetic or environmental factors. DS phenotype has been mainly found associated with truncation mutations, while predominantly missense mutations and very few prematurely terminating substitutions have been reported in GEFS+ patients.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 295,
                "text": "myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Clinical and molecular diagnosis of the skeletal dysplasias associated with mutations in the gene encoding Fibroblast Growth Factor Receptor 3 (FGFR3) in Portugal. Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. Two known mutations were found in the Thanatophoric Dysplasia referred cases. No mutations were identified in the LADD syndrome patient. In Achondroplasia and Hypochondroplasia, genetic heterogeneity was present amongst the 70 clinically diagnosed patients with 5 different mutations identified. As in other studies, complex phenotypic heterogeneity amongst patients carrying the same gene defect was observed. In several cases, the new amino acids encoded, as a consequence of mutations, were related to the severity of patients' phenotype. The presence of 10 misdiagnosed cases emphasizes the importance of performing mutation analysis of the hotspot regions responsible for both dysplasias (Ach and Hch). For patients with an unquestionable clinical diagnosis, lacking the most common mutations, a complete screening of FGFR3 is necessary.",
            "question": "Which gene is associated with Muenke syndrome?",
            "answers": {
                "answer_start": 199,
                "text": "Fibroblast Growth Factor Receptor 3 (FGFR3)"
            }
        },
        {
            "context": "Mammalian target of rapamycin inhibitor-associated stomatitis. With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 109,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "Calsequestrin targeting to sarcoplasmic reticulum of skeletal muscle fibers. Calsequestrin (CS) is the low-affinity, high-capacity calcium binding protein segregated to the lumen of terminal cisternae (TC) of the sarcoplasmic reticulum (SR). The physiological role of CS in controlling calcium release from the SR depends on both its intrinsic properties and its localization. The mechanisms of CS targeting were investigated in skeletal muscle fibers and C2C12 myotubes, a model of SR differentiation, with four deletion mutants of epitope (hemagglutinin, HA)-tagged CS: CS-HA24NH2, CS-HA2D, CS-HA3D, and CS-HAHT, a double mutant of the NH2 terminus and domain III. As judged by immunofluorescence of transfected skeletal muscle fibers, only the double CS-HA mutant showed a homogeneous distribution at the sarcomeric I band, i.e., it did not segregate to TC. As shown by subfractionation of microsomes derived from transfected skeletal muscles, CS-HAHT was largely associated to longitudinal SR whereas CS-HA was concentrated in TC. In C2C12 myotubes, as judged by immunofluorescence, not only CS-HAHT but also CS-HA3D and CS-HA2D were not sorted to developing SR. Condensation competence, a property referable to CS oligomerization, was monitored for the several CS-HA mutants in C2C12 myoblasts, and only CS-HA3D was found able to condense. Together, the results indicate that 1) there are at least two targeting sequences at the NH2 terminus and domain III of CS, 2) SR-specific target and structural information is contained in these sequences, 3) heterologous interactions with junctional SR proteins are relevant for segregation, 4) homologous CS-CS interactions are involved in the overall targeting process, and 5) different targeting mechanisms prevail depending on the stage of SR differentiation.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 77,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "Genetic dissection between coeliac disease and dermatitis herpetiformis in sib pairs. Gluten sensitive enteropathy has various manifestations, of which the two major forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH). In cCD predominantly the small intestine is affected, whereas in DH also the skin is affected showing typical rash and IgA deposits. The symptoms in both forms are dependent on gluten intake. The factors diversifying these two clinical outcomes are unknown. In the present report we evaluated the role of the major genetic susceptibility locus, HLA DQ, in 25 families, in which both forms of the disease, cCD and DH, occurred in siblings. By using the family-based approach it can be assumed that within each family variation in environmental factors is substantially lower than in the standard case-control setting, and also the problems related to population stratification can be avoided. Results from the Finnish family material with 25 discordant and 85 concordant sib pairs, and from additional case-control material comprising 71 unrelated Hungarian DH and 68 cCD patients, together indicated that the HLA DQ locus did not differ between the two major outcomes of gluten sensitive enteropathy. The non-HLA DR;DQ factors are critical for the different clinical manifestations of gluten sensitivity.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 212,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 805,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Idarucizumab for Reversing Dabigatran-Induced Anticoagulation: A Systematic Review. BACKGROUND: The approval of the oral direct thrombin inhibitor, dabigatran etexilate, gave patients an alternative to oral anticoagulation with warfarin. Like all anticoagulants, the primary adverse event (AE) associated with dabigatran is bleeding. Until the FDA approval of idarucizumab, there had been no reversal agent for dabigatran-induced anticoagulation in patients with life-threatening or uncontrollable bleeding, or those requiring emergent procedures. AREAS OF UNCERTAINTY: The primary purpose of this review is to summarize the safety and efficacy of idarucizumab, a monoclonal antibody fragment, and its use as a reversal agent for dabigatran. DATA SOURCES: A literature search was conducted through MEDLINE (1946 to November week 1 2015) and Embase (1980-2015 week 46) using the search term idarucizumab. Clinicaltrials.gov was consulted for a comprehensive list of ongoing and completed studies. Additional studies were identified through bibliographical citations. Clinical trials in animals and humans published in English evaluating the safety and efficacy of idarucizumab for reversal of anticoagulant treatment with dabigatran were included for review. RESULTS: Idarucizumab has been shown to significantly reverse the anticoagulant effects of dabigatran in both healthy volunteers and patients requiring a reversal agent because of either overt bleeding or an emergency surgery or invasive procedure. The most common AEs were headache, nasopharyngitis, back pain, skin irritation, hypokalemia, delirium, constipation, pyrexia, and pneumonia. Deaths reported in idarucizumab studies were attributed to either the index event or a preexisting comorbidity. Most adverse effects were minor, but 21 serious AEs have been reported in the published data including thrombotic events. CONCLUSIONS: Given the increased use of direct oral anticoagulants, such as dabigatran, a need for specific reversal agents exists. Idarucizumab has been shown to be safe and effective in the reversal of dabigatran-induced anticoagulation in patients requiring emergent or urgent surgery or in patients with severe bleeding.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 27,
                "text": "Dabigatran"
            }
        },
        {
            "context": "Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). BACKGROUND: Secukinumab is a fully human anti-interleukin-17A monoclonal antibody. OBJECTIVE: Determine the efficacy, safety and usability of secukinumab administered via autoinjector/pen. METHODS: This phase III trial randomized subjects with moderate to severe plaque psoriasis to secukinumab 300 mg, 150 mg or placebo self-injection once weekly to Week 4, then every 4 weeks. Co-primary end points at Week 12 were > 75% improvement in Psoriasis Area and Severity Index (PASI 75) and clear/almost clear skin by investigator's global assessment 2011 modified version (IGA mod 2011 0/1). Secondary end points included autoinjector usability, assessed by successful, hazard-free self-injection and subject-reported acceptability on Self-Injection Assessment Questionnaire. RESULTS: Week 12 PASI 75 and IGA mod 2011 0/1 responses were superior with secukinumab 300 mg (86.7% and 73.3%, respectively) and 150 mg (71.7% and 53.3%, respectively) vs. placebo (3.3% and 0%, respectively) (P < 0.0001 for all). All subjects successfully self-administered treatment at Week 1, without critical use-related hazards. Subject acceptability of autoinjector was high throughout 12 weeks. Adverse events were higher with secukinumab (300 mg, 70.0%; 150 mg, 63.9%) vs. placebo (54.1%), with differences largely driven by mild/moderate nasopharyngitis. CONCLUSION: Secukinumab delivered by autoinjector/pen is efficacious, well-tolerated and associated with high usability in moderate to severe plaque psoriasis.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 184,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone-bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC(50) values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.",
            "question": "What histone modification is recognized by the bromodomain?",
            "answers": {
                "answer_start": 232,
                "text": "acetylated lysines"
            }
        },
        {
            "context": "Influence of lateral association on forced unfolding of antiparallel spectrin heterodimers. Protein extensibility appears to be based broadly on conformational changes that can in principle be modulated by protein-protein interactions. Spectrin family proteins, with their extensible three-helix folds, enable evaluation of dimerization effects at the single molecule level by atomic force microscopy. Although some spectrin family members function physiologically only as homodimers (e.g. alpha-actinin) or are strictly monomers (e.g. dystrophin), alpha- and beta-spectrins are stable as monomeric forms but occur physiologically as alpha,beta-heterodimers bound laterally lengthwise. For short constructs of alpha- and beta-spectrin, either as monomers or as alpha,beta-dimers, sawtooth patterns in atomic force microscopy-forced extension show that unfolding stochastically extends repeats approximately 4-5-fold greater in length than native conformations. For both dimers and monomers, distributions of unfolding lengths appear bimodal; major unfolding peaks reflect single repeats, and minor unfolding peaks at twice the length reflect tandem repeats. Cooperative unfolding thus propagates through helical linkers between serial repeats (1, 2). With lateral heterodimers, however, the force distribution is broad and shifted to higher forces. The associated chains in a dimer can stay together and unfold simultaneously in addition to unfolding independently. Weak lateral interactions do not inhibit unfolding, but strong lateral interactions facilitate simultaneous unfolding analogous to serial repeat coupling within spectrin family proteins.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 56,
                "text": "antiparallel"
            }
        },
        {
            "context": "Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 247,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 932,
                "text": "H3K4"
            }
        },
        {
            "context": "Primary cutaneous pre-B lymphoblastic lymphoma immunohistologically mimics Ewing's sarcoma/primitive neuroectodermal tumor. Precursor B-cell lymphoblastic lymphomas (B-LBLs) are rare and most often involve the skin in the head and neck region. Histologically, cutaneous B-LBLs may be confused with other small round-cell neoplasms. Moreover, half of B-LBL patients are negative for CD45 (leucocyte common antigen, LCA), a widely used marker for the diagnosis of lymphoma, and a significant portion express CD99, a marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET). Therefore, an extranodal B-LBL may be misinterpreted as PNET or ES. Here, we report on 2 boys, aged 10 and 5 years, with primary cutaneous B-LBL of the scalp. PNET was initially misdiagnosed because the tumor cells were negative for CD45 but strongly positive for CD99. Advanced stage of acute lymphoblastic leukemia (ALL) developed later and both patients died during the course of treatment for ALL. In retrospective analyses, tumor cells in the initial biopsy specimens of both patients were found to be reactive to terminal deoxynucleotidyl transferase (TdT), CD43 and CD10. Thus, the diagnosis of B-LBL was confirmed. These cases illustrate the possibility that primary cutaneous B-LBL may mimic ES or PNET immunophenotypically, and that correct diagnosis in doubtful cases may be facilitated by analysis using a complete panel of antibodies, particularly including TdT and CD43.",
            "question": "Which biomarker is widely used in the diagnosis of Ewing sarcoma?",
            "answers": {
                "answer_start": 506,
                "text": "CD99"
            }
        },
        {
            "context": "Efficacy and limitations of transarterial acrylic glue embolization for intracranial dural arteriovenous fistulas. The efficacy and limitations of transarterial acrylic glue embolization for the treatment of intracranial dural arteriovenous fistulas (DAVFs) were investigated. Thirty-four DAVFs treated by transarterial embolization using n-butyl cyanoacrylate were retrospectively reviewed. The locations of DAVFs were the transverse-sigmoid sinus in 11, tentorium in 10, cranial vault in 9, and superior sagittal sinus, jugular bulb, foramen magnum, and middle cranial fossa in 1 each. Borden classification was type I in 7, type II in 3, and type III in 24. Eight patients had undergone prior transvenous coil embolization. Complete obliteration rate was 56% immediately after embolization, 71% at follow-up angiography, and 85% after additional treatments (1 transvenous embolization and 4 direct surgery). Complications occurred in three patients, consisting of asymptomatic vessel perforations during cannulation in two patients and leakage of contrast medium resulting in medullary infarction in one patient. Transarterial glue embolization is highly effective for Borden type III DAVF with direct cortical venous drainage, but has limitations for Borden type I and II DAVFs in which the affected sinus is part of the normal venous circulation. Onyx is a new liquid embolic material and is becoming the treatment of choice for DAVF. The benefits of glue embolization compared to Onyx embolization are high thrombogenicity, and relatively low risks of cranial nerve palsies and of excessive migration into the draining veins of high flow fistula. Transarterial glue embolization continues to be useful for selected patients, and complete cure can be expected in most patients with fewer complications if combined with transvenous embolization or direct surgery.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 409,
                "text": "DAVF"
            }
        },
        {
            "context": "Assessing manganese efflux using SEA0400 and cardiac T1-mapping manganese-enhanced MRI in a murine model. The sodium-calcium exchanger (NCX) is one of the transporters contributing to the control of intracellular calcium (Ca(2+)) concentration by normally mediating net Ca(2+) efflux. However, the reverse mode of the NCX can cause intracellular Ca(2+) concentration overload, which exacerbates the myocardial tissue injury resulting from ischemia. Although the NCX inhibitor SEA0400 has been shown to therapeutically reduce myocardial injury, no in vivo technique exists to monitor intracellular Ca(2+) fluctuations produced by this drug. Cardiac manganese-enhanced MRI (MEMRI) may indirectly assess Ca(2+) efflux by estimating changes in manganese (Mn(2+)) content in vivo, since Mn(2+) has been suggested as a surrogate marker for Ca(2+). This study used the MEMRI technique to examine the temporal features of cardiac Mn(2+) efflux by implementing a T(1)-mapping method and inhibiting the NCX with SEA0400. The change in (1)H(2)O longitudinal relaxation rate, Delta R(1), in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl(2)) in healthy adult male mice. The results showed 50% MEMRI signal attenuation at 3.4 +/- 0.6 h post-MnCl(2) infusion without drug intervention. Furthermore, treatment with 50 +/- 0.2 mg/kg of SEA0400 significantly reduced the rate of decrease in Delta R(1). At 4.9-5.9 h post-MnCl(2) infusion, the average Delta R(1) values for the two groups treated with SEA0400 were 2.46 +/- 0.29 and 1.72 +/- 0.24 s(-1) for 50 and 20 mg/kg doses, respectively, as compared to the value of 1.27 +/- 0.28 s(-1) for the control group. When this in vivo data were compared to ex vivo absolute manganese content data, the MEMRI T(1)-mapping technique was shown to effectively quantify Mn(2+) efflux rates in the myocardium. Therefore, combining an NCX inhibitor with MEMRI may be a useful technique for assessing Mn(2+) transport mechanisms and rates in vivo, which may reflect changes in Ca(2+) transport.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 136,
                "text": "NCX"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 535,
                "text": "7"
            }
        },
        {
            "context": "Development of a genetic assay to distinguish between Leishmania viannia species on the basis of isoenzyme differences. BACKGROUND: Tegumentary leishmaniasis in Latin America is caused mainly by Leishmania viannia braziliensis complex parasites. L. braziliensis and Leishmania viannia peruviana are the 2 predominant Leishmania species in Peru. L. braziliensis is more virulent, because it can cause mucocutaneous leishmaniasis, known as espundia, that results in severe facial destruction. Early identification of the species that causes the initial cutaneous infection would greatly help to prevent mucocutaneous leishmaniasis, because it would allow more aggressive treatment and follow-up. However, because of the close genetic similarity of L. braziliensis and L. peruviana, there currently exists no simple assay to distinguish between these species. METHODS: We cloned the mannose phosphate isomerase gene from both L. braziliensis and L. peruviana. It is the only known isoenzyme capable of differentiating between L. braziliensis and L. peruviana in multilocus enzyme electrophoresis. Interestingly, only a single nucleotide polymorphism was found between the mannose phosphate isomerase genes from L. braziliensis and L. peruviana, resulting in an amino acid change from threonine to arginine at amino acid 361. A polymerase chain reaction assay was developed to distinguish the single nucleotide polymorphism of the mannose phosphate isomerase gene to allow for the specific identification of L. braziliensis or L. peruviana. RESULTS: This assay was validated with 31 reference strains that were previously typed by multilocus enzyme electrophoresis, successfully applied to patient biopsy samples, and adapted to a real-time polymerase chain reaction assay. CONCLUSIONS: This innovative approach combines new genetic knowledge with traditional biochemical fundamentals of multilocus enzyme electrophoresis to better manage leishmaniasis in Latin America.",
            "question": "What causes leishmaniasis?",
            "answers": {
                "answer_start": 317,
                "text": "Leishmania species"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 218,
                "text": "tyr"
            }
        },
        {
            "context": "Inter-subunit interactions in erythroid and non-erythroid spectrins. Spectrins comprise α- and β-subunits made up predominantly of a series of homologous repeating units of about 106 amino acids; the α- and β-chains form antiparallel dimers by lateral association, and tetramers through head-to-head contacts between the dimers. Here we consider the first of these interactions. (1) We confirm earlier observations, showing that the first two paired repeats (βIR1 with αIR21, and βIR2 with αRI20) at one end of the erythroid spectrin (αIβI) dimer are necessary and sufficient to unite the chains; (2) we resolve a conflict in published reports by showing that the strength of the interaction is considerably increased on adding the adjoining pair of repeats (βIR3-αIR19); (3) in brain (αIIβII) spectrin the first two pairs of repeats are similarly essential and sufficient for heterodimer formation; (4) this interaction is ~60-fold stronger than that in the erythroid counterpart, but no enhancement can be detected on addition of three further pairs of repeats; (5) formation of a tight αIβI dimer probably depends on structural coupling of the first two repeats in each chain; (6) an analysis of the sequences of the strongly interacting repeats, βIR1, βIIR1, αIR21 and αIIR20 and repeats in α-actinin, which also interact very strongly in forming an antiparallel dimer, affords a possible explanation for the different properties of the two spectrin isoforms in respect of the stability of the inter-chain interactions, and also suggests the evolutionary path by which the erythroid and non-erythroid sequences diverged.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 221,
                "text": "antiparallel"
            }
        },
        {
            "context": "Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in the NOTCH3 gene, most which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor-like repeats in the extracellular domain of Notch3 receptor (N3ECD). CADASIL is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we used proteomic analysis to characterize the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs, and cellular stress. Our findings indicate that misfolding of Notch3 may cause endoplasmic reticulum stress and activation of unfolded protein response, leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signaling system of VSMC contraction. The accumulation of N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 245,
                "text": "NOTCH3 gene"
            }
        },
        {
            "context": "Label-free MSE proteomic analysis of chronic myeloid leukemia bone marrow plasma: disclosing new insights from therapy resistance. Chronic myeloid leukemia (CML) is a pluripotent hematopoietic disorder that is currently considered incurable. The tyrosine kinase product of the Philadelphia chromosome, P210 BCR-ABL, provided a pathogenetic explanation for the initiation of the CML chronic phase and is the molecular therapeutic target for the disease. Imatinib mesylate, an orally available BCR-ABL kinase inhibitor, can induce haematologic and cytogenetic remission of CML. However, imatinib resistance occurs frequently, resulting in relapse. New treatment strategies are focusing on resistant CML stem cells and the bone marrow stroma. The identification of novel pathways and mechanisms in the bone marrow microenvironment could significantly contribute to the development of such strategies. In this work, we used a high-resolution label-free MS(E) proteomic approach to identify differential protein expression in the CML bone marrow plasma of responsive and resistant patients. Oxidative lipid metabolism and regulation of the switch from canonical to noncanonical WNT signaling may contribute to CML resistance in the bone marrow compartment.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 492,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy. Potential role of antiepileptic drugs. Among people with epilepsy, there is a 20-fold higher risk of dying suddenly and unexpectedly compared with the general population. This phenomenon is called sudden unexpected death in epilepsy (SUDEP) and the term is used when sudden death occurs in an otherwise reasonably healthy person with epilepsy and the autopsy is unrevealing. In most cases, SUDEP occurs during sleep and is unwitnessed. Risk factors for SUDEP include the presence or number of generalized tonic-clonic seizures (GTCS), nocturnal seizures, young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic aetiology of epilepsy and alcohol abuse. Suggested factors predisposing to SUDEP have included long-QT-related mutations, impaired serotonergic brain stem control of respiration, altered autonomic control and seizures with a pronounced postictal suppression and respiratory compromise. Final events that may lead up to SUDEP are a postictal CNS shutdown with pronounced EEG suppression, ictal or postictal apnoea, and ictal cardiac arrhythmia. It is unknown whether antiepileptic drugs (AEDs) modify the risk for SUDEP. Studies have consistently found that the presence or number of GTCS is associated with an increased risk for SUDEP. Since continued presence of GTCS clearly necessitates the use of AEDs, both factors must be taken into account to determine whether one or both increases the risk for SUDEP. Some studies suggest that AEDs, such as lamotrigine and carbamazepine, may increase the risk of SUDEP, but rarely adjust for GTCS. Other studies, which have found that AEDs are associated with a decreased SUDEP risk, either adjust for the number of GTCS or are meta-analyses of randomized clinical trials. Studies assessing the impact of AEDs on the risk for SUDEP are limited because SUDEP is a rare event, making randomized clinical trials impossible to conduct. Observational studies focus on whether or not an AED was prescribed. When postmortem AED concentrations are assessed they are usually low or absent, perhaps due to sampling in deceased individuals, making it difficult to fully resolve whether AEDs increase or decrease SUDEP risk. Despite these caveats, the evidence suggests that AEDs are not associated with an increased risk for SUDEP on a population level, although some individuals may be susceptible to effects of AEDs. Recent evidence from a meta-analysis of randomized clinical trials of adjunctive AEDs at efficacious doses provides strong support for AED treatment as mono- or polytherapy to increase seizure control and protect against SUDEP in patients with refractory epilepsy. For patients for whom seizure control is unattainable, supervision or monitoring may prevent SUDEP, though this has never been formally tested.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 234,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "A new method for rapid detection of the mutant allele for Chediak-Higashi syndrome in Japanese black cattle. Chediak-Higashi syndrome (CHS) is an autosomal recessive hereditary disorder in Japanese Black cattle, caused by a mutation of the Lyst gene. So far, the mutation has been detected by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis. However, this method is disadvantaged by its low-throughput performance. Here, we report an alternative method involving real-time PCR with TaqMan minor groove binder probes, which shortens the total assay time by more than 120 min, analyzing 10 samples in a duplicated manner. Using this method, we examined 102 Japanese Black cattle and found that 8.8% of the cattle were CHS-carriers. These data indicate that our technique is useful for routine diagnostic testing for CHS in Japanese Black cattle.",
            "question": "Which mutated gene causes the Chédiak–Higashi Syndrome?",
            "answers": {
                "answer_start": 240,
                "text": "Lyst gene"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 225,
                "text": "CCs"
            }
        },
        {
            "context": "One-year safety and tolerability profile of pridopidine in patients with Huntington disease. OBJECTIVE: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease. METHODS: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day). RESULTS: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported > 1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and > 1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported > 1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified. CONCLUSION: Pridopidine ( < 90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that pridopidine ( < 90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 73,
                "text": "Huntington disease"
            }
        },
        {
            "context": "The tyrosinase gene in gorillas and the albinism of 'Snowflake'. The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla ('Snowflake'). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in 'Snowflake', indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 611,
                "text": "TYR"
            }
        },
        {
            "context": "Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport. Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts. Our understanding of the function of phospholamban stems primarily from studies in genetically altered mouse models. To evaluate the significance of this protein in larger mammalian species, which exhibit Ca cycling properties similar to humans, we overexpressed phospholamban in adult rabbit cardiomyocytes. Adenoviral-mediated gene transfer, at high multiplicities of infection, resulted in an insignificant 1.22-fold overexpression of phospholamban. There were no effects on twitch Ca-transient amplitude or decay under basal or isoproterenol-stimulated conditions. Furthermore, the SR Ca load and Na/Ca exchanger function were not altered. These apparent differences between phospholamban overexpression in rabbit compared with previous findings in the mouse may be due to a significantly higher (1.5-fold) endogenous phospholamban-to-sarco(endo)plasmic reticulum Ca-ATPase (SERCA) 2a ratio and potential functional saturation of SERCA2a by phospholamban in rabbit cardiomyocytes. The findings suggest that important species-dependent differences in phospholamban regulation of SERCA2a occur. In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 1381,
                "text": "phospholamban"
            }
        },
        {
            "context": "Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Although most eukaryotic genomes lack operons, they contain some physical clusters of genes that are related in function despite being unrelated in sequence. How these clusters are formed during evolution is unknown. The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. We show here that the DAL cluster was assembled, quite recently in evolutionary terms, through a set of genomic rearrangements that happened almost simultaneously. Six of the eight genes involved in allantoin degradation, which were previously scattered around the genome, became relocated to a single subtelomeric site in an ancestor of S. cerevisiae and Saccharomyces castellii. These genomic rearrangements coincided with a biochemical reorganization of the purine degradation pathway, which switched to importing allantoin instead of urate. This change eliminated urate oxidase, one of several oxygen-consuming enzymes that were lost by yeasts that can grow vigorously in anaerobic conditions. The DAL cluster is located in a domain of modified chromatin involving both H2A.Z histone exchange and Hst1-Sum1-mediated histone deacetylation, and it may be a coadapted gene complex formed by epistatic selection.",
            "question": "Which is the largest metabolic gene cluster in yeast?",
            "answers": {
                "answer_start": 289,
                "text": "The DAL cluster"
            }
        },
        {
            "context": "Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities. Rapid laboratory methods provide optimal support for active surveillance efforts to screen for methicillin-resistant Staphylococcus aureus (MRSA). Most laboratories struggle to determine the optimal use of resources, considering options to balance cost, speed, and diagnostic accuracy. To assess the performance of common methods, the first comparison of MRSASelect agar (MS) and CHROMagar MRSA (CA), with and without broth enrichment followed by a 24-h subculture to MS, was performed. Results were compared to those of the Xpert MRSA assay. For direct culture methods, the agreement between MS and CA was 98.8%. At 18 h, direct MS identified 93% of all positive samples from direct culture and 84% of those identified by the Xpert MRSA. For Trypticase soy broth-enriched MS culture, incubated overnight and then subcultured for an additional 24 h, the agreement with Xpert MRSA was 96%. The agreement between direct MS and Xpert MRSA was 100% when semiquantitative culture revealed a bacterial density of 2+ or greater; however, discrepancies between culture and Xpert MRSA arose for MRSA bacterial densities of 1+ or less, indicating low density as a common cause of false-negative culture results. Since 1+ or less was established as the most common MRSA carrier state, broth enrichment or PCR may be critical for the identification of all MRSA carriers who may be reservoirs for transmission. In this active-surveillance convenience sample, the use of broth enrichment followed by subculture to MS offered a low-cost but sensitive method for MRSA screening, with performance similar to that of Xpert MRSA PCR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 110,
                "text": "MRSA"
            }
        },
        {
            "context": "[Botulinum toxin: from poison to drug. A historical review]. Botulinumtoxin (BTX) is a neurotoxin produced from Clostridium botulinum under anaerobic conditions and is responsible for botulism, a notifiable, bacterial form of food poisoning. The first case of botulism is believed to have occurred in 1735. An epidemic in Southern Germany in 1793 claimed the death of over the half of those patients who had become ill through eating uncooked blood sausages. The term \"pharmakon\" is Greek and implicates that a drug originates from poison (potion, remedy). Theophrastus Bombast von Hohenheim known as Paracelsus (1493/94-1541) first described this duality with his dictum \"alle ding sind gift und nichts on gift; alein die dosis macht das ein ding kein gift ist\" (only the dose makes a remedy poisonous). In Baden-Württemberg in 1817, the poet and physician Dr. Justinus Christian Kerner described the symptoms of botulism, so that at this time botulism was also called Kerner disease. Until the turn of the century the reason for poisoning was not known. Van Ermengem succeeded in isolating the anaerobic bacterium causing botulism, but the specific mechanism of BTX was only established after the second World War. In the late seventies the ophthalmologist Dr. Alan Scott used BTX the first time in the treatment of strabismus. The drug was then used in the treatment of several muscle spasticities such as, for example, torticollis or hemifacial spasm. Only recently BTX has been successfully used for focal hyperhidrosis. We review the history of botulinum toxin from its discovery in the nineteenth century and the research into its effect in the middle of the 20th century up to its clinical use at the present time.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 112,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Phenomenology of \"Lubag\" or X-linked dystonia-parkinsonism. X-linked dystonia-parkinsonism (XDP), or Lubag syndrome, is known to cause progressive dystonia, with or without parkinsonism, among Filipino male adults with maternal roots from the Philippine island of Panay. We present cinematographic material of 11 cases of Lubag carrying the XDP haplotypes who manifest with a wide spectrum of movement disorders, including dystonia, tremor, parkinsonism, myoclonus, chorea, and myorhythmia. Because of overlapping features, Lubag patients are commonly misdiagnosed as idiopathic dystonia, essential tremor, Parkinson's disease, or Parkinson's-plus syndromes. Thus, it is imperative to elicit an exhaustive family history in any Filipino male adult who presents with a movement disorder.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 60,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex. The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 878,
                "text": "SWR1"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 256,
                "text": "7"
            }
        },
        {
            "context": "Fusarium graminearum Possesses Virulence Factors Common to Fusarium Head Blight of Wheat and Seedling Rot of Soybean but Differing in Their Impact on Disease Severity. Fusarium graminearum is a toxigenic fungal pathogen that causes Fusarium head blight (FHB) and crown rot on cereal crops worldwide. This fungus also causes damping-off and crown and root rots at the early stage of crop development in soybean cultivated in North and South America. Several F. graminearum genes were investigated for their contribution to FHB in cereals but no inherent study is reported for the dicotyledonous soybean host. In this study we determined the disease severity on soybean seedlings of five single gene disrupted mutants of F. graminearum, previously characterized in wheat spike infection. Three of these mutants are impaired on a specific function as the production of deoxynivalenol (DON, Δtri5), lipase (ΔFgl1), and xylanase (Δxyl03624), while the remaining two are MAP kinase mutants (ΔFgOS-2, Δgpmk1), which are altered in signaling pathways. The mutants that were reduced in virulence (Δtri5, ΔFgl1, and ΔFgOS-2) or are avirulent (Δgpmk1) on wheat were correspondently less virulent or avirulent in soybean seedlings, as shown by the extension of lesions and seedling lengths. The Δxyl03624 mutant was as virulent as the wild type mirroring the behavior observed in wheat. However, a different ranking of symptom severity occurred in the two hosts: the ΔFgOS-2 mutant, that infects wheat spikelets similarly to Δtri5 and ΔFgl1 mutants, provided much reduced symptoms in soybean. Differently from the other mutants, we observed that the ΔFgOS-2 mutant was several fold more sensitive to the glyceollin phytoalexin suggesting that its reduced virulence may be due to its hypersensitivity to this phytoalexin. In conclusion, lipase and DON seem important for full disease symptom development in soybean seedlings, OS-2 and Gpmk1 MAP kinases are essential for virulence, and OS-2 is involved in conferring resistance to the soybean phytoalexin.",
            "question": "The pathogen Fusarium graminearum affects what type of plant species?",
            "answers": {
                "answer_start": 276,
                "text": "cereal crops"
            }
        },
        {
            "context": "Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by a deficiency of frataxin, a conserved mitochondrial protein of unknown function. Mitochondrial iron accumulation, loss of iron-sulfur cluster-containing enzymes and increased oxidative damage occur in yeast and mouse frataxin-depleted mutants as well as tissues and cell lines from FRDA patients, suggesting that frataxin may be involved in export of iron from the mitochondria, synthesis of iron-sulfur clusters and/or protection from oxidative damage. We have previously shown that yeast frataxin has structural and functional features of an iron storage protein. In this study we have investigated the function of human frataxin in Escherichia coli and Saccharomyces cerevisiae. When expressed in E.coli, the mature form of human frataxin assembles into a stable homopolymer that can bind approximately 10 atoms of iron per molecule of frataxin. The iron-loaded homopolymer can be detected on non-denaturing gels by either protein or iron staining demonstrating a stable association between frataxin and iron. As analyzed by gel filtration and electron microscopy, the homopolymer consists of globular particles of approximately 1 MDa and ordered rod-shaped polymers of these particles that accumulate small electron-dense cores. When the human frataxin precursor is expressed in S.cerevisiae, the mitochondrially generated mature form is separated by gel filtration into monomer and a high molecular weight pool of >600 kDa. A high molecular weight pool of frataxin is also present in mouse heart indicating that frataxin can assemble under native conditions. In radiolabeled yeast cells, human frataxin is recovered by immunoprecipitation with approximately five atoms of (55)Fe bound per molecule. These findings suggest that FRDA results from decreased mitochondrial iron storage due to frataxin deficiency which may impair iron metabolism, promote oxidative damage and lead to progressive iron accumulation.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 198,
                "text": "frataxin"
            }
        },
        {
            "context": "Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Calcineurin signaling has been implicated in a broad spectrum of developmental processes in a variety of organ systems. Calcineurin is a calmodulin-dependent, calcium-activated protein phosphatase composed of catalytic and regulatory subunits. The serine/threonine-specific phosphatase functions within a signal transduction pathway that regulates gene expression and biological responses in many developmentally important cell types. Calcineurin signaling was first defined in T lymphocytes as a regulator of nuclear factor of activated T cells (NFAT) transcription factor nuclear translocation and activation. Recent studies have demonstrated the vital nature of calcium/calcineurin/NFAT signaling in cardiovascular and skeletal muscle development in vertebrates. Inhibition, mutation, or forced expression of calcineurin pathway genes result in defects or alterations in cardiomyocyte maturation, heart valve formation, vascular development, skeletal muscle differentiation and fiber-type switching, and cardiac and skeletal muscle hypertrophy. Conserved calcineurin genes are found in invertebrates such as Drosophila and Caenorhabditis elegans, and genetic studies have demonstrated specific myogenic functions for the phosphatase in their development. The ability to investigate calcineurin signaling pathways in vertebrates and model genetic organisms provides a great potential to more fully comprehend the functions of calcineurin and its interacting genes in heart, blood vessel, and muscle development.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 213,
                "text": "Calcineurin"
            }
        },
        {
            "context": "Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis in mammals. Mutations at a single N-glycosylation sequon of tyrosinase have been reported to be responsible for oculocutaneous albinism type IA in humans, characterized by inactive tyrosinase and the total absence of pigmentation. To probe the role that each N-glycosylation site plays in the synthesis of biologically active tyrosinase, we analyzed the calnexin mediated folding of tyrosinase N-glycosylation mutants. We have determined that four of the six potential N-glycosylation sites, including that associated with albinism, are occupied. Analysis of the folding pathway and activity of 15 tyrosinase mutants lacking one or more of the occupied N-glycosylation sites shows that glycans at any two N-glycosylation sites are sufficient to interact with calnexin and give partial activity, but a specific pair of sites (Asn(86) and Asn(371)) is required for full activity. The mutants with less than two N-glycosylation sites do not interact with calnexin and show a complete absence of enzyme activity. Copper analysis of selected mutants suggests that the observed partial activity is due to two populations with differential copper content. By correlating the degree of folding with the activity of tyrosinase, we propose a local folding mechanism for tyrosinase that can explain the mechanism of inactivation of tyrosinase N-glycosylation mutants found in certain pigmentation disorders.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 249,
                "text": "tyr"
            }
        },
        {
            "context": "The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. The p53 protein is the cell's principal bastion of defense against tumor-associated DNA damage. Commonly referred as a \"guardian of the genome\", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged. The development of tumors requires breaching this defense line. All known tumor cells either mutate the p53 gene, or in a similar number of cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable its function. The release of functional p53 from the inhibition by Mdm2 and Mdmx should in principle provide an efficient, nongenotoxic means of cancer therapy. In recent years substantial progress has been made in developing novel p53-activating molecules thanks to several reported crystal structures of Mdm2/x in complex with p53-mimicking peptides and nonpeptidic drug candidates. Understanding the structural attributes of ligand binding holds the key to developing novel, highly effective, and selective drug candidates. Two low-molecular-weight compounds have just recently progressed into early clinical studies.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 214,
                "text": "p53"
            }
        },
        {
            "context": "Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs disease. Two affected HEXA alleles were found in an Israeli Druze Tay-Sachs child born to first-cousin parents. His paternal allele contained two adjacent changes in exon 5: delta496C, which resulted in a frameshift and premature termination codon 96 nucleotides downstream, and 498C-->G, a silent mutation. The maternal allele had a 835T-->C transition in exon 8 (S279P). Phosphoimaging quantitation of the parents' RNAs showed that the steady-state levels of mRNAs of the mutant exons 5 and 8 were 5% and 50%, respectively, of normal levels. The exon 5 mutated allele with the premature translation termination resulted in severe deficiency of Hex A. Transient expression of the exon 8 mutated alpha-chain cDNA in COS-1 cells resulted in deficiency of enzymatic activity. The child exhibited a late-infantile-type disease.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 96,
                "text": "HEXA"
            }
        },
        {
            "context": "FullSSR: Microsatellite Finder and Primer Designer. Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. The software was tested with 2000 sequences of Oryza sativa shotgun sequencing project from the National Center of Biotechnology Information Trace Archive and with partial genome sequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla platensis, and Zilchiopsis collastinensis. FullSSR performance was compared against other similar SSR search programs. The results of the use of this kind of approach depend on the parameters set by the user. In addition, results can be affected by the analyzed sequences because of differences among the genomes. FullSSR simplifies the detection of SSRs and primer design on a big data set. The command line interface of FullSSR was intended to be used as part of genomic analysis tools pipeline; however, it can be used as a stand-alone program because the results are easily interpreted for a nonexpert user.",
            "question": "Which tool exists for microsatellite (SSR) loci detection and primer design?",
            "answers": {
                "answer_start": 202,
                "text": "FullSSR"
            }
        },
        {
            "context": "Oral findings in patients with Apert syndrome. INTRODUCTION: The Apert syndrome is a rare disorder of autosomal dominant inheritance caused by mutations in the FGFR2 gene at locus 10q26; patients with this syndrome present severe syndactyly, exophthalmia, ocular hypertelorism and hypoplastic midface with Class III malocclusion, besides systemic alterations. Most investigations available on the Apert syndrome address the genetic aspect or surgical management, with little emphasis on the oral aspects. OBJECTIVE: To investigate the oral findings, including dental anomalies, ectopic eruption of the maxillary permanent first molars and soft tissue alterations, in subjects with Apert syndrome. MATERIALS AND METHODS: Clinical and radiographic examination of nine patients with Apert syndrome, aged 6 to 15 years, not previously submitted to orthodontic or orthognathic treatment. RESULTS: Dental anomalies were present in all patients, with one to eight anomalies per individual. The most frequent anomalies were tooth agenesis, mainly affecting maxillary canines, and enamel opacities (44.4% for both). Ectopic eruption of maxillary first molars was found in 33.3% of patients; lateral palatal swellings were observed in 88.8% of patients. CONCLUSIONS: The occurrence of typical lateral palatal swellings agrees with the literature. The high prevalence of dental anomalies and ectopic eruption may suggest a possible etiologic relationship with the syndrome.",
            "question": "What is the inheritance pattern of Apert syndrome?",
            "answers": {
                "answer_start": 102,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Measurement and reversal of the direct oral anticoagulants. Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Unlike VKAs, DOACs do not require routine laboratory monitoring of anticoagulant effect and dose adjustment. In certain situations, however, laboratory assessment of anticoagulant effect may be desirable. Here we review the utility of currently available assays for assessment of DOAC effect and recommend an optimal assessment strategy for each drug, including calibrated dilute thrombin time or ecarin-based assays for dabigatran and calibrated anti-Xa activity assays for the factor Xa inhibitors. We also discuss reversal strategies, both specific and nonspecific, for each drug, including the preferential use of idarucizumab for the reversal of dabigatran and two agents, andexanet and ciraparantag, currently under development for the reversal of rivaroxaban, apixaban, and edoxaban.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 984,
                "text": "dabigatran"
            }
        },
        {
            "context": "A new procedure for extraction of collagen from modern and archaeological bones for 14C dating. Bones are potentially the best age indicators in a stratigraphic study, because they are closely related to the layer in which they are found. Collagen is the most suitable fraction and is the material normally used in radiocarbon dating. Bone contaminants can strongly alter the carbon isotopic fraction values of the samples, so chemical pretreatment for (14)C dating by accelerator mass spectrometry (AMS) is essential. The most widespread method for collagen extraction is based on the Longin procedure, which consists in HCl demineralization to dissolve the inorganic phase of the samples, followed by dissolution of collagen in a weak acid solution. In this work the possible side effects of this procedure on a modern bone are presented; the extracted collagen was analyzed by ATR-IR spectroscopy. An alternative procedure, based on use of HF instead of HCl, to minimize unwanted degradation of the organic fraction, is also given. A study by ATR-IR spectroscopic analysis of collagen collected after different demineralization times and with different acid volumes, and a study of an archaeological sample, are also presented.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 34,
                "text": "collagen"
            }
        },
        {
            "context": "The database of the smallest known auto-replicable RNA species: viroids and viroid-like RNAs. This is an online database in order to facilitate research on viroid, viroid-like RNAs and human hepatitis delta virus by presenting a large number of sequences and related data in a comprehensive and user-friendly format (e.g., position of their self-catalytic domains, open reading frame, prediction of the most stable secondary structures, etc.). This online database is available on the WWW at http://www.callisto.si. usherb.ca/jpperra",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 64,
                "text": "viroids"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 479,
                "text": "xa"
            }
        },
        {
            "context": "Origin of human chromosome 2: an ancestral telomere-telomere fusion. We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 27,
                "text": "2"
            }
        },
        {
            "context": "[Variations in the composition of breast milk in Wilson's disease]. Wilson's disease is a rare genetic disorder of copper metabolism with autosomal recessive inheritance. It occurs between the 6th and 45th year of life. An early and reliable diagnosis, if possible in the preclinical stage, is the prerequisite for starting therapy in time. By the treatment the quality of life and the expectation of life are raised considerably. If consistent treatment is given, there will be no objections to pregnancy in Wilson's disease. It should be interrupted only in case of marked portal hypertension and in the presence of oesophageal varices. The examination of the breast milk of a patient suffering from Wilson's disease showed a reduction in the trace elements copper and zinc. It may be necessary to think of copper and zinc substitution in children fed with breast milk only.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 138,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. Specific outcomes upon activation of the c-Jun N-terminal kinase (JNK) pathway critically depend on the intensity and duration of signal transmission. Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. It has been shown that M3/6 itself is phosphorylated by JNK upon stimulation with arsenite, but the role of this phosphorylation has not been investigated. In this study, we mapped JNK-induced phosphorylation sites on M3/6 using mass spectrometry. Phosphorylated residues Ser 515, Thr 518 and Ser 520 were identified and site-directed mutagenesis was employed to investigate their role. Upon arsenite stimulation, M3/6 mutated at these sites exhibited decreased phosphorylation compared to the wild-type protein. No difference was observed in terms of the enzyme's in vitro phosphatase activity, its substrate specificity towards JNK isoforms, its interactions with JNK and the scaffold family of JNK-interacting proteins (JIPs), its stability or its subcellular localization. Interestingly, expression of M3/6 phosphorylation mutants delayed the time-course of JNK phosphorylation and activation by arsenite. We propose that phosphorylation of the M3/6 phosphatase by JNK in response to stress stimuli results in attenuation of phosphatase activity and acceleration of JNK activation.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 545,
                "text": "JNK"
            }
        },
        {
            "context": "Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.",
            "question": "Does dasatinib promote or inhibit T-cell proliferation?",
            "answers": {
                "answer_start": 63,
                "text": "inhibits"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome. A 14-month-old male child presented with recurrent generalized seizures, spastic hemiplegia, microcephaly and had developmental delay in motor and speech domains. CT of the brain revealed characteristic features diagnostic of infantile type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 275,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape. PURPOSE OF REVIEW: Despite ongoing efforts to decipher the cancer genome, discoveries of new targetable genetic lesions within cancer cells are rare. Therefore, alternative approaches are needed. Signals from the microenvironment are increasingly recognized as drivers of disease progression in hematologic and solid cancers. Consequently, there is growing interest in targeting the tumor-microenvironment cross-talk. This review highlights recent therapeutic advances in targeting the microenvironment in chronic lymphocytic leukemia (CLL). RECENT FINDINGS: CLL is the poster child for microenvironment-dependent malignancies, because the clonal CLL B cells are highly dependent on external signals for maintenance and expansion. These pathways recapitulate those responsible for normal B-cell expansion in germinal centers. The most prominent, conserved mechanism is B-cell receptor (BCR) signaling, which promotes CLL cell survival and expansion in lymphatic tissue areas designated proliferation centers. BCR signaling now can be targeted by new targeted kinase inhibitors. SUMMARY: Small molecule inhibitors of BCR signaling kinases, Bruton's tyrosine kinase (Btk) inhibitor ibrutinib and the phosphoinositide 3'-kinase delta (PI3Kδ) inhibitor GS-1101, are currently transforming the landscape of CLL therapy. This development exemplifies that the microenvironment has become a lively successful area of translational research.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1282,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Ca2+ binding to site I of the cardiac Ca2+ pump is sufficient to dissociate phospholamban. Phospholamban (PLB) inhibits the activity of SERCA2a, the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum, by decreasing the apparent affinity of the enzyme for Ca(2+). Recent cross-linking studies have suggested that PLB binding and Ca(2+) binding to SERCA2a are mutually exclusive. PLB binds to the E2 conformation of the Ca(2+)-ATPase, preventing formation of E1, the conformation that binds two Ca(2+) (at sites I and II) with high affinity and is required for ATP hydrolysis. Here we determined whether Ca(2+) binding to site I, site II, or both sites is sufficient to dissociate PLB from the Ca(2+) pump. Seven SERCA2a mutants with amino acid substitutions at Ca(2+)-binding site I (E770Q, T798A, and E907Q), site II (E309Q and N795A), or both sites (D799N and E309Q/E770Q) were made, and the effects of Ca(2+) on N30C-PLB cross-linking to Lys(328) of SERCA2a were measured. In agreement with earlier reports with the skeletal muscle Ca(2+)-ATPase, none of the SERCA2a mutants (except E907Q) hydrolyzed ATP in the presence of Ca(2+); however, all were phosphorylatable by P(i) to form E2P. Ca(2+) inhibition of E2P formation was observed only in SERCA2a mutants retaining site I. In cross-linking assays, strong cross-linking between N30C-PLB and each Ca(2+)-ATPase mutant was observed in the absence of Ca(2+). Importantly, however, micromolar Ca(2+) inhibited PLB cross-linking only to mutants retaining a functional Ca(2+)-binding site I. The dynamic equilibrium between Ca(2+) pumps and N30C-PLB was retained by all mutants, demonstrating normal regulation of cross-linking by ATP, thapsigargin, and anti-PLB antibody. From these results we conclude that site I is the key Ca(2+)-binding site regulating the physical association between PLB and SERCA2a.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 106,
                "text": "PLB"
            }
        },
        {
            "context": "Prevalence of tuberculosis infection and comparison of multiple-puncture liquid tuberculin test and Mantoux test among drug users. In order to determine the prevalence of latent infection due to Mycobacterium tuberculosis in drug users and to provide centres for drug users with a practical tool for tuberculosis screening, 237 drug users were subjected to the Monotest and, for reference purposes, to the Mantoux test. The overall prevalence of subjects with a tuberculin skin reaction size > or = 5 mm in the Mantoux test was 25.7%; utilizing a cut-off of > or = 10 mm, the prevalence was 11.4%. Irrespective of cut-off, the Monotest showed a sensitivity of > 90% and a specificity of > 80%. At a prevalence of 25.7%, and with cut-offs of > or = 5 or > or = 10 mm, the positive predictive value was 83% or 62.2%, respectively. Irrespective of cut-off, the negative predictive value was > 97%. In conclusion, the Monotest proved satisfactory as a tool for epidemiological screening in a population with a high prevalence for latent tuberculosis, namely drug users.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 300,
                "text": "tuberculosis"
            }
        },
        {
            "context": "Reactivation of an inactive human X chromosome introduced into mouse embryonal carcinoma cells by microcell fusion with persistent expression of XIST. An inactive human X chromosome was introduced by microcell fusion into two mouse embryonal carcinoma cell lines, PSA1-TG8 and OTF9-63, each of which has a single X chromosome. The donor cell line was a mouse-human somatic cell hybrid, CF150, retaining one or more inactive human X chromosome(s) per cell as its only human element. Twenty hybrid clones isolated retained EC morphology and contained the intact human X chromosome(s) or its truncated derivative(s). Replication banding analysis showed that the introduced human X chromosome(s) or its derivative(s) replicated synchronously with other mouse chromosomes, suggesting reactivation of the human X chromosomal elements after transfer. Reversal of inactivation was further confirmed by the expression of five human X-linked genes repressed in CF150, although the XIST (X inactive specific transcript) gene continued to be active. The level of XIST expression in our hybrid cells was almost identical to that of parental CF150 cells. Methylation status of 5' end of the active XIST gene varied considerably from almost full methylation to unmethylation in these hybrids. Thus, mouse EC cells used in this study were capable of altering methylation status of the human XIST gene in a manner lacking consistency and unable to repress its transcription. Furthermore, we failed to obtain any positive evidence for the occurrence of X chromosome inactivation in differentiating monochromosome EC hybrids. Taken together, these findings suggest that the human X chromosome inactivation center including the XIST gene is unable to function effectively in mouse cells.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 971,
                "text": "XIST"
            }
        },
        {
            "context": "Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus. Mouse microphthalmia transcription factor (Mitf) mutations affect the development of four cell types: melanocytes, mast cells, osteoclasts, and pigmented epithelial cells of the eye. The mutations are phenotypically diverse and can be arranged in an allelic series. In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. Mitf mice thus represent an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcriptionally complex and is capable of generating at least 13 different Mitf isoforms. Some of these isoforms are missing important functional domains of the protein, suggesting that they might play an inhibitory role in Mitf function and signal transduction. In addition, we determined the molecular basis for six microphthalmia mutations. Two of the mutations are reported for the first time here (Mitf(mi-enu198) and Mitf(mi-x39)), while the others (Mitf(mi-ws), Mitf(mi-bws), Mitf(mi-ew), and Mitf(mi-di)) have been described but the molecular basis for the mutation not determined. When analyzed in terms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects. Interestingly, three of the mutations (Mitf(mi-x39), Mitf(mi-bws), and Mitf(mi-ws)) produce proteins that are missing important functional domains of the protein identified in in vitro studies, further confirming a biological role for these domains in the whole animal.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 361,
                "text": "MITF"
            }
        },
        {
            "context": "Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). PURPOSE: To investigate refractive, topometric, pachymetric, and visual rehabilitation changes induced by anterior surface normalization for keratoconus by partial topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking. METHODS: Two hundred thirty-one keratoconic cases subjected to the Athens Protocol procedure were studied for visual acuity, keratometry, pachymetry, and anterior surface irregularity indices up to 3 years postoperatively by Scheimpflug imaging (Oculus Optikgeräte GmbH, Wetzlar, Germany). RESULTS: Mean visual acuity changes at 3 years postoperatively were +0.38 ± 0.31 (range: -0.34 to +1.10) for uncorrected distance visual acuity and +0.20 ± 0.21 (range: -0.32 to +0.90) for corrected distance visual acuity. Mean K1 (flat meridian) keratometric values were 46.56 ± 3.83 diopters (D) (range: 39.75 to 58.30 D) preoperatively, 44.44 ± 3.97 D (range: 36.10 to 55.50 D) 1 month postoperatively, and 43.22 ± 3.80 D (range: 36.00 to 53.70 D) up to 3 years postoperatively. The average Index of Surface Variance was 98.48 ± 43.47 (range: 17 to 208) pre-operatively and 76.80 ± 38.41 (range: 7 to 190) up to 3 years postoperatively. The average Index of Height Decentration was 0.091 ± 0.053 μm (range: 0.006 to 0.275 μm) preoperatively and 0.057 ± 0.040 μm (range: 0.001 to 0.208 μm) up to 3 years postoperatively. Mean thinnest corneal thickness was 451.91 ± 40.02 μm (range: 297 to 547 μm) preoperatively, 353.95 ± 53.90 μm (range: 196 to 480 μm) 1 month postoperatively, and 370.52 ± 58.21 μm (range: 218 to 500 μm) up to 3 years postoperatively. CONCLUSIONS: The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. Progressive potential for long-term flattening validates using caution in the surface normalization to avoid overcorrection.",
            "question": "Which eye condition is managed by the athens protocol?",
            "answers": {
                "answer_start": 0,
                "text": "Keratoconus"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 0,
                "text": "traseR"
            }
        },
        {
            "context": "A multicenter evaluation of the safety and efficacy of isradipine and atenolol in the treatment of hypertension. Isradipine in Hypertension Study Group. A total of 152 patients with essential hypertension (World Health Organization classification I/II) entered a multicenter randomized study to assess the safety and efficacy of isradipine compared with, and in combination with, the beta-blocker atenolol. After a three-week placebo treatment period, patients received either isradipine (2.5, 5, 7.5, or 10 mg twice daily) or atenolol (50 or 100 mg once daily) for seven weeks. Patients who did not have an adequate response (diastolic blood pressure less than 90 mm Hg) with the maximal doses of single-drug therapy were given a combination of both drugs for a further seven weeks. Both drugs resulted in significant and clinically relevant reductions in blood pressures. Although the reduction in diastolic blood pressure was the same for patients receiving the two drugs, there was a statistically significant greater reduction in systolic blood pressure in the isradipine group, suggesting that this drug has a more favorable effect on vascular impedance. Of the 14 patients who did not attain normal blood pressure levels (sitting diastolic blood pressure less than 90 mm Hg) receiving monotherapy, 12 patients reached this goal with a combination of the two drugs.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 99,
                "text": "hypertension"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1590,
                "text": "xa"
            }
        },
        {
            "context": "Gene structure and sequence analysis of mouse centromere proteins A and C. We have determined the genomic structure and organization of the mouse Cenpa and Cenpc genes. CENPA is a member of the histone H3-like proteins and is thought to replace histone H3 in centromeric nucleosomes. CENPC is a DNA-binding protein that is located at the inner kinetochore plate of active mammalian centromeres. The Cenpa cDNA encodes a 134-amino-acid product that is 70% identical and 84% similar to its human homolog. The mouse Cenpa gene is approximately 8 kb in length and contains five exons. Sequence analysis of the 5' DNA sequence of the gene revealed two consensus CAAT boxes, a putative TFIID-binding site, an Sp1-binding domain, and two cell cycle regulatory motifs, but no consensus TATA element. The mouse Cenpc gene spans 60 kb and contains 19 exons that range in size from 44 to 602 bp. Sequence analysis of the C+G-rich promoter region showed the presence of known promoter elements, including a CpG island, a CAAT box, and several GC boxes, but the absence of a consensus TATA element.",
            "question": "Where is the histone variant CENPA preferentially localized?",
            "answers": {
                "answer_start": 382,
                "text": "centromeres"
            }
        },
        {
            "context": "Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 826,
                "text": "L-dopa"
            }
        },
        {
            "context": "Functional variation of MC1R alleles from red-haired individuals. Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 351,
                "text": "Mc1r"
            }
        },
        {
            "context": "Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6-month extension study, long-term ( < 8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term ( < 2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for > 2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB.",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 155,
                "text": "tuberculosis"
            }
        },
        {
            "context": "McLeod syndrome resulting from a novel XK mutation. McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 39,
                "text": "XK"
            }
        },
        {
            "context": "Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1995,
                "text": "factor Xa"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1352,
                "text": "thyroid"
            }
        },
        {
            "context": "A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 80,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Regulation and functions of ADAR in drosophila. Drosophila melanogaster has a single Adar gene encoding a protein related to mammalian ADAR2 that edits transcripts encoding glutamate receptor subunits. We describe the structure of the Drosophila Adar locus and use ModENCODE information to supplement published data on Adar gene transcription, and splicing. We discuss the roles of ADAR in Drosophila in terms of the two main types of RNA molecules edited and roles of ADARs as RNA-binding proteins. Site-specific RNA editing events in transcripts encoding ion channel subunits were initially found serendipitously and subsequent directed searches for editing sites and transcriptome sequencing have now led to 972 edited sites being identified in 597 transcripts. Four percent of D. melanogaster transcripts are site-specifically edited and these encode a wide range of largely membrane-associated proteins expressed particularly in CNS. Electrophysiological studies on the effects of specific RNA editing events on ion channel subunits do not suggest that loss of RNA editing events in ion channels consistently produce a particular outcome such as making Adar mutant neurons more excitable. This possibility would have been consistent with neurodegeneration seen in Adar mutant fly brains. A further set of ADAR targets are dsRNA intermediates in siRNA generation, derived from transposons and from structured RNA loci. Transcripts with convergent overlapping 3' ends are also edited and the first discovered instance of RNA editing in Drosophila, in the Rnp4F transcript, is an example. There is no evidence yet to show that Adar antagonizes RNA interference in Drosophila. Evidence has been obtained that catalytically inactive ADAR proteins exert effects on microRNA generation and RNA interference. Whether all effects of inactive ADARs are due to RNA-binding or to even further roles of these proteins remains to be determined.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 135,
                "text": "ADAR"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis. A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice-daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (Cave50) of ~100 nM. Tofacitinib potency (ED50) in clinical studies was ~3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of ~40 nM, derived using Disease Activity Scores from patients with RA. The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy, rather than maximum or minimum plasma concentration (Cmax or Cmin), where Cave50 values were within ~2-fold of each other.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 39,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Mowat-Wilson syndrome: the first report of an association with central nervous system tumors. Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprung's disease, intellectual disability, and prominent facial features are present. At molecular level, MWS is characterized by many different described mutations in the zinc finger E-box protein 2 (ZEB2) gene, ultimately leading to loss of gene function. This report is the first to describe the association of MWS with two different asynchronous malignant brain tumors (medulloblastoma and glioblastoma) occurring in a child.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 416,
                "text": "ZEB2"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 253,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Novel approaches in the management of myeloma-related skeletal complications. Patients with multiple myeloma (MM) experience pathologic fractures, bone pain, hypercalcemia, neurologic symptoms, and renal insufficiency with substantial morbidity and mortality. Bisphosphonates have been used successfully for the management of MM-related bone disease. Increased incidence of osteonecrosis of the jaw has been observed in patients with cancer receiving bisphosphonate therapy. Recent advances in the pathobiology of MM-related bone disease and other cancer-related bone metastases have led to the identification of novel therapeutic targets, such as receptor activator of nuclear factor-kappaB (RANK); its ligand (RANKL); and a decoy receptor, osteoprotegerin, for the development of potential targeted agents. Initials studies have demonstrated that targeting RANK/ RANKL signaling with the fully human monoclonal antibody denosumab prevented skeletal complications in patients with MM and other cancers with bone metastases. Ongoing studies evaluating the clinical utility of denosumab in cancer- related bone destruction have been discussed. In addition, several potential targets, such as macrophage inflammatory protein-1alpha, chemokine receptors 1 and 5, interleukin-3, and Wnt signaling, are b riefly described.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 865,
                "text": "RANKL"
            }
        },
        {
            "context": "False positivity of monospot test in an immunocompetent elderly woman with acute cytomegalovirus infection. A 75-year-old woman presented with altered mental status, septic picture, and influenza-like symptoms. Initial investigations revealed atypical lymphocytosis, thrombocytopenia, elevated liver enzymes, and a positive monospot test result. Further investigation showed the Epstein-Barr virus viral capsid antibody IgM/IgG and Epstein-Barr virus DNA by polymerase chain reaction to be negative; however, interestingly her cytomegalovirus (CMV) IgM and IgG were positive, suggesting that her mononucleosis-like syndrome was due to acute CMV infection. Herein, we report the first case of a heterophile-positive mononucleosis syndrome caused by acute CMV infection in an elderly immunocompetent woman. This case conveys that monospot test can yield false-positive result in the setting of acute CMV infection.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 432,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Can the FAST and ROSIER adult stroke recognition tools be applied to confirmed childhood arterial ischemic stroke? BACKGROUND: Stroke recognition tools have been shown to improve diagnostic accuracy in adults. Development of a similar tool in children is needed to reduce lag time to diagnosis. A critical first step is to determine whether adult stoke scales can be applied in childhood stroke.Our objective was to assess the applicability of adult stroke scales in childhood arterial ischemic stroke (AIS) METHODS: Children aged 1 month to < 18 years with radiologically confirmed acute AIS who presented to a tertiary emergency department (ED) (2003 to 2008) were identified retrospectively. Signs, symptoms, risk factors and initial management were extracted. Two adult stroke recognition tools; ROSIER (Recognition of Stroke in the Emergency Room) and FAST (Face Arm Speech Test) scales were applied retrospectively to all patients to determine test sensitivity. RESULTS: 47 children with AIS were identified. 34 had anterior, 12 had posterior and 1 child had anterior and posterior circulation infarcts. Median age was 9 years and 51% were male. Median time from symptom onset to ED presentation was 21 hours but one third of children presented within 6 hours. The most common presenting stroke symptoms were arm (63%), face (62%), leg weakness (57%), speech disturbance (46%) and headache (46%). The most common signs were arm (61%), face (70%) or leg weakness (57%) and dysarthria (34%). 36 (78%) of children had at least one positive variable on FAST and 38 (81%) had a positive score of > 1 on the ROSIER scale. Positive scores were less likely in children with posterior circulation stroke. CONCLUSION: The presenting features of pediatric stroke appear similar to adult strokes. Two adult stroke recognition tools have fair to good sensitivity in radiologically confirmed childhood AIS but require further development and modification. Specificity of the tools also needs to be determined in a prospective cohort of children with stroke and non-stroke brain attacks.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 107,
                "text": "stroke"
            }
        },
        {
            "context": "Regulated specific proteolysis of the Cajal body marker protein coilin. Cajal bodies (CB) are subnuclear domains that contain various proteins with diverse functions including the CB marker protein coilin. In this study, we investigate the proteolytic activity of calpain on coilin. Here, we report a 28-kDa cleaved coilin fragment detected by two coilin antibodies that is cell cycle regulated, with levels that are consistently reduced during mitosis. We further show that an in vitro calpain assay with full-length or C-terminal coilin recombinant protein releases the same size cleaved fragment. Furthermore, addition of exogenous RNA to purified coilin induces proteolysis by calpain. We also report that the relative levels of this cleaved coilin fragment are susceptible to changes induced by various cell stressors, and that coilin localization is affected by inhibition or knockdown of calpain both under normal and stressed conditions. Collectively, our data suggest that coilin is subjected to regulated specific proteolysis by calpain, and this processing may play a role in the regulation of coilin activity and CB formation.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 198,
                "text": "coilin"
            }
        },
        {
            "context": "Genetic diversity of methicillin-resistant Staphylococcus aureus in a tertiary hospital in The Netherlands between 2002 and 2006. The aim of this study was to investigate the methicillin-resistant Staphylococcus aureus (MRSA) clones isolated in a Dutch university hospital, situated near the borders of Belgium and Germany, between 2002 and 2006. MRSA strains (n = 175) were characterized using spa and SCCmec typing. The presence of Panton Valentine leukocidin (PVL) was determined. Between 2002 and 2005, ST5-MRSA-IV was predominant, and the spa type of ST5-MRSA-IV changed from t002 to t447. ST5-MRSA-I, ST5-MRSA-II, ST228-MRSA-I, and ST247-MRSA-I were also observed in this period. From 2004, the MRSA genetic background became more diverse, and in 2006, ST5-MRSA-IV was only sporadically observed. From 2005, ST5-MRSA-II, ST8-MRSA-IV, ST22-MRSA-IV, and ST45-MRSA-IV were increasingly observed. Several other MRSA clones, such as ST239-MRSA-III, were found sporadically. Four PVL-positive MRSA isolates were observed, associated with ST80-MRSA-IV and ST8-MRSA-IV. ST5-MRSA-I, ST5-MRSA-II, ST5-MRSA-IV, and ST228-MRSA-I have not been described previously in The Netherlands.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 220,
                "text": "MRSA"
            }
        },
        {
            "context": "Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys. Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 781,
                "text": "L-Dopa"
            }
        },
        {
            "context": "Fam118B, a newly identified component of Cajal bodies, is required for Cajal body formation, snRNP biogenesis and cell viability. Cajal bodies are specialized and dynamic compartments in the nucleus that are involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs). Because of the dynamic and varied roles of Cajal bodies, it is of great interest to identify the components of Cajal bodies to better understand their functions. We performed a genome-wide screen to identify proteins that colocalize with coilin, the marker protein of Cajal bodies. In this study, we identified and characterized Fam118B as a newly discovered component of Cajal bodies. Fam118B is widely expressed in a variety of cell lines derived from various origins. Overexpression of Fam118B changes the canonical morphology of Cajal bodies, whereas depletion of Fam118B disrupts the localization of components of Cajal bodies, including coilin, the survival of motor neuron protein (SMN) and the Sm protein D1 (SmD1, also known as SNRPD1). Moreover, depletion of Fam118B reduces splicing capacity and inhibits cell proliferation. In addition, Fam118B associates with coilin and SMN proteins. Fam118B depletion reduces symmetric dimethylarginine modification of SmD1, which in turn diminishes the binding of SMN to this Sm protein. Taken together, these data indicate that Fam118B, by regulating SmD1 symmetric dimethylarginine modification, plays an important role in Cajal body formation, snRNP biogenesis and cell viability.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 519,
                "text": "coilin"
            }
        },
        {
            "context": "Focal cortical dysplasia in meningioangiomatosis. Meningioangiomatosis is a rare, benign, developmental, or hamartomatous lesion which may involve the leptomeninges and underlying brain parenchyma. Histologically, meningioangiomatosis is marked by a proliferation of blood vessels in the parenchyma, rimmed by collars of spindled meningothelial cells. There are anecdotal reports of an association of meningioangiomatosis with focal cortical dysplasia. We retrospectively analyzed the clinical, histopathologic, and treatment outcomes of 16 patients with a diagnosis of meningioangiomatosis, specifically investigating these cases for evidence of adjacent focal cortical dysplasia. Patients ranged in age from 1 to 34 years (median 18), 12 of whom had medically-intractable epilepsy as their presenting symptom. No patients in this study had a confirmed diagnosis of neurofibromatosis type II. Four patients (25%) were found to have fibrous meningiomas associated with the meningioangiomatosis. Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. Seven of the patients (44%) had no post-operative seizures, and were off anti-epileptic drugs, while 2 patients relapsed, and required pharmacologic treatment for seizure control. This study therefore presents evidence to support inclusion of meningioangiomatosis as a focal cortical dysplasia-associated entity, as suggested by the ILAE classification (type IIIc). As focal cortical dysplasia is a developmental malformation, its association with meningioangiomatosis supports a developmental etiology of sporadic meningioangiomatosis.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1118,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.",
            "question": "To which disease does the loss of CD28 expression by liver-infiltrating T cells contribute?",
            "answers": {
                "answer_start": 85,
                "text": "primary sclerosing cholangitis"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 537,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease. Here we define the role of phosphorylation of Ser129 in alpha-synuclein toxicity and inclusion formation using a Drosophila model of Parkinson disease. Mutation of Ser129 to alanine to prevent phosphorylation completely suppresses dopaminergic neuronal loss produced by expression of human alpha-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances alpha-synuclein toxicity. The G protein-coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances alpha-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating alpha-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity.",
            "question": "Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?",
            "answers": {
                "answer_start": 160,
                "text": "serine 129"
            }
        },
        {
            "context": "Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1257,
                "text": "thyroid"
            }
        },
        {
            "context": "Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone. Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 287,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Effect of genetic and environmental factors on protein biomarkers for common non-communicable disease and use of personally normalized plasma protein profiles (PNPPP). OBJECTIVE: To study the impact of genetic and lifestyle factors on protein biomarkers and develop personally normalized plasma protein profiles (PNPPP) controlling for non-disease-related variance. MATERIALS AND METHODS: Proximity extension assays were used to measure 145 proteins in 632 controls and 344 cases with non-communicable diseases. RESULTS: Genetic and lifestyle factors explained 20-88% of the variation in healthy controls. Adjusting for these factors reduced the number of candidate biomarkers by 63%. CONCLUSION: PNPPP efficiently controls for non-disease-related variance, allowing both for efficient discovery of novel biomarkers and for covariate-independent linear cut-offs suitable for clinical use.",
            "question": "What is PNPPP?",
            "answers": {
                "answer_start": 266,
                "text": "personally normalized plasma protein profiles"
            }
        },
        {
            "context": "Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries. Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 275,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 901,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Multiplex real-time PCR for detecting and typing Clostridium botulinum group III organisms and their mosaic variants. Botulism is a neuroparalytic disease that can occur in all warm-blooded animals, birds, and fishes. The disease in animals is mainly caused by toxins produced by Clostridium botulinum strains belonging to group III, although outbreaks due to toxins produced by group I and II organisms have been recognized. Group III strains are capable of producing botulinum toxins of type C, D, and C/D and D/C mosaic variants. Definitive diagnosis of animal botulism is made by combining clinical findings with laboratory investigations. Detection of toxins in clinical specimens and feed is the gold standard for laboratory diagnosis. Since toxins may be degraded by organisms contained in the gastrointestinal tract or may be present at levels below the detection limit, the recovery of C. botulinum from sick animal specimens is consistent for laboratory confirmation. In this article we report the development and in-house validation of a new multiplex real-time PCR for detecting and typing the neurotoxin genes found in C. botulinum group III organisms. Validation procedures have been carried out according to ISO 16140, using strains and samples recovered from cases of animal botulism in Italy and France.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 280,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. Although pharmacologic therapies have provided gains in reducing the mortality of heart failure, the rising incidence of the disease requires new approaches to combat its health burden. Twenty-five years ago, abnormal calcium cycling was identified as a characteristic of failing human myocardium. Sarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling. With the advancement of gene vectors, SERCA2a emerged as an attractive clinical target for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a upregulation has been found to improve myocardial function in animal models. The clinical benefits of overexpressing SERCA2a have been demonstrated in the phase I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID). This study has demonstrated that a persistent expression of the transgene SERCA2a is associated with a significant improvement in associated biochemical alterations and clinical symptoms of heart failure. In the coming years, additional targets will likely emerge that are amenable to genetic manipulations along with the development of more advanced vector systems with safer delivery approaches.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 402,
                "text": "SERCA2"
            }
        },
        {
            "context": "Tofacitinib: The First Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy and safety, dosage administration, and adverse effects of tofacitinib for rheumatoid arthritis (RA) treatment. DATA SOURCES: Primary sources of information were obtained from clinical studies, which were identified through PubMed (1966 to June 2013) and International Pharmaceutical Abstracts (1970 to March 2013) using terms: tofacitinib, tasocitinib, CP-690550, and CP-690,550. Information was used from tofacitinib package insert, guidelines, and published abstracts from the American College of Rheumatology (ACR) and the European League Against Rheumatism. STUDY SELECTION AND DATA EXTRACTION: Data search was limited to include publications in English language and from human subjects. DATA SYNTHESIS: Tofacitinib is the first oral Janus kinase inhibitor indicated for treatment of moderate to severe RA. Tofacitinib demonstrated efficacy and safety comparable to other disease-modifying antirheumatic drugs (DMARDs). Tofacitinib was efficacious in RA patients, indicated by achievements of ACR20, ACR50, and ACR70 criteria. Similar improvements were observed in patients who met remission criteria based on the Disease Activity Scores 28 criteria and quality of life as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Tofacitinib was associated with infections and malignancies; and elevations in serum creatinine and lipids were observed. Drug interactions with inducers and inhibitors of the cytochrome P-450 3A4 and 2C9 isoenzymes were reported. CONCLUSIONS: Tofacitinib is an oral treatment option for RA patients who have inadequate response or intolerance to methotrexate. Postmarket surveillance will provide further insight to tofacitinib's role in RA therapy, especially in patients who may require different types of combination therapy with DMARDS.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 869,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 297,
                "text": "MITF"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy (SUDEP): what do patients think? OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in epilepsy. Despite its devastating consequences, SUDEP appears to be poorly discussed with patients by health professionals. The risk of causing psychological distress to the patient is highlighted as a reason for not discussing SUDEP. However, no studies have assessed the adult patients' views on this important question. We conducted this cross-sectional study to evaluate the awareness and perspectives on SUDEP among adult patients with epilepsy. METHODS: One hundred five consecutive adult patients with epilepsy, referred to the Epilepsy Clinic of a tertiary hospital between October 2012 and November 2013, were surveyed to ascertain their views and understanding of SUDEP. The data were analyzed using logistic regression to explore the association between patients' awareness of SUDEP and characteristics such as age, gender, duration of epilepsy, level of education, and employment. RESULTS: Awareness of SUDEP among adult patients with epilepsy was poor (14.3%). However, the vast majority (89.5%) wished to be informed about SUDEP, and 59% requested detailed information. The treating neurologist was considered to be the most appropriate source of SUDEP information by 85.6% of patients. Multivariable analysis of the data showed no association between characteristics of patients (age, gender, duration of epilepsy, level of education, and employment) and their awareness of SUDEP or desire to get SUDEP-related information. CONCLUSIONS: Our study suggests that the majority of adult patients wish to be informed about SUDEP. This is in contrast to the general reluctance of medical professionals to inform all patients routinely about this condition.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 0,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. To clarify the roles of Bmi-1 in colorectal carcinoma, we examined the expression of Bmi-1 in 41 samples out of 46 colorectal carcinomas by reverse transcription-PCR, whereas all 46 were analyzed by immunostaining. In addition, we analyzed the expression patterns of Bmi-1 in association with p16INK4a and p14ARF (in mouse p19ARF) in a series of colorectal carcinomas. The level of Bmi-1 mRNA in the carcinoma tissues was significantly higher than those of the adjacent non-neoplastic colonic mucosal tissues. Immunohistochemistry for Bmi-1 showed moderate or strong expression levels in 65% (30/46) of colorectal carcinomas. Colorectal carcinomas with moderate or strong Bmi-1 expression were more likely to have low levels of the INK4 locus proteins (p16INK4a/p14ARF) (P<0.07). These results suggested that modulation of Bmi-1 protein might be involved in human colorectal carcinogenesis by repressing the INK4a/ARF proteins.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 98,
                "text": "p16INK4"
            }
        },
        {
            "context": "Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 25,
                "text": "cancer"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 99,
                "text": "7"
            }
        },
        {
            "context": "Delayed myelination is not a constant feature of Allan-Herndon-Dudley syndrome: report of a new case and review of the literature. INTRODUCTION: Allan-Herndon-Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. CASE REPORT: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14months, were normal. DISCUSSION: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan-Herndon-Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 1503,
                "text": "thyroid"
            }
        },
        {
            "context": "Adductor laryngeal breathing dystonia in a patient with lubag (X-linked dystonia-Parkinsonism syndrome). We report a patient with Lubag (X-linked dystonia-parkinsonism) who presented with severe respiratory stridor from adductor laryngeal breathing dystonia. Emergency tracheostomy was necessary, and subsequent laryngeal injection with botulinum toxin led to worsening aspiration. Botulinum toxin injection for severe lingual dystonia was successful.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 137,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings. The McLeod syndrome is an X-linked disorder caused by mutations of the XK gene encoding the XK protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxy-glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X-linked trait should be examined for acanthocytosis and Kell/Kx blood group serology.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 535,
                "text": "XK"
            }
        },
        {
            "context": "Surviving competitive athletics with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HC) is probably the most common cause of sudden cardiac death in youthful athletes, and this diagnosis has represented a contraindication to continued participation in competitive sports. Less well appreciated is the fact that within the clinical spectrum of HC are patients who, despite having this disease, have been able to undertake particularly intensive and often extraordinary levels of training for sports competition over many years without dying suddenly. Fourteen such patients (13 men and 1 woman, aged 30 to 66 years [mean 43]) form the present study group. HC was initially identified at 24 to 57 years of age (mean 34), usually under fortuitous circumstances. Patients most often competed in distance running (including the marathon, 7), but also in swimming, triathalon, basketball, and football. The duration of training ranged from 6 to 22 years (mean 15) and 5 continue to train and compete actively. The magnitude of training, competition, and achievement was considerable in most patients; 12 of the 14 performed either at the national, collegiate or professional level in their sport, completed numerous marathon and triathalon events, or sustained particularly rigorous training regimens of > or = 50 miles/week. Echocardiographic studies demonstrated a left ventricular wall thickness of 18 to 28 mm (mean 20) in most patients (12 of 14) having a relatively localized pattern of ventricular septal hypertrophy. It is possible for some patients with HC to tolerate particularly intense athletic training and competition for many years, and even maintain high levels of achievement without incurring symptoms and disease progression or dying suddenly.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 66,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Assessing manganese efflux using SEA0400 and cardiac T1-mapping manganese-enhanced MRI in a murine model. The sodium-calcium exchanger (NCX) is one of the transporters contributing to the control of intracellular calcium (Ca(2+)) concentration by normally mediating net Ca(2+) efflux. However, the reverse mode of the NCX can cause intracellular Ca(2+) concentration overload, which exacerbates the myocardial tissue injury resulting from ischemia. Although the NCX inhibitor SEA0400 has been shown to therapeutically reduce myocardial injury, no in vivo technique exists to monitor intracellular Ca(2+) fluctuations produced by this drug. Cardiac manganese-enhanced MRI (MEMRI) may indirectly assess Ca(2+) efflux by estimating changes in manganese (Mn(2+)) content in vivo, since Mn(2+) has been suggested as a surrogate marker for Ca(2+). This study used the MEMRI technique to examine the temporal features of cardiac Mn(2+) efflux by implementing a T(1)-mapping method and inhibiting the NCX with SEA0400. The change in (1)H(2)O longitudinal relaxation rate, Delta R(1), in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl(2)) in healthy adult male mice. The results showed 50% MEMRI signal attenuation at 3.4 +/- 0.6 h post-MnCl(2) infusion without drug intervention. Furthermore, treatment with 50 +/- 0.2 mg/kg of SEA0400 significantly reduced the rate of decrease in Delta R(1). At 4.9-5.9 h post-MnCl(2) infusion, the average Delta R(1) values for the two groups treated with SEA0400 were 2.46 +/- 0.29 and 1.72 +/- 0.24 s(-1) for 50 and 20 mg/kg doses, respectively, as compared to the value of 1.27 +/- 0.28 s(-1) for the control group. When this in vivo data were compared to ex vivo absolute manganese content data, the MEMRI T(1)-mapping technique was shown to effectively quantify Mn(2+) efflux rates in the myocardium. Therefore, combining an NCX inhibitor with MEMRI may be a useful technique for assessing Mn(2+) transport mechanisms and rates in vivo, which may reflect changes in Ca(2+) transport.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 318,
                "text": "NCX"
            }
        },
        {
            "context": "Validation of the STOP-Bang Questionnaire as a Screening Tool for Obstructive Sleep Apnea among Different Populations: A Systematic Review and Meta-Analysis. BACKGROUND: Diagnosing obstructive sleep apnea (OSA) is clinically relevant because untreated OSA has been associated with increased morbidity and mortality. The STOP-Bang questionnaire is a validated screening tool for OSA. We conducted a systematic review and meta-analysis to determine the effectiveness of STOP-Bang for screening patients suspected of having OSA and to predict its accuracy in determining the severity of OSA in the different populations. METHODS: A search of the literature databases was performed. Inclusion criteria were: 1) Studies that used STOP-Bang questionnaire as a screening tool for OSA in adult subjects (>18 years); 2) The accuracy of the STOP-Bang questionnaire was validated by polysomnography--the gold standard for diagnosing OSA; 3) OSA was clearly defined as apnea/hypopnea index (AHI) or respiratory disturbance index (RDI) > 5; 4) Publications in the English language. The quality of the studies were explicitly described and coded according to the Cochrane Methods group on the screening and diagnostic tests. RESULTS: Seventeen studies including 9,206 patients met criteria for the systematic review. In the sleep clinic population, the sensitivity was 90%, 94% and 96% to detect any OSA (AHI > 5), moderate-to-severe OSA (AHI > 15), and severe OSA (AHI > 30) respectively. The corresponding NPV was 46%, 75% and 90%. A similar trend was found in the surgical population. In the sleep clinic population, the probability of severe OSA with a STOP-Bang score of 3 was 25%. With a stepwise increase of the STOP-Bang score to 4, 5, 6 and 7/8, the probability rose proportionally to 35%, 45%, 55% and 75%, respectively. In the surgical population, the probability of severe OSA with a STOP-Bang score of 3 was 15%. With a stepwise increase of the STOP-Bang score to 4, 5, 6 and 7/8, the probability increased to 25%, 35%, 45% and 65%, respectively. CONCLUSION: This meta-analysis confirms the high performance of the STOP-Bang questionnaire in the sleep clinic and surgical population for screening of OSA. The higher the STOP-Bang score, the greater is the probability of moderate-to-severe OSA.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 66,
                "text": "Obstructive Sleep Apnea"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 433,
                "text": "xa"
            }
        },
        {
            "context": "Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 24,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Effect of partial blockade of the Na(+)/Ca(2+)-exchanger on Ca(2+) handling in isolated rat ventricular myocytes. SEA0400 is a selective inhibitor of the Na(+)/Ca(2+) exchanger having equal potencies to suppress both the forward and reverse mode operation of the Na(+)/Ca(2+) exchanger. Present experiments were designed to study the effect of partial blockade of Na(+)/Ca(2+) exchanger on Ca(2+) handling in isolated rat ventricular myocytes. Intracellular Ca(2+) transient and cell shortening were measured in ventricular myocytes loaded with Fura-2-AM fluorescent dye. Partial blockade of Na(+)/Ca(2+) exchanger was induced by superfusion of the cells with SEA0400 at a concentration of 0.3 microM. Amplitude of the intracellular Ca(2+) transient and cell shortening was significantly increased by SEA0400 in both field stimulated and voltage clamped myocytes, without significant elevation of diastolic Ca(2+) level and the decay time constant of the Ca(2+) transient. In patch clamped myocytes the SEA0400 induced increase in the Ca(2+) transient and cell shortening was accompanied by significant reduction of peak L-type Ca(2+) current. These effects can be explained by the autoregulative nature of cardiac Ca(2+) handling, as the reduced Ca(2+) efflux from the cell results in an increased Ca(2+) load to the sarcoplasmic reticulum leading to increased Ca(2+) release, which in turn may decrease the L-type Ca(2+) current by accelaration of Ca(2+) dependent inactivation of L-type Ca(2+) current. Our results suggest that complex changes in the Ca(2+) cycling can occur after selective pharmacological inhibition of the Na(+)/Ca(2+) exchanger.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 263,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 1618,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1083,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 102,
                "text": "DBA"
            }
        },
        {
            "context": "Genetic galactocerebrosidase deficiency (globoid cell leukodystrophy, Krabbe disease) in rhesus monkeys (Macaca mulatta). Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. Cloning of the human and animal GALC genes opened opportunities for therapeutic trials using animal models. We describe the clinical, pathologic, and biochemical features of the affected rhesus monkey. Affected monkeys had very low GALC activity and a two base pair deletion in both copies of the GALC gene. Clinical signs of tremors, hypertonia, and incoordination led to humane euthanasia by 5 months of age. At necropsy, peripheral nerves were enlarged. Microscopically, the cerebral, cerebellar, and spinal cord white matter was infiltrated with periodic acid-Schiff-positive multinucleated globoid cells, and there was a striking lack of myelin. Peripheral nerve fibers were decreased in number and separated by Alcian blue- and safranin O-positive material. Myelin sheaths were greatly diminished. Lipid analysis of brains of 12-day-old and 158-day-old affected monkeys revealed a great excess of psychosine in white matter. The rhesus monkey model will be especially useful for exploring treatment options, including prenatal bone marrow transplantation and various approaches to gene therapy.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 263,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Endoplasmic reticulum-specific BH3-only protein BNIP1 induces mitochondrial fragmentation in a Bcl-2- and Drp1-dependent manner. Bcl-2/adenovirus E1B 19-kDa interacting protein 1 (BNIP1), which is predominantly localized to the endoplasmic reticulum (ER), is a pro-apoptotic Bcl-2 homology domain 3 (BH3)-only protein. Here, we show that the expression of BNIP1 induced not only a highly interconnected ER network but also mitochondrial fragmentation in a BH3 domain-dependent manner. Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission. Both BNIP1-induced mitochondrial fission and the translocation of Drp1 were abrogated by Bcl-2 overexpression. These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 922,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 969,
                "text": "PD-L1"
            }
        },
        {
            "context": "Effect of dural detachment on long-term tumor control for meningiomas treated using Simpson grade IV resection. OBJECT: Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrence-free survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection. METHODS: This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth. RESULTS: A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm(3) or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41-45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18-218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm(3) or more was not a statistically significant risk factor. CONCLUSIONS: Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long-term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high-risk meningiomas not amenable to gross-total resection.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 769,
                "text": "meningioma"
            }
        },
        {
            "context": "Late response to low-dose imatinib in patients with chronic phase chronic myeloid leukemia. Imatinib was the first BCR-ABL tyrosine kinase inhibitor to become clinically available. In this study, we retrospectively evaluated the long-term efficacy of low-dose imatinib (final maintenance dose <300 mg per day) due to intolerance, in comparison to optimal-dose imatinib ( > 300 mg per day) in patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase. The Kaplan-Meier estimates of the median time to complete cytogenetic response, major molecular response, and complete molecular response were longer for 31 patients receiving low-dose imatinib (360, 1360, and 1420 days, respectively) than 74 patients receiving optimal-dose imatinib (170, 420, and 720 days, respectively). However, the differences in response shrank over time and progression-free survival were comparable between the two groups. These findings suggest that long-term treatment with low-dose imatinib is an acceptable alternative for patients with intolerance to the optimal dose.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 115,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Comparison of the Xpert methicillin-resistant Staphylococcus aureus (MRSA) assay, BD GeneOhm MRSA assay, and culture for detection of nasal and cutaneous groin colonization by MRSA. Detection of methicillin (meticillin)-resistant Staphylococcus aureus colonization was assessed using combined nose and groin swabs in two commercial PCR assays (the Xpert MRSA assay and the BD GeneOhm MRSA assay). Compared to routine culture, both had similar sensitivities (87.0% versus 84.8%, respectively) and specificities (93.8% versus 92.7%, respectively). Combined PCR assays provide a rapid and more-complete assessment of colonization at a cost similar to that of single-site analysis.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 69,
                "text": "MRSA"
            }
        },
        {
            "context": "Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH2-terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 291,
                "text": "DBA"
            }
        },
        {
            "context": "Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson's disease. A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 360,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis. A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice-daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (Cave50) of ~100 nM. Tofacitinib potency (ED50) in clinical studies was ~3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of ~40 nM, derived using Disease Activity Scores from patients with RA. The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy, rather than maximum or minimum plasma concentration (Cmax or Cmin), where Cave50 values were within ~2-fold of each other.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 352,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Exploring the effectiveness of combined mentalization-based group therapy and dialectical behaviour therapy for inpatients with borderline personality disorder - A pilot study. OBJECTIVES: Borderline personality disorder (BPD) is characterized by emotional instability, interpersonal dysfunction, and other features that typically develop before a background of insecure attachment and traumatic experiences. Dialectical behaviour therapy (DBT) has proven highly effective in reducing self-harm and improving emotion regulation, whereby problems concerning social cognition, which are also characteristic of BPD, may need additional approaches such as mentalization-based treatment (MBT). METHODS: Here, we examined, in a pilot study, the effectiveness of MBT given adjunct to DBT, compared to DBT alone, in an inpatient sample with BPD, whereby mentalization was measured using a novel cartoon-based task. RESULTS: Both treatments were highly effective in reducing symptom severity. The combination of DBT and MBT was superior in reducing fearful attachment and in improving affective mentalizing. CONCLUSIONS: Mentalization-based treatment in combination with DBT may improve certain aspects of social cognitive skills and attachment security, as compared to DBT alone, although the exact mechanisms that led to these changes need to be studied further. PRACTITIONER POINTS: Clinical implications Dialectical behaviour therapy (DBT) can usefully be combined with mentalization-based treatment (MBT). The combination of DBT and MBT reduces self-harm more than DBT alone. DBT plus MBT may lead to a reduction in fearful attachment and improvement of affective mentalizing. Short-term combinations of evidence-based borderline treatments may enrich psychiatric inpatient care. Therefore, such approaches deserve further research. Limitations The treatment condition was therapeutically more intense than the control condition. The study lacked a follow-up assessment. The impact of comorbid conditions on treatment response was not taken into account. Adherence to the manualized approach was not measured.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 128,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Kinetic manifestation of processivity during multiple methylations catalyzed by SET domain protein methyltransferases. Processive versus distributive methyl group transfer was assessed for pea Rubisco large subunit methyltransferase, a SET domain protein lysine methyltransferase catalyzing the formation of trimethyllysine-14 in the large subunit of Rubisco. Catalytically competent complexes between an immobilized form of des(methyl) Rubisco and Rubisco large subunit methyltransferase were used to demonstrate enzyme release that was co-incident with and dependent on formation of trimethyllysine. Catalytic rate constants determined for formation of trimethyllysine were considerably lower ( approximately 10-fold) than rate constants determined for total radiolabel incorporation from [3H-methyl]-S-adenosylmethionine. Double-reciprocal velocity plots under catalytic conditions favoring monomethyllysine indicated a random or ordered reaction mechanism, while conditions favoring trimethyllysine suggested a hybrid ping-pong mechanism. These results were compared with double-reciprocal velocity plots and product analyses obtained for HsSET7/9 (a monomethyltransferase) and SpCLR4 (a dimethyltransferase) and suggest a predictive ability of double-reciprocal velocity plots for single versus multiple methyl group transfers by SET domain protein lysine methyltransferases. A model is proposed for SET domain protein lysine methyltransferases in which initial binding of polypeptide substrate and S-adenosylmethionine is random, with polypeptide binding followed by deprotonation of the epsilon-amine of the target lysyl residue and subsequent methylation. Following methyl group transfer, S-adenosylhomocysteine and monomethylated polypeptide dissociate from monomethyltransferases, but di- and trimethyltransferases begin a successive and catalytically obligatory deprotonation of enzyme-bound methylated lysyl intermediates, which along with binding and release of S-adenosylmethionine and S-adenosylhomocysteine is manifested as a hybrid ping-pong-like reaction mechanism.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 1335,
                "text": "SET domain"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Genetic variation within coat color genes of MC1R and ASIP in Chinese brownish red Tibetan pigs. Melanocortin receptor 1 (MC1R) and agouti signaling protein (ASIP) are two major genes affecting coat color phenotypes in mammals, and inactivation mutations in the MC1R gene are responsible for red coat color in European pig breeds. Conversely, the gain-of-function ASIP mutations block MC1R signaling and lead to the production of red pheomelanin. Chinese Tibetan pigs have three types of coat color phenotypes, including brownish red, solid black and black with patches of brownish red and white. Herein, we investigated variations of the MC1R and ASIP genes in Tibetan pigs. The results showed that the brownish red Tibet pig had the dominant black MC1R allele (E(D1)). No loss-of-function mutation in MC1R responsible for red coat color in European breeds was observed in this breed. No causal mutation for the red coat color phenotype was found in the coding sequence of the ASIP gene. A novel missense mutation c.157G > A was firstly identified in exon 2 of ASIP, which was further genotyped in 285 pigs from five Chinese breeds and three Western breeds having different coat color phenotypes. Nearly all pigs were GG homozygotes. In conclusion, no functional variant responsible for brownish red coloration was found in the coding region of MC1R and ASIP in Tibetan pigs.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 122,
                "text": "MC1R"
            }
        },
        {
            "context": "Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1043,
                "text": "telomerase"
            }
        },
        {
            "context": "ACS chemical neuroscience molecule spotlight on Telcagepant (MK-0974). Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html). MK-0974 is currently being studied in phase III clinical trials.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 104,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation. Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 341,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations. The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 316,
                "text": "5p15.3"
            }
        },
        {
            "context": "Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 345,
                "text": "PLN"
            }
        },
        {
            "context": "The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. Dnmt1 (DNA methyltransferase 1) is the principal enzyme responsible for maintenance of cytosine methylation at CpG dinucleotides in the mammalian genome. The N-terminal replication focus targeting sequence (RFTS) domain of Dnmt1 has been implicated in subcellular localization, protein association, and catalytic function. However, progress in understanding its function has been limited by the lack of assays for and a structure of this domain. Here, we show that the naked DNA- and polynucleosome-binding activities of Dnmt1 are inhibited by the RFTS domain, which functions by virtue of binding the catalytic domain to the exclusion of DNA. Kinetic analysis with a fluorogenic DNA substrate established the RFTS domain as a 600-fold inhibitor of Dnmt1 enzymatic activity. The crystal structure of the RFTS domain reveals a novel fold and supports a mechanism in which an RFTS-targeted Dnmt1-binding protein, such as Uhrf1, may activate Dnmt1 for DNA binding.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 96,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Mechanisms of activation of NADPH oxidases. The members of the NOX family of enzymes are expressed in a variety of tissues and serve a number of functions. There is a high level of conservation of primary protein sequence, as well as functional features, although specialized responses are beginning to emerge. In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function. Studies of cytosolic co-factors showed that the C-terminal cytoplasmic domain of NOX1 was absolutely required for activation with NOXO1 and NOXA1 and that this activity required interaction of the putative NADPH-binding region of this domain with NOXA1. Finally, we have provided the first example of how alternative splicing of a NOX co-factor may be involved in the regulation of NADPH oxidase function.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 657,
                "text": "NOX1"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 175,
                "text": "MRSA"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 499,
                "text": "xa"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 767,
                "text": "miR-7"
            }
        },
        {
            "context": "Pallidal and thalamic neurostimulation in severe tardive dystonia. A 70 year old woman presented with a 6 year history of medically refractory severe tardive dystonia. After informed consent, a bilateral stereotactic electrode placement targeting the ventral intermediate thalamic nucleus (VIM) and the globus pallidus internus (GPi) was performed. After bilateral stimulation of the GPi, the patient showed a clear and stable improvement of the painful dystonic syndrome within hours. Stimulation of the VIM did not improve the hyperkinetic movements and simultaneous stimulation of both the GPi and the VIM did not result in any additional benefit. The possible pathophysiological mechanisms are discussed.",
            "question": "Neurostimulation of which nucleus is used for treatment of dystonia?",
            "answers": {
                "answer_start": 303,
                "text": "globus pallidus internus"
            }
        },
        {
            "context": "Impact of training for healthcare professionals on how to manage an opioid overdose with naloxone: effective, but dissemination is challenging. BACKGROUND: Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). Training in these skills has been successfully trialled internationally with opioid users themselves. Healthcare professionals working in substance misuse are in a prime position to deliver overdose prevention training to drug users and may themselves witness opioid overdoses. The best method of training dissemination has not been identified. The study assessed post-training change in clinician knowledge for managing an opioid overdose and administering naloxone, evaluated the 'cascade method' for disseminating training, and identified barriers to implementation. METHODS: A repeated-measures design evaluated knowledge pre-and-post training. A sub-set of clinicians were interviewed to identify barriers to implementation. Clinicians from addiction services across England received training. Participants self-completed a structured questionnaire recording overdose knowledge, confidence and barriers to implementation. RESULTS: One hundred clinicians were trained initially, who trained a further 119 clinicians (n=219) and thereafter trained 239 drug users. The mean composite score for opioid overdose risk signs and actions to be taken was 18.3/26 (±3.8) which increased to 21.2/26 (±4.1) after training, demonstrating a significant improvement in knowledge (Z=9.2, p<0.001). The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation. CONCLUSIONS: Training clinicians how to manage an opioid overdose and administer naloxone was effective. However the 'cascade method' was only modestly successful for disseminating training to a large clinician workforce, with a range of clinician and service perceived obstacles. Drug policy changes and improvements to educational programmes for drug services would be important to ensure successful implementation of overdose training internationally.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 259,
                "text": "naloxone"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers. METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 and 1,200 mg) were administered to eight groups of eight subjects per group (two subjects randomized to placebo and six subjects to opicapone), under a double-blind, randomized, placebo-controlled design. In an additional group of 12 subjects, a 50 mg single dose of opicapone was administered on two occasions, once having fasted overnight and once with a high-fat high-calorie meal. RESULTS: Opicapone was well tolerated at all doses tested. The extent of systemic exposure (area under the plasma concentration-time curve and maximum plasma concentration) to opicapone and metabolites increased in an approximately dose-proportional manner and showed a decrease following concomitant ingestion of a high-fat high-calorie meal. The apparent terminal elimination half-life of opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway for opicapone, and both opicapone and the main sulphated metabolite are likely excreted by the biliary route. Maximum COMT inhibition by opicapone was dose dependent, ranged from 36.1% (10 mg) to 100% (200 mg and above), and reached statistical significance at all doses tested. The long duration of COMT inhibition by opicapone, however, tended to be independent from the dose taken. The observed half-life of opicapone-induced COMT inhibition in human erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an underlying dissociative process with a kinetic rate constant of 3.1 × 10(-6) s(-1) (SD = 1.9 × 10(-6) s(-1)). Such a process compares well to the estimated dissociation rate constant (k(off)) of the COMT-opicapone molecular complex (k(off) = 1.9 × 10(-6) s(-1)). CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 74,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 535,
                "text": "CD38"
            }
        },
        {
            "context": "Platelet 5-HT concentration and comorbid depression in war veterans with and without posttraumatic stress disorder. BACKGROUND: The serotonergic system is implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and depression. The present study focused on platelet serotonin (5-HT) concentration and symptoms of comorbid depression in war veterans with or without PTSD. METHODS: PTSD and depression were evaluated using Clinician Administered PTSD Scale, Davidson Trauma Scale, Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Scale. Sixty-five male drug-free war veterans (48 with PTSD and 17 without PTSD) and 65 age- and sex-matched healthy controls were studied. RESULTS: Comorbid depression occurred in 54 and 31% of war veterans with PTSD and without PTSD, respectively. Platelet 5-HT concentration was similar in the groups of depressed and nondepressed war veterans with or without PTSD and healthy controls. Platelet 5-HT concentration was found to differ between war veterans with various degrees of appetite loss. A positive correlation was observed between platelet 5-HT concentration and severity of appetite loss in veterans with PTSD. There was no relationship between platelet 5-HT concentration and severity of other symptoms of PTSD or depression. LIMITATIONS: War veterans included in the study were outpatients. CONCLUSIONS: War veterans with PTSD had a high incidence of comorbid depression, that was not related to platelet 5-HT concentration. The marked relationship between platelet 5-HT concentration and severity of appetite loss, suggested that 5-HT system is involved in the regulation of appetite, at least in depressed war veterans with PTSD.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 382,
                "text": "PTSD"
            }
        },
        {
            "context": "Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats. Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 134,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Neuronal calcium sensor proteins are unable to modulate NFAT activation in mammalian cells. Calcium activated gene transcription through Nuclear Factor of Activated T-cells, (NFAT) proteins, is emerging as a ubiquitous mechanism for the control of important physiological processes. Of the five mammalian NFAT isoforms, transcriptional activities of NFATs 1-4 are stimulated by a calcium driven association between the ubiquitous phosphatase calcineurin and the calcium-sensing protein calmodulin. Published in vitro evidence has suggested that other members of the calmodulin super-family, in particular the neuronal calcium sensor (NCS) proteins, can similarly modulate calcineurin activity. In this study we have assessed the ability of NCS proteins to interact directly with calcineurin in vitro and report a specific if weak association between various NCS proteins and the phosphatase. In an extension to these analyses we have also examined the effects of over-expression of NCS-1 or NCS-1 mutants on calcineurin signalling in HeLa cells in experiments examining the dephosphorylation of an NFAT-GFP reporter construct as a readout of calcineurin activity. Results from these experiments indicate that NCS-1 was not able to detectably modulate calcineurin/NFAT signalling in a live mammalian cell system, findings that are consistent with the idea that calmodulin and not NCS-1 or other NCS family proteins is the physiologically relevant modulator of calcineurin activity.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 442,
                "text": "calcineurin"
            }
        },
        {
            "context": "Expression of TAP73 and DeltaNP73 in malignant gliomas. The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. We studied differential expression of these forms in normal brain as well as glial tumors, by semiquantitative RT-PCR. The expression of p73 was low or undetectable in normal brain tissues. Most of the tumors and non-tumor brain tissues also lacked significant expression of p73 in patients with low-grade astrocytomas. In contrast, most high-grade glial tumors displayed strong up-regulation of TAp73, whereas only a few displayed DeltaNp73 expression. These aberrations may reflect the inactivation of retinoblastoma pathway in these tumors which result in the activation of E2F transcription factors, since TAp73 is a known target of E2F1 gene. The study of TAp73 expression in brain tumors may serve as a means to evaluate the retinoblastoma pathway-dependent tumor progression.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 61,
                "text": "7"
            }
        },
        {
            "context": "MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. UNLABELLED: Hepatitis C virus (HCV) directly induces oxidative stress and liver injury. Bach1, a basic leucine zipper mammalian transcriptional repressor, negatively regulates heme oxygenase 1 (HMOX1), a key cytoprotective enzyme that has antioxidant and anti-inflammatory activities. microRNAs (miRNAs) are small noncoding RNAs ( approximately 22 nt) that are important regulators of gene expression. Whether and how miRNAs regulate Bach1 or HCV are largely unknown. The aims of this study were to determine whether miR-196 regulates Bach1, HMOX1, and/or HCV gene expression. HCV replicon cell lines (Con1 and 9-13) of the Con1 isolate and J6/JFH1-based HCV cell culture system were used in this study. The effects of miR-196 mimic on Bach1, HMOX1, and HCV RNA, and protein levels were measured by way of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. The Dual Glo Luciferase Assay System was used to determine reporter activities. miR-196 mimic significantly down-regulated Bach1 and up-regulated HMOX1 gene expression and inhibited HCV expression. Dual luciferase reporter assays demonstrated that transfection of miR-196 mimic resulted in a significant decrease in Bach1 3'-untranslated region (UTR)-dependent luciferase activity but not in mutant Bach1 3'-UTR-dependent luciferase activity. Moreover, there was no detectable effect of mutant miR-196 on Bach1 3'-UTR-dependent luciferase activity. CONCLUSION: miR-196 directly acts on the 3'-UTR of Bach1 messenger RNA and translationally represses the expression of this protein, and up-regulates HMOX1. miR-196 also inhibits HCV expression in HCV replicon cell lines (genotype 1b) and in J6/JFH1 (genotype 2a) HCV cell culture system. Thus, miR-196 plays a role in both HMOX1/Bach1 expression and the regulation of HCV expression in human hepatocytes. Overexpression of miR-196 holds promise as a potential novel strategy to prevent or ameliorate hepatitis C infection, and to protect against liver injury in chronic HCV infection.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 282,
                "text": "repressor"
            }
        },
        {
            "context": "Translational efficiency in patients with Diamond-Blackfan anemia. BACKGROUND AND OBJECTIVES: Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. Ribosomal protein S19 (RPS19), currently the only gene associated with DBA, is mutated in 25% of DBA patients, but its role in erythropoiesis is unknown. We attempted to elucidate the importance of RPS19 in translation in relation to the pathogenesis of DBA. DESIGN AND METHODS: We measured translation and proliferation rates in unstimulated and phytohemagglutinin (PHA)-stimulated lymphocytes isolated from DBA patients, as well as in K562 cells expressing several RPS19 mutants to directly test the effect of RPS19 mutations on translation. The effect of leucine on overall translation was also studied. RESULTS: We found that the level of translation was on average 48-73% of controls in both unstimulated and PHA-activated DBA lymphocytes irrespective of mutations in RPS19. The addition of leucine increased the translational level in RPS19-non-mutated DBA cells, but not in cells with an RPS19 mutation. In unstimulated DBA cells, proliferation was significantly impaired in both RPS19-mutated and non-mutated cells, but in both groups could be efficiently activated by PHA. Studies on K562 cells showed that RPS19 mutations affecting RPS19 conserved arginines R56Q and R62Q could significantly inhibit the rate of protein synthesis, indicating the importance of RPS19 in translation. INTERPRETATION AND CONCLUSIONS: Our results indicate that inefficient translation may be the main cause of DBA, and administration of leucine may be beneficial for at least some DBA patients.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 389,
                "text": "DBA"
            }
        },
        {
            "context": "Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab-A Case Report. INTRODUCTION: Idarucizumab is a reversal agent for dabigatran etexilate. By reversing the anticoagulating effect of dabigatran etexilate with idarucizumab (Praxbind), patients presenting with an acute ischemic stroke can now be eligible for thrombolysis. PATIENT: We describe our experience with idarucizumab in a 71-year-old male patient pretreated with dabigatran etexilate. The patient arrived with a hemiparesis, central facial palsy, and dysarthria. METHOD: Dabigatran etexilate was antagonized with idarucizumab, approximately 2.5 hours after the patient's last dose. Immediately after the infusion of idarucizumab, the patient received thrombolytic therapy. RESULTS: The hemiparesis and the central facial palsy were fully remitted 3 days after the onset of symptoms, and the dysarthria was remitted 2 days afterwards. DISCUSSION: Non-vitamin K oral anticoagulants (NOACs) are widely used for the prevention of embolic stroke in patients with atrial fibrillation. Dabigatran etexilate is an oral thrombin inhibitor that can be reversed by idarucizumab. Idarucizumab, a monoclonal antibody fragment, directly binds dabigatran etexilate and neutralizes its activity. CONCLUSION: Reversal of dabigatran etexilate using idarucizumab was safe and successful with no recombinant tissue plasminogen activator interactions.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1087,
                "text": "Dabigatran"
            }
        },
        {
            "context": "The long non-coding RNA H19 promotes cardiomyocyte apoptosis in dilated cardiomyopathy. In the previous study, we generated a rat model of dilated cardiomyopathy (DCM) induced by adriamycin and found that the expression of lncRNA H19 was significantly upregulated in myocardial tissue. The present study was aimed to investigate the potential role of H19 in the pathogenesis of adriamycin-induced DCM. H19 knockdown in the myocardium of DCM rats attenuated cardiomyocyte apoptosis and improved left ventricular structure and function. Adriamycin treatment was associated with elevated H19 and miR-675 expression and increased apoptosis in neonatal cardiomyocytes. Enforced expression of miR-675 was found to induce apoptosis in cardiomyocytes with adriamycin treatment and H19-siRNA transfection. The 3'-untranslated region of PA2G4 was cloned downstream of a luciferase reporter construct and cotransfected into HEK293 cells with miR-675 mimic. The results of luciferase assay showed that PA2G4 was a direct target of miR-675. The expression of PA2G4 was reduced in cardiomyocytes transfected with miR-675 mimic. Moreover, H19 knockdown was found to increase PA2G4 expression and suppress apoptosis in cardiomyocytes exposed to adriamycin. In conclusion, our study suggests that H19/miR-675 axis is involved in the promotion of cardiomyocyte apoptosis by targeting PA2G4, which may provide a new therapeutic strategy for the treatment of adriamycin-induced DCM.",
            "question": "Name an lncRNA associated with dilated cardiomyopathy.",
            "answers": {
                "answer_start": 223,
                "text": "lncRNA H19"
            }
        },
        {
            "context": "Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519. The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator. We examined the modulatory effect of JTV-519 on the antitumor activity of several platinum compounds (cisplatin, carboplatin, and nedaplatin) in a human cancer cell line resistant to cisplatin (PC-14 / CDDP) in vitro. PC-14 / CDDP cells showed 8-fold resistance to cisplatin compared with the parental PC-14 cells as determined by dye formation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] assay. In PC-14 / CDDP, but not PC-14 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 mM) of JTV-519 was combined with the platinum compounds. Increased intracellular cisplatin accumulation was observed in PC-14 / CDDP cells in the presence of JTV-519 as measured by atomic absorption assay. Therefore, increased cisplatin accumulation was considered to be a possible mechanism underlying the reversing effect of JTV-519 on cisplatin resistance. These results suggest that JTV-519 is a potent agent reversing cisplatin resistance.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 89,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "X inactive-specific transcript (Xist) expression and X chromosome inactivation in the preattachment bovine embryo. Expression of the X inactive-specific transcript (Xist) is thought to be essential for the initiation of X chromosome inactivation and dosage compensation during female embryo development. In the present study, we analyzed the patterns of Xist transcription and the onset of X chromosome inactivation in bovine preattachment embryos. Reverse transcription-polymerase chain reaction (RT-PCR) revealed the presence of Xist transcripts in all adult female somatic tissues evaluated. In contrast, among the male tissues examined, Xist expression was detected only in testis. No evidence for Xist transcription was observed after a single round of RT-PCR from pools of in vitro-derived embryos at the 2- to 4-cell stage. Xist transcripts were detected as a faint amplicon at the 8-cell stage initially, and consistently thereafter in all stages examined up to and including the expanded blastocyst stage. Xist transcripts, however, were subsequently detected from the 2-cell stage onward after nested RT-PCR. Preferential [3H]thymidine labeling indicative of late replication of one of the X chromosomes was noted in female embryos of different developmental ages as follows: 2 of 7 (28.5%) early blastocysts, 6 of 13 (46.1%) blastocysts, 8 of 11 (72.1%) expanded blastocysts, and 14 of 17 (77.7%) hatched blastocysts. These results suggest that Xist expression precedes the onset of late replication in the bovine embryo, in a pattern compatible with a possible role of bovine Xist in the initiation of X chromosome inactivation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 165,
                "text": "Xist"
            }
        },
        {
            "context": "Small-cell lung cancer presenting with Lambert-Eaton myasthenic syndrome and respiratory failure. Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder characterized by defective neurotransmitter release at presynaptic terminals. It is caused by an IgG autoantibody reacting against voltage-gated calcium channels. Severe LEMS complicated by ventilatory failure is rare. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. LEMS was diagnosed through electrophysiologic studies. Chest radiography and computerized tomography showed a huge mass lesion over the left anterior and middle mediastinum with an encasement of the left pulmonary artery. Cytologic examination of ultrasound-guided fine needle aspiration disclosed SCLC. Successful treatment in combination with plasma exchange and chemotherapy resulted in dramatic tumor regression and LEMS remission, which were confirmed by chest radiography and electrophysiologic studies. This case suggests that plasma exchange and chemotherapy can be effective in treating SCLC with severe LEMS that produces ventilatory failure.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 406,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 450,
                "text": "positive"
            }
        },
        {
            "context": "New synthetic antithrombotic agents for venous thromboembolism: pentasaccharides, direct thrombin inhibitors, direct Xa inhibitors. Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 671,
                "text": "Xa"
            }
        },
        {
            "context": "[Effect of selective estrogen receptor modulators on estrogen-sensitive tissues]. Selective estrogen receptor modulators (SERMs) act exclusively through estrogen receptors and possess tissue-specific agonistic or antagonistic properties. The effects of all referred SERMs in bone and cardiovascular system are estrogenic, namely they inhibit postmenopausal bone loss and favorably influence plasma lipoproteins and some coagulation factors. The aim of this paper is to review the effects of SERMs on estrogen-dependent breast tissues and on the endometrium. There are two types of SERMs in clinical use, based on their chemical structure: the triphenylethylenes and the benzothiophenes. The prototype of the SERMs with triphenylethylene structure is tamoxifen. Tamoxifen, like all other SERMs, is an estrogen antagonist in the breast and is widely used for adjuvant treatment of breast cancer. A recent study suggests that tamoxifen also may prevent breast cancer in patients at risk. Because of the partial estrogenic activity of tamoxifen in the endometrium, its clinical use is associated with uterine hypertrophy and an increased risk of endometrial cancer. Other triphenylethylene SERMs, droloxifene, toremifene, and idoxifene, also show efficacy in the treatment of breast cancer, in a manner similar to tamoxifen. A better toxicology profile and a decreased endometrial estrogen agonism may be advantages of the new triphenylethylene SERMs. Raloxifene is a SERM with a chemical structure different from triphenylethylenes. Raloxifene, a benzothiophene, possesses an estrogen-antagonistic effect in the breast similar to triphenylethylenes. Clinical studies on postmenopausal osteoporotic women on raloxifene as compared with placebo show a significant decrease in the rate of newly diagnosed breast cancers. In clinical studies, in contrast to tamoxifen, no stimulatory effect in the endometrium could be observed with raloxifene.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 82,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH2-terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 266,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 560,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Expression of non-replicating persistence associated genes of Mycobacterium bovis in lymph nodes from skin test-reactor cattle. Upon oxygen shift-down, Mycobacterium tuberculosis complex bacteria can induce a genetic program characterized by halted duplication, which is called Non-replicating persistence (NRP). During this phase, at least 48 genes, collectively named Dormancy survival regulator (DosR) regulon, are important for the long-term survival of bacilli under a non-respiring state, a condition that bacilli encounter inside granulomatous lesions. It remains unclear whether expression of NRP genes occurs within the tissue of Mycobacterium bovis naturally infected cattle. In order to start dissecting this question, total RNA from bovine lymph node tissues of sacrificed tuberculin reacting animals was isolated and transcription of genes required for in vivo duplication (esxB and fbpB) and in vitro NRP (hspX, pfkB, and mb2660c) were analyzed by RT-PCR approaches. Detection of transcripts was positive in bovine tissue samples for genes hspX, pfkB, and mb2660c in 84, 32, and 21%, respectively. NRP genes were upregulated even in animals with a negative IFN-γ in vitro test, and the expression of NRP genes occurred more often than expression of the esxB gene.",
            "question": "How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?",
            "answers": {
                "answer_start": 341,
                "text": "48 genes"
            }
        },
        {
            "context": "Microenvironments created by liquid-liquid phase transition control the dynamic distribution of bacterial division FtsZ protein. The influence of membrane-free microcompartments resulting from crowding-induced liquid/liquid phase separation (LLPS) on the dynamic spatial organization of FtsZ, the main component of the bacterial division machinery, has been studied using several LLPS systems. The GTP-dependent assembly cycle of FtsZ is thought to be crucial for the formation of the septal ring, which is highly regulated in time and space. We found that FtsZ accumulates in one of the phases and/or at the interface, depending on the system composition and on the oligomerization state of the protein. These results were observed both in bulk LLPS and in lipid-stabilized, phase-separated aqueous microdroplets. The visualization of the droplets revealed that both the location and structural arrangement of FtsZ filaments is determined by the nature of the LLPS. Relocation upon depolymerization of the dynamic filaments suggests the protein may shift among microenvironments in response to changes in its association state. The existence of these dynamic compartments driven by phase transitions can alter the local composition and reactivity of FtsZ during its life cycle acting as a nonspecific modulating factor of cell function.",
            "question": "What is liquid liquid phase transition?",
            "answers": {
                "answer_start": 146,
                "text": "membrane-free microcompartments"
            }
        },
        {
            "context": "Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Multiple endocrine neoplasia type 2 (MEN2) is an inherited, autosomal-dominant disorder caused by deleterious mutations within the RET protooncogene. MEN2 RET mutations are mainly heterozygous, missense sequence changes found in RET exons 10, 11, and 13-16. Our group has developed the publicly available, searchable MEN2 RET database to aid in genotype/phenotype correlations, using Human Genome Variation Society recommendations for sequence variation nomenclature and database content. The MEN2 RET database catalogs all RET sequence variation relevant to the MEN2 syndromes, with associated clinical information. Each database entry lists a RET sequence variation's location within the RET gene, genotype, pathogenicity classification, MEN2 phenotype, first literature reference, and comments (which may contain information on other clinical features, complex genotypes, and additional literature references). The MEN2 phenotype definitions were derived from the International RET Mutation Consortium guidelines for classification of MEN2 disease phenotypes. Although nearly all of the 132 RET sequence variation entries initially cataloged in the database were from literature reports, novel sequence variation and updated phenotypic information for any existing database entry can be submitted electronically on the database website. The database website also contains links to selected MEN2 literature reviews, gene and protein information, and RET reference sequences. The MEN2 RET database (www.arup.utah.edu/database/MEN2/MEN2_welcome.php) will serve as a repository for MEN2-associated RET sequence variation and reference for RET genotype/MEN2 phenotype correlations.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 299,
                "text": "RET"
            }
        },
        {
            "context": "BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 190,
                "text": "poly(ADP-ribose) polymerase"
            }
        },
        {
            "context": "Obesity medications: what does the future look like? PURPOSE OF REVIEW: Lifestyle modification remains the mainstay of treatment for obesity despite the lack of substantial long-term efficacy. For many who do not respond to lifestyle therapy and are not candidates for weight loss surgery, pharmacotherapy is a viable treatment option. Advances in understanding mechanisms of appetite control, nutrient sensing, and energy expenditure have not only helped shape current drug development but have also changed the way in which antiobesity medications are prescribed. Current antiobesity medications and pharmacological strategies will be reviewed. RECENT FINDINGS: Two new antiobesity drugs - naltrexone/bupropion (Contrave) and liraglutide (Saxenda) - were approved by the US Food and Drug Administration in 2014 and join four other approved obesity medications, including phentermine/topiramate XR (Qsymia) and lorcaserin (Belviq), to form the largest number of medications available for the treatment of obesity. In addition, investigational drugs, like belnoranib, show promise in early clinical trials, brightening the outlook on drug development. SUMMARY: To combat the complex physiological system of energy regulation and the known variation of treatment response, combinatory therapies for obesity, including pharmacotherapy, are needed. Now six US Food and Drug Administration-approved antiobesity medications, including two combination medications, will allow providers to tailor obesity treatment in combination with lifestyle modification for a great number of individuals with obesity.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 578,
                "text": "obesity"
            }
        },
        {
            "context": "Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 3379,
                "text": "dabigatran"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1551,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1924,
                "text": "fungi"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "Dnmt1 structure and function. Dnmt1, the principal DNA methyltransferase in mammalian cells, is a large and a highly dynamic enzyme with multiple regulatory features that can control DNA methylation in cells. This chapter highlights how insights into Dnmt1 structure and function can advance our understanding of DNA methylation in cells. The allosteric site(s) on Dnmt1 can regulate processes of de novo and maintenance DNA methylation in cells. Remaining open questions include which molecules, by what mechanism, bind at the allosteric site(s) in cells? Different phosphorylation sites on Dnmt1 can change its activity or ability to bind DNA target sites. Thirty-one different molecules are currently known to have physical and/or functional interaction with Dnmt1 in cells. The Dnmt1 structure and enzymatic mechanism offer unique insights into those interactions. The interacting molecules are involved in chromatin organization, DNA repair, cell cycle regulation, and apoptosis and also include RNA polymerase II, some RNA-binding proteins, and some specific Dnmt1-inhibitory RNA molecules. Combined insights from studies of different enzymatic features of Dnmt1 offer novel ideas for development of drug candidates, and can be used in selection of promising drug candidates from more than 15 different compounds that have been identified as possible inhibitors of DNA methylation in cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 365,
                "text": "Dnmt1"
            }
        },
        {
            "context": "[Secrets of the red-headed]. Only 1-2% of people is red-headed but in the Russian Udmurt Republic or United Kingdom they can be met more often. A specific variant of MC1R gene (R allele) is responsible for the red hair. The gene encodes a receptor for melanocortins. These substances stimulate melanocytes to product melanin- a dye of the skin which is transported to keratinocytes. It protects a cellular nucleus from ultraviolet radiation. Melanin has two types: eumelanin which is dark brown or even black and red/orange pheomelanin. The second one is mostly observed in red-headed which is caused by R allele. The DNA damage occurs more easily because of worse protecting ability of pheomelanin. Moreover this allele is connected with inefficient DNA repair. People with R allele have not only flaming red hairstyle but also very fair skin (often with freckles) and blue eyes. Unfortunately this phenotype is more exposed to harmful effects of UV rays. It means that too extensive exposition to solar light leads to sunburn and development of cancerous skin diseases with melanoma as the worst. R allele is a recessive variant of the gene so only in homozygous persons this characteristic phenotype is observed. Nevertheless blond- or auburn-haired carriers of this allele are also more prone to develop carcinomas. The red-headed also differ from the others in sensitivity to anaesthetics, what is shown by increased MAC. On the other hand these persons less often suffer from vitamin D deficiency. The aim of the article is to present facts and myths of red-headed.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 166,
                "text": "MC1R"
            }
        },
        {
            "context": "Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 234,
                "text": "FSHD"
            }
        },
        {
            "context": "Applying the Milwaukee protocol to treat canine rabies in Equatorial Guinea. In this first report of rabies in Equatorial Guinea, problems accompanying the application of the Milwaukee Protocol are described. With its apparent success, and despite a subsequent death from complications of malnutrition, we sound a note of optimism that canine as well as bat rabies may be treatable.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 48,
                "text": "rabies"
            }
        },
        {
            "context": "Identification of a heteromeric complex that promotes DNA replication origin firing in human cells. Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holohelicase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.",
            "question": "Which factor interacts with Treslin/TICRR throughout the cell cycle of human cells?",
            "answers": {
                "answer_start": 403,
                "text": "MDM two binding protein (MTBP)"
            }
        },
        {
            "context": "Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1. Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.",
            "question": "What causes leishmaniasis?",
            "answers": {
                "answer_start": 709,
                "text": "Leishmania species"
            }
        },
        {
            "context": "In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. BACKGROUND: Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML. METHODS: The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software. RESULTS: STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures. CONCLUSIONS: In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 362,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Lambert-Eaton syndrome with large-cell neuroendocrine carcinoma of the lung. Lambert-Eaton syndrome (LES) is an immune-mediated disorder of the presynaptic neuromuscular junction due to the blocking effect of the voltage-gated calcium channel (VGCC) antibodies. Small-cell lung cancer (SCLC) is the most common cause of LES. We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung. In this case, clinical symptoms of LES predated the diagnosis of LCNEC by 6 years. After tumor resection, the patient experienced clinical and electrophysiological improvement. In addition, he had a decrease in VGCC antibody titer from 130 to 80 pmol/L. The onset of LES can be prolonged, and tumor surveillance should continue in these cases.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 262,
                "text": "Small-cell lung cancer"
            }
        },
        {
            "context": "Incidence of liver injury among cancer patients receiving chemotherapy in an integrated health system. PURPOSE: Using liver laboratory tests (LLTs), Hy's law is a method used to identify drug-induced liver injury (DILI), after excluding other causes. Elevated LLTs in chemotherapy-exposed patients may result from tumor effects or comorbidities. This study evaluated incidence of Hy's law in chemotherapy-treated cancer patients. METHODS: We identified breast, colorectal, and lung cancer patients diagnosed in 1 January 2000 to 31 December 2007 at a Midwestern health system. Using automated data, potential Hy's law (PHL) cases were defined by patterns of elevated LLTs suggestive of DILI. Among those treated with chemotherapy, we excluded PHL patients with pre-existing conditions that could cause liver injury, producing a cohort meeting Hy's law criteria, according to automated data. Medical record review, conducted among these automated data-derived Hy's law patients, further excluded those with causes of liver injury other than chemotherapy. RESULTS: Using automated data, among chemotherapy-exposed patients (N = 2788), 91 (3.3%) met PHL criteria using LLTs and 64 (2.3%) met Hy's law after excluding underlying liver injury using the International Classification of Diseases, 9th Revision codes. After a medical record review, 62 of 64 patients qualifying as Hy's law through automated data had other potential causes, leaving two patients (0.07%; 95%CI: 0.01-0.24%) with chemotherapy as a likely alternative cause of liver injury. CONCLUSIONS: Abnormal LLTs are common in chemotherapy-treated patients. Medical record review showed that the incidence of Hy's law events is rare. These data provide context for evaluating DILI in clinical trials and postmarketing surveillance of anticancer therapies, understanding that automated data alone may substantially overestimate the number of Hy's law cases.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 200,
                "text": "liver"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 333,
                "text": "CO2"
            }
        },
        {
            "context": "Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 326,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Detection of BCR-ABL1 kinase domain mutations causing imatinib resistance in chronic myelogenous leukemia. The reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11), Philadelphia chromosome] creates a BCR-ABL1 fusion protein that occurs in approximately 95% of cases of chronic myelogenous leukemia (CML), 15% of cases of adult acute lymphoblastic leukemia, and 5% of adult cases of acute myeloid leukemia. The BCR-ABL1 protein is a constitutively activated tyrosine kinase that induces and maintains the neoplastic phenotype in these leukemias. PCR-based methods to identify and quantitate the tumor-specific BCR-ABL1 RNA have been shown to be an ultrasensitive diagnostic, prognostic, and monitoring tool for Philadelphia-positive leukemias. A novel tyrosine kinase inhibitor (TKI), imatinib, has been confirmed as an effective targeted treatment in most CML patients. However, a significant minority of patients being treated with imatinib develop resistance to the drug as evidenced by rising BCR-ABL1 levels. The most common mechanism of resistance in these patients is the development of mutations in the BCR-ABL1 kinase domain (KD) that abrogate binding of imatinib. Although KD mutations are quite heterogeneous, the identification of the exact mutation site is clinically important, as some mutations, but not others, can be effectively treated with second-generation TKIs. One mutation, T315I, for example, renders the leukemia resistant to all first- and second-line TKIs. Thus, DNA sequencing of the BCR-ABL1 kinase domain in resistant patients helps identify those who may benefit from a change in TKI agents, or those who should be considered for other therapeutic measures, such as stem cell transplantation. We describe here a method for sequencing the BCR-ABL1 kinase domain in peripheral blood or bone marrow of CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 219,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Incidence of red-green color blindness in the Basque population. The incidence of red-green colour vision defects was studied in a sample of 392 Basque students (174 males and 218 females), using the Ishihara test cards (1987). The frequency of red-green colour blindness was 4.02 percent in the males and 0.46 percent in the females. The colour blindness frequencies found among males are within the range of other Spanish samples. Nevertheless they are lower than the values reported in other European populations.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 200,
                "text": "Ishihara"
            }
        },
        {
            "context": "Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 22,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "Centrosome amplification in CHO and DT40 cells by inactivation of cyclin-dependent kinases. To study the mechanism of centrosome duplication in cycling cells, we established a novel system of multiple centrosome formation in two types of cells: CHO cells treated with RO3306, a Cyclin-dependent kinase 1 (Cdk1) inhibitor and DT40 cells, in which Cdks were knocked out by chemical genetics. Cdk1-inactivated cells initiated DNA replication and centrosome duplication at the onset of S phase. They became arrested at the end of G2, but the centrosome cycle continued to produce supernumerary centrioles/centrosomes without DNA endoreplication in those cells. Centrosomes were amplified in a highly synchronous and reproducible manner: all of them were located next to the nucleus and spread widely apart from each other with several μm in distance. Double knockout of Cdk1 and Cdk2 caused cell cycle arrest at G1/S and centrosomes were no longer duplicated. However, cells continued to grow and increased their volume over 10-fold during 48 hr of culture. Centrosome components, including γ-tubulin and Cep135, were synthesized and accumulated during the arrest, allowing rapid centrosome multiplication upon recovery from the cell cycle arrest or expression of exogenous Plk4 in G1/S cells. Thus centrosome amplification results from the discoordination of the centrosome cycle from the progression of other cell cycle events, which is controlled by different levels of Cdk activities.",
            "question": "Where in the cell do we find the protein Cep135?",
            "answers": {
                "answer_start": 1054,
                "text": "Centrosome"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 557,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Wilson's disease: update on integrated Chinese and Western medicine. Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism caused by ATP7B gene mutation. As WD is an inherited disease of the nervous system that is not curable; early diagnosis with early and life-long treatment leads to better prognoses. Currently, the recommended treatment for WD is integrated Chinese and Western medicine. A number of studies indicate that treatment of integrative medicine can not only enforce the de-copper effect but also improve liver function, intelligence, and other factors. This article reviewed in detail the advantages of WD treated with Chinese and Western medicine together.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 132,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Yield of CT Pulmonary Angiography in the Emergency Department When Providers Override Evidence-based Clinical Decision Support. Purpose To determine the frequency of, and yield after, provider overrides of evidence-based clinical decision support (CDS) for ordering computed tomographic (CT) pulmonary angiography in the emergency department (ED). Materials and Methods This HIPAA-compliant, institutional review board-approved study was performed at a tertiary care, academic medical center ED with approximately 60 000 annual visits and included all patients who were suspected of having pulmonary embolism (PE) and who underwent CT pulmonary angiography between January 1, 2011, and August 31, 2013. The requirement to obtain informed consent was waived. Each CT order for pulmonary angiography was exposed to CDS on the basis of the Wells criteria. For patients with a Wells score of 4 or less, CDS alerts suggested d-dimer testing because acute PE is highly unlikely in these patients if d-dimer levels are normal. The yield of CT pulmonary angiography (number of positive PE diagnoses/total number of CT pulmonary angiographic examinations) was compared in patients in whom providers overrode CDS alerts (by performing CT pulmonary angiography in patients with a Wells score < 4 and a normal d-dimer level or no d-dimer testing) (override group) and those in whom providers followed Wells criteria (CT pulmonary angiography only in patients with Wells score >4 or < 4 with elevated d-dimer level) (adherent group). A validated natural language processing tool identified positive PE diagnoses, with subsegmental and/or indeterminate diagnoses removed by means of chart review. Statistical analysis was performed with the χ test, the Student t test, and logistic regression. Results Among 2993 CT pulmonary angiography studies in 2655 patients, 563 examinations had a Wells score of 4 or less but did not undergo d-dimer testing and 26 had a Wells score of 4 or less and had normal d-dimer levels. The yield of CT pulmonary angiography was 4.2% in the override group (25 of 589 studies, none with a normal d-dimer level) and 11.2% in the adherent group (270 of 2404 studies) (P < .001). After adjustment for the risk factor differences between the two groups, the odds of an acute PE finding were 51.3% lower when providers overrode alerts than when they followed CDS guidelines. Comparison of the two groups including only patients unlikely to have PE led to similar results. Conclusion The odds of an acute PE finding in the ED when providers adhered to evidence presented in CDS were nearly double those seen when providers overrode CDS alerts. Most overrides were due to the lack of d-dimer testing in patients unlikely to have PE.  RSNA, 2016.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 590,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif. Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the \"guardian of the genome.\"",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 1279,
                "text": "p53"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 662,
                "text": "naloxone"
            }
        },
        {
            "context": "Initiation of spectrin dimerization involves complementary electrostatic interactions between paired triple-helical bundles. The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit, each of which comprises largely a series of homologous triple-helical motifs. Initiation of dimer assembly involves strong binding between complementary motifs near the actin-binding end of the dimer. In this study, the mechanism of lateral spectrin association at this dimer nucleation site was investigated using the analytical ultracentrifuge to analyze heterodimers formed from recombinant peptides containing two or four homologous motifs from each subunit (alpha20-21/beta1-2; alpha18-21/beta1-4). Both the two-motif and four-motif dimer associations were weakened substantially with increasing salt concentration, indicating that electrostatic interactions are important for the dimer initiation process. Modeling of the electrostatic potential on the surface of the alpha20 and beta2 motifs showed that the side of the motifs comprising the A and B helices is the most favorable for association, with an area of positive electrostatic potential on the AB face of the beta2 motif opposite negative potential on the AB face of the alpha20 motif and vise versa. Protease protection analysis of the alpha20-21/beta1-2 dimer showed that multiple trypsin and proteinase K sites in the A helices of the beta2 and alpha21 motifs become buried upon dimer formation. Together, these data support a model where complementary long range electrostatic interactions on the AB faces of the triple-helical motifs in the dimer nucleation site initiate the correct pairing of motifs, i.e. alpha21-beta1 and alpha20-beta2. After initial docking of these complementary triple-helical motifs, this association is probably stabilized by subsequent formation of stronger hydrophobic interactions in a complex involving the A helices of both subunits and possibly most of the AB faces. The beta subunit A helix in particular appears to be buried in the dimer interface.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 167,
                "text": "antiparallel"
            }
        },
        {
            "context": "Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germline mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' and 3' breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12-kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 149,
                "text": "NF1"
            }
        },
        {
            "context": "Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. p53 is well known as the \"guardian of the genome\" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for pro-oncogenic cells, p53 also plays an important role as the central regulator of stress response by maintaining cellular homeostasis at the molecular and biochemical level. p53 regulates aerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) steps via transcriptional regulation of its downstream genes TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose-2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS through upregulation of SCO2, a member of the COX-2 assembly involved in the electron-transport chain. It is interesting to notice that p53 antagonistically regulates the inter-dependent glycolytic and OXPHOS cycles. It is important to understand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 is temporally segregated in cancer cells and what is the relation between these paradoxical regulations of glycolytic pathway with the tumor suppressor activity of p53. In this review we will elucidate the importance of p53-mediated regulation of glycolysis and OXPHOS and its relation with the tumor suppressor function of p53. Further since cellular metabolism shares great relation with the process of aging we will also try and establish the role of p53 in regulation of aging via its transcriptional control of cellular metabolism.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 86,
                "text": "p53"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 874,
                "text": "xa"
            }
        },
        {
            "context": "Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction. Results are presented of a comparison of the amino acid (AA) δ(13)C values obtained by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) and liquid chromatography-isotope ratio mass spectrometry (LC/IRMS). Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ(13)C values are required. We compare LC/IRMS with the most up-to-date GC/C/IRMS method using N-acetyl methyl ester (NACME) AA derivatives. This comparison involves the analysis of standard AAs and hydrolysates of archaeological human bone collagen, which have been previously investigated as N-trifluoroacetyl isopropyl esters (TFA/IP). It was observed that, although GC/C/IRMS analyses required less sample, LC/IRMS permitted the analysis of a wider range of AAs, particularly those not amenable to GC analysis (e.g. arginine). Accordingly, reconstructed bulk δ(13)C values based on LC/IRMS-derived δ(13)C values were closer to the EA/IRMS-derived δ(13)C values than those based on GC/C/IRMS values. The analytical errors for LC/IRMS AA δ(13)C values were lower than GC/C/IRMS determinations. Inconsistencies in the δ(13)C values of the TFA/IP derivatives compared with the NACME- and LC/IRMS-derived δ(13)C values suggest inherent problems with the use of TFA/IP derivatives, resulting from: (i) inefficient sample combustion, and/or (ii) differences in the intra-molecular distribution of δ(13)C values between AAs, which are manifested by incomplete combustion. Close similarities between the NACME AA δ(13)C values and the LC/IRMS-derived δ(13)C values suggest that the TFA/IP derivatives should be abandoned for the natural abundance determinations of AA δ(13)C values.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 590,
                "text": "collagen"
            }
        },
        {
            "context": "Molecular cloning of cDNA encoding a bovine selenoprotein P-like protein containing 12 selenocysteines and a (His-Pro) rich domain insertion, and its regional expression. When cDNA containing proteins enriched in the bovine cerebellar cortex were cloned, a clone which seemed to encode a selenoprotein P-like protein was isolated. The coding nucleotide sequence of its cDNA insert displayed high homology to rat and human selenoprotein P cDNA but contained 12 rather than 10 TGAs (12 rather than 10 selenocysteines in deduced amino acids), a tandem repeat of one CACTCC (His-Ser) and seven CATCCCs (His-Pro), and a 3' untranslated region approximately 890 bases shorter than that of rat liver selenoprotein P. RT-PCR using a set of primers flanking to the repeat displayed the existence of mRNA without the repeat. The tandem repeat and its adjacent region consisted of a similar motif of CAC/TCC/AC/T. Thus, these proteins included a (His-Pro) rich domain with a slightly negative free energy change irrespective of having the tandem repeat or not. Such His-Pro repeats reportedly exist in the segmentation gene paired or homeobox protein Om(1D) of Drosophila. Moreover, both this selenoprotein P-like protein mRNA and selenoprotein P mRNA were expressed in all the areas of the brain but most prominently in the cerebellar cortex, hippocampus, and olfactory bulb. These findings suggest the possibility that these selenoproteins are major selenium carriers in the brain and play a role in the morphological response of nerve or glial cells.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 44,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "Ryanodine receptor defects in muscle genetic diseases. Ryanodine receptor (RyR), a homotetrameric Ca2+ release channel, is one of the main actors in the generation of Ca2+ signals that trigger muscle contraction. Three genes encode three isoforms of RyRs, which have tissue-restricted distribution. RyR1 and RyR2 are typical of muscle cells, with RyR1 originally considered the skeletal muscle type and RyR2 the cardiac type. However, RyR1 and RyR2 have recently been found in numerous other cell types, including, for instance, peripheral B and T lymphocytes. In contrast, RyR3 is widely distributed among cells. RyR1 and RyR2 are localized in a specialized portion of the sarcoplasmic reticulum (SR), the terminal cisternae, which is the portion of the SR Ca2+ store that releases Ca2+ to control the process of muscle contraction. A specific role for RyR3 has not yet been established: probably, its co-expression with the other RyR isoforms contributes to qualitatively modulate Ca2+-dependent processes in muscle cells and in neurons. Several mutations in the genes encoding RyR1 and RyR2 have been identified in autosomal dominant diseases of skeletal and cardiac muscle, such as malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). More recently, CCD cases with recessive inheritance have also been described. MH is a pharmacogenetic disease, but the others manifest as congenital myopathies. Even if their clinical phenotypes are well established, particularly in skeletal muscle, the molecular mechanisms that generate the conditions are not clear. A number of studies on cellular models have attempted to elucidate the molecular defects associated with the different mutations, but the problem of understanding how mutations in the same gene generate such an array of diverse pathological traits and diseases of widely different degrees of severity is still open. This review will consider the molecular and cellular effects of RyR mutations, summarizing recent data in the literature on Ca2+ dysregulation, which may lead to a better understanding of the functioning of RyRs.",
            "question": "What is the inheritance pattern of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) caused by RYR2 mutations?",
            "answers": {
                "answer_start": 1118,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Deletion of the CSB homolog, RAD26, yields Spt(-) strains with proficient transcription-coupled repair. It has been previously shown that disruption of RAD26 in yeast strain W303-1B results in a strain that is deficient in transcription-coupled repair (TCR), the preferential repair of the transcribed strand of an expressed gene over the non-transcribed strand and the rest of the genome. RAD26 encodes a protein that is homologous to Cockayne syndrome group B protein (CSB) and is a member of the SWI2/SNF2 family of DNA-dependent ATPases involved in chromatin remodeling. Like the rad26 mutant, cells from Cockayne syndrome patients are defective in TCR. We examined the role of Rad26 in TCR by disrupting RAD26 in two repair-proficient laboratory strains and, remarkably, observed no effect upon TCR. Our results indicate that disruption of RAD26 alone is insufficient to impair TCR. Thus, W303-1B must already possess a mutation that, together with disruption of RAD26, causes a deficiency in TCR. We suggest that other genes are mutated in Cockayne syndrome cells that contribute to the deficiency in TCR. Surprisingly, deletion of RAD26 results in expression of genes that are repressed by flanking transposon delta elements, an Spt(-) phenotype. The delta elements appear to perturb local chromatin structure. Expression of genes flanked by delta elements in rad26Delta mutants is consistent with a role for Rad26 in chromatin remodeling.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 286,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Identification of a specific domain responsible for JNK2alpha2 autophosphorylation. c-Jun N-terminal kinases (JNKs) are a group of mitogen-activated protein kinase family members that are important in regulating cell growth, proliferation, and apoptosis. Activation of the JNK pathway has been implicated in the formation of several human tumors. We have previously demonstrated that a 55-kDa JNK isoform is constitutively activated in 86% of human brain tumors and more recently demonstrated that this isoform is either JNK2alpha2 or JNK2beta2. Importantly, we have also found that among the 10 known JNK isoforms, the JNK2 isoforms are unique in their ability to autophosphorylate in vitro and in vivo. This does not require the participation of any upstream kinases and also leads to substrate kinase activity in vitro and in vivo. To clarify the mechanism of JNK2alpha2 autoactivation, we have generated a series of chimeric cDNAs joining portions of JNK1alpha2, which does not have detectable autophosphorylation activity, with portions of JNK2alpha2, which has the strongest autophosphorylation activity. Through in vivo and in vitro kinase assays, we were able to define a domain ranging from amino acids 218 to 226 within JNK2alpha2 that is required for its autophosphorylation. Mutation of JNK2alpha2 to its counterpart of JNK1alpha2 in this region abrogated the autophosphorylation activity and c-Jun substrate kinase activity in vivo and in vitro. Notably, switching of JNK1alpha2 to JNK2alpha2 at this 9-amino acid site enabled JNK1alpha2 to gain the autophosphorylation activity in vivo and in vitro. We also found two other functional sites that participate in JNK2alpha2 activity. One site ranging from amino acids 363 to 382 of JNK2alpha2 is required for efficient c-Jun binding in vitro, and a site ranging from amino acids 383 to 424 enhances autophosphorylation intensity, although it is not required for triggering the autophosphorylation in vitro. These findings have uncovered the regions required for JNK2alpha2 autophosphorylation, and this information could be used as potential targets to block JNK2alpha2 activation.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 110,
                "text": "JNK"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 1242,
                "text": "libFLASM"
            }
        },
        {
            "context": "Progesterone/RANKL is a major regulatory axis in the human breast. Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 577,
                "text": "RANKL"
            }
        },
        {
            "context": "Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. DESIGN: A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. SETTING: An 800-bed, teaching, university-affiliated hospital. PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant \"waking\" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 3656,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Cysteine shotgun-mass spectrometry (CS-MS) reveals dynamic sequence of protein structure changes within mutant and stressed cells. Questions of if and when protein structures change within cells pervade biology and include questions of how the cytoskeleton sustains stresses on cells--particularly in mutant versus normal cells. Cysteine shotgun labeling with fluorophores is analyzed here with mass spectrometry of the spectrin-actin membrane skeleton in sheared red blood cell ghosts from normal and diseased mice. Sheared samples are compared to static samples at 37 °C in terms of cell membrane intensity in fluorescence microscopy, separated protein fluorescence, and tryptic peptide modification in liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spectrin labeling proves to be the most sensitive to shear, whereas binding partners ankyrin and actin exhibit shear thresholds in labeling and both the ankyrin-binding membrane protein band 3 and the spectrin-actin stabilizer 4.1R show minimal differential labeling. Cells from 4.1R-null mice differ significantly from normal in the shear-dependent labeling of spectrin, ankyrin, and band 3: Decreased labeling of spectrin reveals less stress on the mutant network as spectrin dissociates from actin. Mapping the stress-dependent labeling kinetics of α- and β-spectrin by LC-MS/MS identifies Cys in these antiparallel chains that are either force-enhanced or force-independent in labeling, with structural analyses indicating the force-enhanced sites are sequestered either in spectrin's triple-helical domains or in interactions with actin or ankyrin. Shear-sensitive sites identified comprehensively here in both spectrin and ankyrin appear consistent with stress relief through forced unfolding followed by cytoskeletal disruption.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 1370,
                "text": "antiparallel"
            }
        },
        {
            "context": "Abnormal sensorimotor plasticity in CADASIL correlates with neuropsychological impairment. OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease of the brain caused by mutations in the NOTCH3 gene. CADASIL progresses, in some cases, to subcortical dementia with a particular cognitive impairment. Different diseases in the dementia spectrum share a central cholinergic and sensorimotor plasticity alteration. We aimed to study different intracortical circuits and sensorimotor plasticity in CADASIL patients using transcranial magnetic stimulation protocols, and to determine whether these characteristics correlated with the results of clinical neuropsychological evaluation. METHODS: Ten CADASIL patients and 10 healthy subjects were included in the study. All subjects underwent a transcranial magnetic stimulation study examining different intracortical circuits. Sensorimotor plasticity was also assessed using a paired associative stimulation and extensive neuropsychological tests. RESULTS: CADASIL patients showed a lack of intracortical facilitation, short latency afferent inhibition and sensorimotor plasticity when compared with control subjects. CADASIL patients also showed an altered neuropsychological profile. Correlation between sensorimotor plasticity and neuropsychological alterations was observed in CADASIL patients. CONCLUSIONS: These results suggest that acetylcholine and glutamate could be involved in the dementia process in CADASIL and that abnormal sensorimotor plasticity correlates with the neuropsychological profile in CADASIL patients.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 269,
                "text": "NOTCH3 gene"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 822,
                "text": "Xa"
            }
        },
        {
            "context": "Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2. A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 1063,
                "text": "repressor"
            }
        },
        {
            "context": "The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti-PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1(+) MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 143,
                "text": "PD-1"
            }
        },
        {
            "context": "Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 322,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Can the anticoagulant effects of dabigatran be reversed? Idarucizumab is a humanized monoclonal antibody fragment for reversal of the anticoagulant effects of dabigatran. This drug can be used for patients who need emergency surgery or invasive procedures, as well as those with life-threatening or uncontrolled bleeding.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 159,
                "text": "dabigatran"
            }
        },
        {
            "context": "Balanced t(11;15)(q23;q15) in a TP53+/+ breast cancer patient from a Li-Fraumeni syndrome family. Li-Fraumeni Syndrome (LFS) is characterized by early-onset carcinogenesis involving multiple tumor types and shows autosomal dominant inheritance. Approximately 70% of LFS cases are due to germline mutations in the TP53 gene on chromosome 17p13.1. Mutations have also been found in the CHEK2 gene on chromosome 22q11, and others have been mapped to chromosome 11q23. While characterizing an LFS family with a documented defect in TP53, we found one family member who developed bilateral breast cancer at age 37 yet was homozygous for wild-type TP53. Her mother also developed early-onset primary bilateral breast cancer, and a sister had unilateral breast cancer and a soft tissue sarcoma. Cytogenetic analysis using fluorescence in situ hybridization of a primary skin fibroblast cell line revealed that the patient had a novel balanced reciprocal translocation between the long arms of chromosomes 11 and 15: t(11;15)(q23;q15). This translocation was not present in a primary skin fibroblast cell line from a brother with neuroblastoma, who was heterozygous for the TP53 mutation. There was no evidence of acute lymphoblastic leukemia in either the patient or her mother, although a nephew did develop leukemia and died in childhood. These data may implicate the region at breakpoint 11q23 and/or 15q15 as playing a significant role in predisposition to breast cancer development.",
            "question": "What is the inheritance pattern of Li–Fraumeni syndrome?",
            "answers": {
                "answer_start": 213,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "The STOP-BANG questionnaire improves the detection of epilepsy patients at risk for obstructive sleep apnea. Patients with epilepsy and obstructive sleep apnea (OSA) are at risk for worsened seizure control and quality of life. We performed a quality improvement project, evaluating for improvements in the screening of OSA in epilepsy patients using the STOP-BANG questionnaire. The electronic medical records of patients seen in our epilepsy clinic were screened for 4 months prior to the intervention. We subsequently implemented the STOP-BANG questionnaire for 3 months. Only 22/664 patients (3.3%) had their sleeping habits explored during the pre-intervention period; 11 (1.7%) were referred to sleep medicine. Following implementation of the STOP-BANG questionnaire, the percentage of patients screened for OSA increased to 41.6% (269/647, Chi-square Fisher's Exact test 2-sided p<0.001). Of the 269 patients screened, 84 (31.2%) met criteria for elevated OSA risk. Forty-one patients were referred to sleep medicine during the subsequent 3 month period, including 33 who met STOP-BANG criteria for OSA. This represented 6.3% and 5.1% (respectively) of all 647 patients, a significant improvement over the percentage referred prior to the intervention (Chi-square Fisher's Exact test 2-sided p<0.001). Twelve of the 33 patients referred based on the STOP-BANG questionnaire saw sleep medicine; 11 (91.7%) were referred for polysomnography (PSG). Of the 10 patients who underwent PSG, 9 (90%) were diagnosed with OSA and offered treatment with continuous positive airway pressure (CPAP).",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 84,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Insulin-like growth factor-binding protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes. Non-melanoma skin cancers (NMSC) are the most common malignancies in caucasians worldwide. Insulin-like growth factor-binding protein-7 (IGFBP7) was suggested to function as a tumor suppressor gene in several cancers, and to play a role in the proliferation of keratinocytes. A-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells. A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function. Two editing sites were identified within the IGFBP7 transcript. To evaluate the expression and editing of IGFBP7 mRNA in NMSC compared to normal epidermis. We examined the expression and mRNA editing level of IGFBP7 in 22 basal cell carcinoma (BCC), 15 squamous cell carcinoma (SCC), and 18 normal epidermis samples that were surgically removed from patients by the Mohs Micrographic Surgery procedure. We studied the effect of IGFBP7 editing on an immortalized HaCaT keratinocyte cell model. IGFBP7 mRNA is over expressed in BCC and SCC compared to normal epidermis. Moreover, the IGFBP7 transcript is highly edited in normal epidermis, but its editing is significantly reduced in BCC and SCC. The edited form of IGFBP7 can inhibit proliferation and induce senescence in cultured keratinocytes. This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin.",
            "question": "Which is the most common editing modification in eukaryotic mRNA?",
            "answers": {
                "answer_start": 66,
                "text": "A-to-I"
            }
        },
        {
            "context": "Chromosome condensation and sister chromatid pairing in budding yeast. We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 740,
                "text": "chromosome XII"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 466,
                "text": "xa"
            }
        },
        {
            "context": "Dialectical behavior therapy for comorbid personality disorders. Dialectical behavior therapy (DBT) was originally designed as a treatment of emotionally dysregulated, impulsive, and dramatic disorders (e.g., borderline personality disorder) and populations (e.g., parasuicidal women). However, a number of complex disorders represent the dialectical opposite of BPD and related disorders; these disorders are characterized by being overcontrolled, emotionally constricted, perfectionistic, and highly risk-averse. In this article, the authors introduce a recent adaptation of DBT that targets cognitive-behavioral rigidity and emotional constriction and illustrates its application through the case of a man suffering from both paranoid personality disorder and obsessive-compulsive personality disorder.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 209,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Pregnancy, delivery, and outcome for the child in maternal epilepsy. PURPOSE: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy. METHODS: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999-2005 were compared to all 369,267 nonepilepsy deliveries in the same period. RESULTS: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001). DISCUSSION: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.",
            "question": "Which antiepileptic drug is most strongly associated with spina bifida? ",
            "answers": {
                "answer_start": 1164,
                "text": "valproate"
            }
        },
        {
            "context": "S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. UNLABELLED: We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 554,
                "text": "SAM"
            }
        },
        {
            "context": "JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4(+) T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1507,
                "text": "tofacitinib"
            }
        },
        {
            "context": "The Use of Oral Disease-Modifying Therapies in Multiple Sclerosis. Three oral disease-modifying drugs-fingolimod, teriflunomide, and dimethyl fumarate (DMF)-are available for treatment of relapsing forms of multiple sclerosis (MS). All three agents were approved in the last decade, primarily on the basis of a moderate to substantial reduction in the occurrence of MS relapses and central nervous system lesion formation detected by MRI. In the trials leading to approval, the first oral disease-modifying drug, fingolimod, reduced the annualized relapse rate (ARR) from 0.40 in placebo-treated patients to 0.18 (FREEDOMS) and from 0.33 in patients treated with interferon β1a intramuscularly to 0.16 (TRANSFORMS). Teriflunomide, approved on the basis of the two placebo-controlled trials TEMSO and TOWER, demonstrated a reduction in the ARR from 0.54 to 0.37 and from 0.50 to 0.32 respectively. The latest oral MS medication, approved in 2014, is DMF, which had been used in a different formulation for treatment of psoriasis for decades. In the 2-year DEFINE study, the proportion of patients with a relapse was reduced to 27 %, compared with 46 % in placebo arm, whereas in the CONFIRM trial, the ARR was reduced from 0.40 (placebo) to 0.22 in the DMF-treated group of patients. In this review, we will elucidate the mechanisms of action of these three medications and compare their efficacy, safety, and tolerability as a practical guideline for their use. We will further discuss effects other than relapse reduction these small molecules may exert, including potential activities within the central nervous system, and briefly summarize emerging data on new oral MS drugs in clinical development.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 716,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Negative regulation of the tumor suppressor p53 gene by microRNAs. The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 88,
                "text": "p53"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 173,
                "text": "teriflunomide"
            }
        },
        {
            "context": "CTCF Binding Polarity Determines Chromatin Looping. CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional (3D) organization of chromatin. In this study, we assayed the 3D genomic contact profiles of a large number of CTCF binding sites with high-resolution 4C-seq. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR/Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal, convergent CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher-order chromatin structure.",
            "question": "What is the preferred orientation of CTCF binding sites for chromatin looping?",
            "answers": {
                "answer_start": 427,
                "text": "convergent"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 222,
                "text": "MRSA"
            }
        },
        {
            "context": "Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 409,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "The evolutionary chromosome translocation 4;19 in Gorilla gorilla is associated with microduplication of the chromosome fragment syntenic to sequences surrounding the human proximal CMT1A-REP. Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 645,
                "text": "2"
            }
        },
        {
            "context": "Blockage of RNA polymerase II at a cyclobutane pyrimidine dimer and 6-4 photoproduct. The blockage of transcription elongation by RNA polymerase II (pol II) at a DNA damage site on the transcribed strand triggers a transcription-coupled DNA repair (TCR), which rapidly removes DNA damage on the transcribed strand of the expressed gene and allows the resumption of transcription. To analyze the effect of UV-induced DNA damage on transcription elongation, an in vitro transcription elongation system using pol II and oligo(dC)-tailed templates containing a cyclobutane pyrimidine dimer (CPD) or 6-4 photoproduct (6-4PP) at a specific site was employed. The results showed that pol II incorporated nucleotides opposite the CPD and 6-4PP and then stalled. Pol II formed a stable ternary complex consisting of pol II, the DNA damage template, and the nascent transcript. Furthermore, atomic force microscopy imaging revealed that pol II stalled at the damaged region. These findings may provide the basis for analysis of the initiation step of TCR.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 181,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 733,
                "text": "MethPed"
            }
        },
        {
            "context": "Initiation of spectrin dimerization involves complementary electrostatic interactions between paired triple-helical bundles. The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit, each of which comprises largely a series of homologous triple-helical motifs. Initiation of dimer assembly involves strong binding between complementary motifs near the actin-binding end of the dimer. In this study, the mechanism of lateral spectrin association at this dimer nucleation site was investigated using the analytical ultracentrifuge to analyze heterodimers formed from recombinant peptides containing two or four homologous motifs from each subunit (alpha20-21/beta1-2; alpha18-21/beta1-4). Both the two-motif and four-motif dimer associations were weakened substantially with increasing salt concentration, indicating that electrostatic interactions are important for the dimer initiation process. Modeling of the electrostatic potential on the surface of the alpha20 and beta2 motifs showed that the side of the motifs comprising the A and B helices is the most favorable for association, with an area of positive electrostatic potential on the AB face of the beta2 motif opposite negative potential on the AB face of the alpha20 motif and vise versa. Protease protection analysis of the alpha20-21/beta1-2 dimer showed that multiple trypsin and proteinase K sites in the A helices of the beta2 and alpha21 motifs become buried upon dimer formation. Together, these data support a model where complementary long range electrostatic interactions on the AB faces of the triple-helical motifs in the dimer nucleation site initiate the correct pairing of motifs, i.e. alpha21-beta1 and alpha20-beta2. After initial docking of these complementary triple-helical motifs, this association is probably stabilized by subsequent formation of stronger hydrophobic interactions in a complex involving the A helices of both subunits and possibly most of the AB faces. The beta subunit A helix in particular appears to be buried in the dimer interface.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 167,
                "text": "antiparallel"
            }
        },
        {
            "context": "Transcription elongation and tissue-specific somatic CAG instability. The expansion of CAG/CTG repeats is responsible for many diseases, including Huntington's disease (HD) and myotonic dystrophy 1. CAG/CTG expansions are unstable in selective somatic tissues, which accelerates disease progression. The mechanisms underlying repeat instability are complex, and it remains unclear whether chromatin structure and/or transcription contribute to somatic CAG/CTG instability in vivo. To address these issues, we investigated the relationship between CAG instability, chromatin structure, and transcription at the HD locus using the R6/1 and R6/2 HD transgenic mouse lines. These mice express a similar transgene, albeit integrated at a different site, and recapitulate HD tissue-specific instability. We show that instability rates are increased in R6/2 tissues as compared to R6/1 matched-samples. High transgene expression levels and chromatin accessibility correlated with the increased CAG instability of R6/2 mice. Transgene mRNA and H3K4 trimethylation at the HD locus were increased, whereas H3K9 dimethylation was reduced in R6/2 tissues relative to R6/1 matched-tissues. However, the levels of transgene expression and these specific histone marks were similar in the striatum and cerebellum, two tissues showing very different CAG instability levels, irrespective of mouse line. Interestingly, the levels of elongating RNA Pol II at the HD locus, but not the initiating form of RNA Pol II, were tissue-specific and correlated with CAG instability levels. Similarly, H3K36 trimethylation, a mark associated with transcription elongation, was specifically increased at the HD locus in the striatum and not in the cerebellum. Together, our data support the view that transcription modulates somatic CAG instability in vivo. More specifically, our results suggest for the first time that transcription elongation is regulated in a tissue-dependent manner, contributing to tissue-selective CAG instability.",
            "question": "Which histone modification is primarily linked to elongating transcription?",
            "answers": {
                "answer_start": 1573,
                "text": "H3K36 trimethylation"
            }
        },
        {
            "context": "Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. BACKGROUND: Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. METHODS: Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. RESULTS: NSD1 gene mutations were detected in 26 (72%) Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations (6 frameshift, 8 nonsense, 2 spice site, and 7 missense). Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. CONCLUSIONS: Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 241,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase. Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARγ antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 14,
                "text": "JNK"
            }
        },
        {
            "context": "Ribociclib Lengthens Breast Cancer Survival. The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. The combination significantly increased progression-free survival compared with letrozole alone in a large phase III trial-data that could lead to FDA approval.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 120,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Riociguat: a review of its use in patients with chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension. Riociguat (Adempas(®)), a soluble guanylate cyclase stimulator, is a new, first-in-class drug approved for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) [inoperable or persistent/recurrent following surgery] or pulmonary arterial hypertension (PAH). It has been designated an orphan medicine by the European Medicines Agency and the US FDA. This article reviews the available pharmacological properties of oral riociguat and its clinical efficacy and tolerability in adults with CTEPH or PAH. Riociguat is effective and well tolerated in patients with inoperable CTEPH or persistent/recurrent CTEPH following pulmonary endarterectomy, and in patients with PAH. It has a positive result on exercise capacity and pulmonary haemodynamics, and improves WHO functional class. Most adverse events can be attributed to the vasodilatory mechanism of riociguat; however, there is a potential for serious bleeding and fetal harm, and riociguat use is contraindicated in pregnant patients. Pulmonary endarterectomy remains the first treatment of choice for CTEPH, as it is potentially curative. Head-to-head trials comparing riociguat with the approved phosphodiesterase type 5 inhibitors in patients with PAH would be of value for the placement of riociguat in the management of this disease. Riociguat is a promising addition to the treatment options for patients with CTEPH or PAH.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 130,
                "text": "Riociguat"
            }
        },
        {
            "context": "The antioxidant enzyme peroxiredoxin-2 is depleted in lymphocytes seven days after ultra-endurance exercise. PURPOSE: Peroxiredoxin-2 (PRDX-2) is an antioxidant and chaperone-like protein critical for cell function. This study examined whether the levels of lymphocyte PRDX-2 are altered over 1 month following ultra-endurance exercise. METHODS: Nine middle-aged men undertook a single-stage, multi-day 233 km (145 mile) ultra-endurance running race. Blood was collected immediately before (Pre), upon completion/retirement (Post), and following the race at Day 1, Day 7 and Day 28. Lymphocyte lysates were examined for PRDX-2 by reducing and non-reducing SDS-PAGE with western blotting. In a sub-group of men who completed the race (n = 4), PRDX-2 oligomeric state (indicative of redox status) was investigated. RESULTS: Ultra-endurance exercise caused significant changes in lymphocyte PRDX-2 (F(4,32) 3.409, p = 0.020, η(2) = 0.299): 7 days after the race, PRDX-2 levels in lymphocytes had fallen to 30% of pre-race values (p = 0.013) and returned to near-normal levels at Day 28. Non-reducing gels demonstrated that dimeric PRDX-2 (intracellular reduced PRDX-2 monomers) was increased in three of four race completers immediately post-race, indicative of an 'antioxidant response'. Moreover, monomeric PRDX-2 was also increased immediately post-race in two of four race-completing subjects, indicative of oxidative damage, which was not detectable by Day 7. CONCLUSIONS: Lymphocyte PRDX-2 was decreased below normal levels 7 days after ultra-endurance exercise. Excessive accumulation of reactive oxygen species induced by ultra-endurance exercise may underlie depletion of lymphocyte PRDX-2 by triggering its turnover after oxidation. Low levels of lymphocyte PRDX-2 could influence cell function and might, in part, explain reports of dysregulated immunity following ultra-endurance exercise.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 149,
                "text": "antioxidant"
            }
        },
        {
            "context": "Ehlers-Danlos syndrome(s) mimicking child abuse: Is there an impact on clinical practice? Ehlers-Danlos syndrome is a heterogeneous group of heritable connective tissue disorders characterized by increased fragility of various non-ossified tissues. It is usually ascertained due to abnormal skin texture, scarring complications, vascular fragility, or chronic symptoms, such as fatigue and musculoskeletal pain. Sometimes, Ehlers-Danlos syndrome remains undetected until the patient, usually in the pediatric age, shows extensive or severe mucocutaneous injuries after only minor traumas. In this scenario, the misdiagnosis of Ehlers-Danlos syndrome with child abuse is a possibility, as occasionally reported in the literature. Recently, more attention was posed by lay people between the possible association of Ehlers-Danlos syndrome and bone fragility. Literature and personal experience show a strong association between Ehlers-Danlos syndrome, generalized joint hypermobility and reduced bone mass density in older children and adults, especially fertile women. The existence of a true increased risk of fracture in Ehlers-Danlos syndrome is still a matter of debate in children and adults with little and conflicting evidence. In case of suspected child abuse, Ehlers-Danlos syndrome is certainly on the differential for bruising, especially in EDS types with marked cutaneous and capillary involvement. In suspected child abuse cases, careful examination of the index case and her/his extended family is routine, as well as exclusion of other disorders such as osteogenesis imperfecta. The hypothesis of Ehlers-Danlos syndrome as an alternative explanation for infantile fractures remains speculative.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 151,
                "text": "connective tissue"
            }
        },
        {
            "context": "Assessing post-traumatic stress symptoms in a Latino prison population. PURPOSE: The purpose of this paper is to assess the reliability and validity of the Spanish version of the Davidson trauma scale (DTS-S) and to determine the prevalence and correlates of post-traumatic stress disorder (PTSD) symptoms in a non-clinical random sample of prison inmates. DESIGN/METHODOLOGY/APPROACH: Probabilistic samples of 1,179 inmates from 26 penal institutions in Puerto Rico were selected using a multistage sampling design. Population estimates and correlations were obtained for PTSD, generalized anxiety and depression. The reliability, factor structure, and convergent validity of the DTS-S were assessed. Cross-validation was employed to confirm the results of the factor analyses. FINDINGS: Using the cut-offs adopted by the scale's author, 136 (13.4 percent) of the inmates are likely to have current PTSD and 117 (11.6 percent) reach the cut-off for sub-threshold PTSD. Confirmatory factor analysis generated two factors explaining 53 percent of the variance. High reliabilities were obtained for the total scale (α=0.95) and for the frequency and severity scales (α=0.90 and 0.91). Significantly higher DTS-S scores were found for females (t=2.26, p<0.025), for inmates diagnosed with depression or anxiety (t=2.02, p<0.05), and those reporting suicide attempts (t=4.47, p<0.0001). ORIGINALITY/VALUE: Findings support that the DTS-S is a reliable and valid measure to assess PTSD symptoms in Latino inmate populations and to identify individuals at risk for the disorder that require confirmatory diagnosis and clinical interventions.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 259,
                "text": "post-traumatic stress disorder"
            }
        },
        {
            "context": "Crystallization of Ranasmurfin, a blue-coloured protein from Polypedates leucomystax. Ranasmurfin, a previously uncharacterized approximately 13 kDa blue protein found in the nests of the frog Polypedates leucomystax, has been purified and crystallized. The crystals are an intense blue colour and diffract to 1.51 A with P2(1) symmetry and unit-cell parameters a = 40.9, b = 59.9, c = 45.0 A, beta = 93.3 degrees . Self-rotation function analysis indicates the presence of a dimer in the asymmetric unit. Biochemical data suggest that the blue colour of the protein is related to dimer formation. Sequence data for the protein are incomplete, but thus far have identified no model for molecular replacement. A fluorescence scan shows a peak at 9.676 keV, indicating that the protein binds zinc and suggesting a route for structure solution.",
            "question": "What is the color of the protein Ranasmurfin?",
            "answers": {
                "answer_start": 34,
                "text": "blue"
            }
        },
        {
            "context": "Functional significance of lysine 1423 of neurofibromin and characterization of a second site suppressor which rescues mutations at this residue and suppresses RAS2Val-19-activated phenotypes. Lysine 1423 of neurofibromin (neurofibromatosis type I gene product [NF1]) plays a crucial role in the function of NF1. Mutations of this lysine were detected in samples from a neurofibromatosis patient as well as from cancer patients. To further understand the significance of this residue, we have mutated it to all possible amino acids. Functional assays using yeast ira complementation have revealed that lysine is the only amino acid that produced functional NF1. Quantitative analyses of different mutant proteins have suggested that their GTPase-activating protein (GAP) activity is drastically reduced as a result of a decrease in their Ras affinity. Such a requirement for a specific residue is not observed in the case of other conserved residues within the GAP-related domain. We also report that another residue, phenylalanine 1434, plays an important role in NF1 function. This was first indicated by the finding that defective NF1s due to an alteration of lysine 1423 to other amino acids can be rescued by a second site intragenic mutation at residue 1434. The mutation partially restored GAP activity in the lysine mutant. When the mutation phenylalanine 1434 to serine was introduced into a wild-type NF1 protein, the resulting protein acquired the ability to suppress activated phenotypes of RAS2Val-19 cells. This suppression, however, does not involve Ras interaction, since the phenylalanine mutant does not stimulate the intrinsic GTPase activity of RAS2Val-19 protein and does not have an increased affinity for Ras proteins.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 262,
                "text": "NF1"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 131,
                "text": "MRSA"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 165,
                "text": "orexin"
            }
        },
        {
            "context": "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 543,
                "text": "MC1R"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 0,
                "text": "traseR"
            }
        },
        {
            "context": "Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 271,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 529,
                "text": "INCA"
            }
        },
        {
            "context": "mDia1-3 in mammalian filopodia. mDia proteins are members of the formin family of actin nucleating proteins that polymerize linear actin filaments. Such filaments form the core of thin, tubular, membrane-bound cell surface protrusions known as filopodia, which are a major feature of mammalian cell morphology. Filopodia are dynamic structures that help cells sense environmental cues, and play a role in cell migration, axon guidance, angiogenesis and other processes. RhoGTPases bind to and control the activity of mDia proteins, and several other binding partners of the three mDia1 isoforms-mDia1, mDia2 and mDia3-have been documented. Two independent pathways controlling mammalian filopodium formation have emerged, with one driven by the RhoGTPase Cdc42, and the other by Rif. While mDia2 has been the main formin implicated in forming filopodia, mDia1 has recently surfaced as the key formin utilized by both the Cdc42 and Rif pathways to drive filopodial protrusion.",
            "question": "What family do mDia proteins belong in?",
            "answers": {
                "answer_start": 32,
                "text": "mDia proteins are members of the formin family"
            }
        },
        {
            "context": "Video-EEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome). We studied 36 drop seizures in 5 patients with myoclonic astatic epilepsy of early childhood (MAEE) with simultaneous split-screen video recording and polygraph. Sixteen were falling attacks and 20 were either less severe attacks exhibiting only deep head nodding or seizures equivalent to drop attacks in terms of ictal pattern but recorded in the supine position. All seizures except those that occurred in patients in the supine position showed sudden momentary head dropping or collapse of the whole body downward. Recovery to the preictal position was observed in 0.3-1 s. As a result of carefully repeated observations, the 36 seizures were classified as myoclonic flexor type in 9, myoclonic atonic type in 2, and atonic type, with and without transient preceding symptoms in the remaining 25. The MF seizure was characterized by sudden forward flexion of the head and trunk as well as both arms, which caused the patient to fall. In the myoclonic atonic seizure, patients showed brief myoclonic flexor spasms, immediately followed by atonic falling. The AT seizure showed abrupt atonic falling, with and without transient preceding facial expression change and/or twitching of extremities. The ictal EEGs of all 36 seizures exhibited generalized bilaterally synchronous single or multiple spike(s) and wave discharges. Atonic drop attacks appear to be a common cause of ictal epileptic falling in MAEE.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 39,
                "text": "myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies. Cortical dysplasias comprise a variable spectrum of clinical, neuroradiological and histopathological findings. We report about a cohort of 25 pediatric patients (mean age 8.1+/-4.8 years) with severe drug-resistant early onset focal epilepsies (mean duration 2.1+/-0.4 years), mental/psychomotor retardation, and multilobar epileptogenesis. Compared to age-matched biopsy controls, microscopical inspection of neurosurgically resected specimens revealed dysplastic neurons with/without balloon cells in only 7 patients. According to Palmini's classification system, these lesions were categorized as focal cortical dysplasia (FCD) type II. All other patients presented with rather subtle but statistically significant neuroanatomical abnormalities. We identified increased numbers of ectopic neurons in white matter and cortical gliosis. However, most intriguing was our finding of a microcolumnar arrangement of cortical neurons in layer III. These microcolumns can be statistically defined as vertical lining of more than eight neurons (two times standard deviation of cell countings obtained from controls). In addition, neuronal perikarya were significantly smaller in epilepsy patients. Although histological abnormalities occurring during postnatal maturation of the brain challenge any neuropathological classification in this group of young patients, we propose that these findings are classified according to FCD type I. Our observations support a concept compatible with regional loss of high-order brain organization.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 692,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "SEA0400, a specific inhibitor of the Na+-Ca2+ exchanger, attenuates sodium nitroprusside-induced apoptosis in cultured rat microglia. 1. Using SEA0400, a potent and selective inhibitor of the Na+-Ca2+ exchanger (NCX), we examined whether NCX is involved in nitric oxide (NO)-induced disturbance of endoplasmic reticulum (ER) Ca2+ homeostasis followed by apoptosis in cultured rat microglia. 2. Sodium nitroprusside (SNP), an NO donor, decreased cell viability in a dose- and time-dependent manner with apoptotic cell death in cultured microglia. 3. Treatment with SNP decreased the ER Ca2+ levels as evaluated by measuring the increase in cytosolic Ca2+ level induced by exposing cells to thapsigargin, an irreversible inhibitor of ER Ca2+-ATPase. 4. The treatment with SNP also increased mRNA expression of CHOP and GPR78, makers of ER stress. 5. SEA0400 at 0.3-1.0 microM protected microglia against SNP-induced apoptosis. 6. SEA0400 blocked not only the SNP-induced decrease in ER Ca2+ levels but also SNP-induced increase in CHOP and GRP78 mRNAs. 7. SEA0400 did not affect capacitative Ca2+ entry in the presence and absence of SNP. 8. SNP increased Na+-dependent 45Ca2+ uptake and this increase was blocked by SEA0400. 9. These results suggest that SNP induces apoptosis via the ER stress pathway and SEA0400 attenuates SNP-induced apoptosis via suppression of the ER stress in cultured microglia. Our findings imply that NCX plays a role in ER Ca2+ depletion under pathological conditions.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 238,
                "text": "NCX"
            }
        },
        {
            "context": "Two cases of myocardial infarction in type 4 Ehlers-Danlos syndrome. Ehlers-Danlos syndrome is an inherited connective tissue disorder. Clinical manifestations of this syndrome are due to fragile connective tissue. Though many cardiovascular disorders in association with it have been reported, myocardial infarction is quite rare. In this report, two cases with type 4 Ehlers-Danlos syndrome and myocardial infarction are described. Patient 1 was a 30-year-old woman. She was diagnosed as having myocardial infarction on the basis of typical changes in electrocardiograms and serum enzymes (CPK, SGOT and LDH). The diagnosis of type 4 Ehlers-Danlos syndrome was made by the microscopic examination of her connective tissue. Patient 2 was a 32-year-old man. He was also diagnosed as having acute myocardial infarction. His fibroblasts were cultured and they could not synthesize type 3 collagen. Type 4 Ehlers-Danlos syndrome was diagnosed. It was likely that myocardial infarction might have resulted from the fragility of their coronary arteries in type 4 Ehlers-Danlos syndrome.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 108,
                "text": "connective tissue"
            }
        },
        {
            "context": "The regulatory domain stabilizes the p53 tetramer by intersubunit contacts with the DNA binding domain. The tumor suppressor protein p53 is often referred to as the guardian of the genome. In the past, controversial findings have been presented for the role of the C-terminal regulatory domain (RD) of p53 as both a negative regulator and a positive regulator of p53 activity. However, the underlying mechanism remained enigmatic. To understand the function of the RD and of a dominant phosphorylation site within the RD, we analyzed p53 variants in vivo and in vitro. Our experiments revealed, surprisingly, that the p53 RD of one subunit interacts with the DNA binding domain of an adjacent subunit in the tetramer. This leads to the formation of intersubunit contacts that stabilize the tetrameric state of p53 and enhance its transcriptional activity in a cooperative manner. These effects are further modulated by phosphorylation of a conserved serine within the RD.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 133,
                "text": "p53"
            }
        },
        {
            "context": "Efficient incorporation of multiple selenocysteines involves an inefficient decoding step serving as a potential translational checkpoint and ribosome bottleneck. Selenocysteine is incorporated into proteins via \"recoding\" of UGA from a stop codon to a sense codon, a process that requires specific secondary structures in the 3' untranslated region, termed selenocysteine incorporation sequence (SECIS) elements, and the protein factors that they recruit. Whereas most selenoprotein mRNAs contain a single UGA codon and a single SECIS element, selenoprotein P genes encode multiple UGAs and two SECIS elements. We have identified evolutionary adaptations in selenoprotein P genes that contribute to the efficiency of incorporating multiple selenocysteine residues in this protein. The first is a conserved, inefficiently decoded UGA codon in the N-terminal region, which appears to serve both as a checkpoint for the presence of factors required for selenocysteine incorporation and as a \"bottleneck,\" slowing down the progress of elongating ribosomes. The second adaptation involves the presence of introns downstream of this inefficiently decoded UGA which confer the potential for nonsense-mediated decay when factors required for selenocysteine incorporation are limiting. Third, the two SECIS elements in selenoprotein P mRNA function with differing efficiencies, affecting both the rate and the efficiency of decoding different UGAs. The implications for how these factors contribute to the decoding of multiple selenocysteine residues are discussed.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 545,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 1340,
                "text": "CisMapper"
            }
        },
        {
            "context": "Preclinical and clinical development of an anti-kappa free light chain mAb for multiple myeloma. Monoclonal antibodies (mAb) have had tremendous success in treating a variety of cancers over the past twenty years. Yet despite their widespread clinical use, which includes treatments for haematological malignancies, there are still no approved mAb therapies for multiple myeloma (MM). This is likely to change within the next few years with a number of mAb therapies being assessed in late stage clinical trials, most notably, the anti-CS-1 mAb, elotuzumab, and the anti-CD38 mAb, daratumumab, which are currently being evaluated in Phase III clinical trials for MM. In this review, we will discuss the preclinical and clinical development of MDX-1097, a Phase II candidate which targets cell membrane-associated kappa immunoglobulin free light chains expressed on the surface of MM cells.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 571,
                "text": "CD38"
            }
        },
        {
            "context": "Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease. Pseudogenes, resulting from duplications of functional genes, contribute to the functional complexity of their parental genes. The glucocerebrosidase gene (GBA), located in a gene-rich region on chromosome 1q 21, is mutated in Gaucher disease. The presence of contiguous, highly homologous pseudogenes for both GBA and metaxin 1 at this locus increases the likelihood of DNA rearrangement. We describe a facile method to identify and analyze recombinant alleles in patients with Gaucher disease. Genomic DNA from 20 patients with recombinant GBA alleles and five controls was evaluated to identify DNA rearrangements or copy number variation using six probes specific for either the GBA gene or pseudogene. Quantitative real-time PCR was performed on genomic DNA, and Southern blot analyses using HincII together with sequencing confirmed the real-time results. Both GBA fusions and duplications could be detected. Different sites of crossover were identified, and alleles resulting from gene conversion could be distinguished from reciprocal recombinant alleles. Quantitative real-time PCR is a sensitive and rapid method to detect fusions and duplications in patients with recombinant GBA alleles. This technique is more sensitive, faster, and cheaper than Southern blot analysis, and can be used in diagnostic laboratories, and to detect other recombinant alleles within the genome.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 236,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1-/+;Trp53-/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1-/-;Trp53-/- astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor-stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 358,
                "text": "NF1"
            }
        },
        {
            "context": "Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus. RATIONALE: Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. OBJECTIVE: The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. METHODS AND RESULTS: Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. CONCLUSIONS: Mitochondrial fission is an obligatory, early step in mammalian O2 sensing and offers a promising target for modulating DA patency.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 50,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Dynamic response of RNA editing to temperature in Drosophila. BACKGROUND: Adenosine-to-inosine RNA editing is a highly conserved process that post-transcriptionally modifies mRNA, generating proteomic diversity, particularly within the nervous system of metazoans. Transcripts encoding proteins involved in neurotransmission predominate as targets of such modifications. Previous reports suggest that RNA editing is responsive to environmental inputs in the form of temperature alterations. However, the molecular determinants underlying temperature-dependent RNA editing responses are not well understood. RESULTS: Using the poikilotherm Drosophila, we show that acute temperature alterations within a normal physiological range result in substantial changes in RNA editing levels. Our examination of particular sites reveals diversity in the patterns with which editing responds to temperature, and these patterns are conserved across five species of Drosophilidae representing over 10 million years of divergence. In addition, we show that expression of the editing enzyme, ADAR (adenosine deaminase acting on RNA), is dramatically decreased at elevated temperatures, partially, but not fully, explaining some target responses to temperature. Interestingly, this reduction in editing enzyme levels at elevated temperature is only partially reversed by a return to lower temperatures. Lastly, we show that engineered structural variants of the most temperature-sensitive editing site, in a sodium channel transcript, perturb thermal responsiveness in RNA editing profile for a particular RNA structure. CONCLUSIONS: Our results suggest that the RNA editing process responds to temperature alterations via two distinct molecular mechanisms: through intrinsic thermo-sensitivity of the RNA structures that direct editing, and due to temperature sensitive expression or stability of the RNA editing enzyme. Environmental cues, in this case temperature, rapidly reprogram the Drosophila transcriptome through RNA editing, presumably resulting in altered proteomic ratios of edited and unedited proteins.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 1077,
                "text": "ADAR"
            }
        },
        {
            "context": "Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy. The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.",
            "question": "What is the major adverse effect of adriamycin(doxorubicin)?",
            "answers": {
                "answer_start": 957,
                "text": "cardiotoxicity"
            }
        },
        {
            "context": "A novel mutation of the McLeod syndrome gene in a Japanese family. McLeod syndrome is a rare X-linked hematologic and neuromuscular disorder manifested by chorea, myopathy, cardiomyopathy, areflexia, hyperCKemia, and acanthocytosis. Only four mutations have been reported in the gene responsible for McLeod syndrome. We report a novel gene mutation in a Japanese family. Direct sequencing of the PCR-amplified genomic DNA revealed the mutation was a single C-nucleotide insertion at codon 151 in exon 2 of the XK gene, which resulted in a 3'-frameshift. Study of family members revealed that the patient's mother was a manifesting carrier heterozygous for this mutation.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 510,
                "text": "XK"
            }
        },
        {
            "context": "Care for MRSA carriers in the outpatient sector: a survey among MRSA carriers and physicians in two regions in Germany. BACKGROUND: Little is known about the management of methicillin-resistant Staphylococcus aureus (MRSA) carriers in the German outpatient sector and about the impact of MRSA on their daily life. Reimbursement for MRSA related costs in the German outpatient sector is available since 2012, but its impact has not been studied yet. The aim of the study was to analyze the outpatient management of MRSA carriers from both, physicians' and MRSA carriers' perspective. METHODS: Paper-based questionnaires were mailed to physicians providing outpatient care and to MRSA carriers in 2013. MRSA carriers were recruited among patients tested positive for MRSA during a hospital stay in 2012. General practitioners, specialists for internal medicine, urologists, and dermatologists working in the outpatient catchment areas of the hospitals were contacted. RESULTS: Out of 910 MRSA carriers 16.5 % completed the questionnaires; among 851 physicians 9.5 % participated. 27.3 % of the responding MRSA carriers stated that no healthcare professional had ever talked to them about MRSA. 17.4 % reported self-stigmatization in terms of restricting social contacts; 47.3 % remembered decolonization and 33.3 % reported that their MRSA status was checked after discharge. Physicians displayed heterogeneous attitude and activity towards MRSA (number of applied decolonization and MRSA screenings). A minority (15.2 %) were satisfied with the reimbursement of costs, 35.9 % reported full agreement with the general recommendations for the handling of MRSA carriers. CONCLUSIONS: MRSA carriers appear not well informed; (self-) stigmatization is occurring and should be tackled. Greater awareness of MRSA as a problem in the outpatient sector could lead to a better handling of MRSA carriers.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 217,
                "text": "MRSA"
            }
        },
        {
            "context": "Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women. Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 25,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? The 2014 outbreak of Ebola virus disease (EVD) in West Africa, caused by Ebola virus (Zaire Ebola virus species), is the largest outbreak of EVD in history. It cause hemorrhagic fever in human and nonhuman primates with high mortality rate up to 90% and can be transmitted by direct contact with blood, body fluids, skin of EVD patients or persons who have died of EVD. As of December 17, 2014, 450 healthcare personnel are known to have been infected with Ebola, of whom 244 died. For development of Ebola vaccine and treatment are highly difficult due to its dangerous and accessibility that requires biosafety level 4 (BSL-4) to conduct experiment. Also there is no specific vaccine and treatment for Ebola virus; however, many candidate vaccines and antiviral-drugs such as ZMapp and TKM-Ebola are being developed for Ebola virus disease. In this review, we focus on the epidemiology of 2014 outbreak of Ebola virus and candidate agent for preventing and curing from Ebola virus.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 896,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 86,
                "text": "Chromosome 2"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 163,
                "text": "Nox1"
            }
        },
        {
            "context": "Biological functions of hCG and hCG-related molecules. BACKGROUND: hCG is a term referring to 4 independent molecules, each produced by separate cells and each having completely separate functions. These are hCG produced by villous syncytiotrophoblast cells, hyperglycosylated hCG produced by cytotrophoblast cells, free beta-subunit made by multiple primary non-trophoblastic malignancies, and pituitary hCG made by the gonadotrope cells of the anterior pituitary. RESULTS AND DISCUSSION: hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy. Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle.",
            "question": "Which protein is associated with hyperemesis gravidarum during pregrancy?",
            "answers": {
                "answer_start": 518,
                "text": "hCG"
            }
        },
        {
            "context": "Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Chaperone-mediated autophagy (CMA) is a selective form of autophagy whose distinctive feature is the fact that substrate proteins are translocated directly from the cytosol across the lysosomal membrane for degradation inside lysosomes. CMA substrates are cytosolic proteins bearing a pentapeptide motif in their sequence that, when recognized by the cytosolic chaperone HSPA8/HSC70, targets them to the surface of the lysosomes. Once there, substrate proteins bind to the lysosome-associated membrane protein type 2 isoform A (LAMP2A), inducing assembly of this receptor protein into a higher molecular weight protein complex that is used by the substrate proteins to reach the lysosomal lumen. CMA is constitutively active in most cells but it is maximally activated under conditions of stress.",
            "question": "Which is the receptor for substrates of Chaperone Mediated Autophagy?",
            "answers": {
                "answer_start": 616,
                "text": "LAMP2A"
            }
        },
        {
            "context": "Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 283,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease. Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Majority of PD are sporadic, for which genetic causes remain largely unknown. Alpha-synuclein, the main component of Lewy bodies, plays a central role in the PD pathogenesis. Macroautophagy is a highly conserved cellular process that digests dysfunctional macromolecules and damaged organelles. Accumulating evidence indicates that macroautophagy (hereafter referred to as autophagy) is involved in alpha-synuclein degradation. Dysregulation of autophagy has been observed in the brain tissues from PD patients and animal models. We hypothesized that change expression levels of autophagy-related genes (ATG), including ATG5, may contribute to PD. In this study, we genetically and functionally analyzed the ATG5 gene promoter in groups of sporadic PD patients and ethnic-matched healthy controls. A novel heterozygous variant, 106774459T>A, was identified in one female patient, but in none of controls, which significantly enhanced transcriptional activities of the ATG5 gene promoter. Furthermore, ATG5 gene expression level in the PD patient was significantly elevated than that in controls. Four novel heterozygous variants, 106774423C>A, 106774418C>A, 106774382C>A and 106774206G>A, were only found in controls. The variant, 106774464C>T, and SNP-106774030A>G (rs510432) were found in PD patients and controls with similar frequencies. Collectively, the variant identified in PD patient may change ATG5 protein levels and alter autophagy activities, contributing to PD onset as a risk factor.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 251,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 518,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Flumazenil: a benzodiazepine antagonist. The mechanism of action, pharmacokinetics, and use of flumazenil in benzodiazepine overdose, as well as in the management of other disease states, are reviewed. Flumazenil interacts at the central benzodiazepine receptor to antagonize or reverse the behavioral, neurologic, and electrophysiologic effects of benzodiazepine agonists and inverse agonists. Flumazenil has been studied for a variety of indications, including as an antidote to benzodiazepine overdose and for awakening of comatose patients, reversal of sedation after surgery and in critically ill patients, and management of hepatic encephalopathy. It improves the level of consciousness in patients with benzodiazepine overdose; however, resedation may occur within one to two hours after administration, so repeated doses or a continuous infusion may be required to maintain therapeutic efficacy. It appears to be effective in reversing sedation induced by midazolam or diazepam, and case reports suggest that it is useful in awakening comatose patients, although its clinical utility is questionable. Flumazenil has proved useful in reversing conscious sedation in critically ill patients, although response may be dose dependent. Animal models indicate that flumazenil is of some benefit in hepatic encephalopathy, but until well-designed clinical trials are conducted, hepatic encephalopathy must be considered an investigational indication for flumazenil. Adverse reactions include CNS manifestations, resedation, cardiovascular effects, seizures, and alterations in intracranial pressure and cerebral perfusion pressure. Hepatic dysfunction results in a substantial change in the pharmacokinetic profile of flumazenil; therefore, dosage adjustment may be necessary in patients with hepatic dysfunction or in those receiving medications that alter flumazenil metabolism. Flumazenil has been shown to reverse sedation caused by intoxication with benzodiazepines alone or benzodiazepines in combination with other agents, but it should not be used when cyclic antidepressant intoxication is suspected. It may be beneficial after surgery when benzodiazepines have been used as part of anesthesia and after a diagnostic or surgical procedure when assessment of CNS function is necessary.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 202,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 416,
                "text": "CaN"
            }
        },
        {
            "context": "Antimicrobial activity of bovine psoriasin. Human psoriasin (S100A7) has originally been described as a member of the family of S100 calcium-binding proteins which is overexpressed in patients suffering from psoriasis. The bovine homolog was first identified as a cow-derived respiratory allergen. As Escherichia coli mastitis is a common problem in dairy cattle, and human psoriasin was found to exhibit antimicrobial activity preferentially against E. coli, we examined whether the bovine mRNA is expressed in the mammary gland. To demonstrate the antimicrobial activity of bovine psoriasin, we isolated cDNA from the udder, cloned the bovine psoriasin gene in a bacterial expression vector, and the recombinant protein was expressed in BL21 cells. The in vitro antibacterial activity was tested by performing microdilution susceptibility tests and radial diffusion assays with eight different bacterial strains, thereof three different E. coli strains, and one yeast. The antimicrobial activity of the recombinant bovine psoriasin is comparable with human psoriasin and also limited to E. coli. Psoriasin appears to be a part of the local host defense mechanism in the udder, is a putative candidate for a cow-specific factor influencing mastitis susceptibility, and a possible alternative to conventional antibiotics.",
            "question": "In which condition was protein S100A7 originally identified?",
            "answers": {
                "answer_start": 208,
                "text": "psoriasis"
            }
        },
        {
            "context": "Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 1335,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "BPP: a sequence-based algorithm for branch point prediction. Motivation: Although high-throughput sequencing methods have been proposed to identify splicing branch points in the human genome, these methods can only detect a small fraction of the branch points subject to the sequencing depth, experimental cost and the expression level of the mRNA. An accurate computational model for branch point prediction is therefore an ongoing objective in human genome research. Results: We here propose a novel branch point prediction algorithm that utilizes information on the branch point sequence and the polypyrimidine tract. Using experimentally validated data, we demonstrate that our proposed method outperforms existing methods. Availability and implementation: https://github.com/zhqingit/BPP. Contact: djguo@cuhk.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which sequence-based algorithm for branch point prediction has been proposed?",
            "answers": {
                "answer_start": 0,
                "text": "BPP"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 201,
                "text": "Xa"
            }
        },
        {
            "context": "Negative feedback regulation of Wnt signaling by Gbetagamma-mediated reduction of Dishevelled. Wnt signaling is known to be important for diverse embryonic and post-natal cellular events and be regulated by the proteins Dishevelled and Axin. Although Dishevelled is activated by Wnt and involved in signal transduction, it is not clear how Dishevelled-mediated signaling is turned off. We report that guanine nucleotide binding protein beta 2 (Gnb2; Gbeta2) bound to Axin and Gbeta2 inhibited Wnt mediated reporter activity. The inhibition involved reduction of the level of Dishevelled, and the Gbeta2gamma2 mediated reduction of Dishevelled was countered by increased expression of Axin. Consistent with these effects in HEK293T cells, injection of Gbeta2gamma2 into Xenopus embryos inhibited the formation of secondary axes induced either by XWnt8 or Dishevelled, but not by beta-catenin. The DEP domain of Dishevelled is necessary for both interaction with Gbeta2gamma2 and subsequent degradation of Dishevelled via the lysosomal pathway. Signaling induced by Gbeta2gamma2 is required because a mutant of Gbeta2, Gbeta2 (W332A) with lower signaling activity, had reduced ability to downregulate the level of Dishevelled. Activation of Wnt signaling by either of two methods, increased Frizzled signaling or transient transfection of Wnt, also led to increased degradation of Dishevelled and the induced Dishevelled loss is dependent on Gbeta1 and Gbeta2. Other studies with agents that interfere with PLC action and calcium signaling suggested that loss of Dishevelled is mediated through the following pathway: Wnt/Frizzled-->Gbetagamma-->PLC-->Ca(+2)/PKC signaling. Together the evidence suggests a novel negative feedback mechanism in which Gbeta2gamma2 inhibits Wnt signaling by degradation of Dishevelled.",
            "question": "Which signaling pathway is activating the dishevelled proteins?",
            "answers": {
                "answer_start": 95,
                "text": "Wnt signaling"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 515,
                "text": "7"
            }
        },
        {
            "context": "Serial ultrasonographic findings of plantar fasciitis after treatment with botulinum toxin a: a case study. Plantar fasciitis is a common cause of heel pain and is the result of a degenerative process of the plantar fascia at its calcaneal attachment. A case study of a preliminary experience with local injections of botulinum toxin A (BTX-A) for the treatment of chronic plantar fasciitis in a 43-year-old woman is presented. We injected the patient with 70 units of BTX-A (0.7mL) in 2 divided doses: 40 units (0.4mL) in the tender region of the heel, and 30 units (0.3mL) in the most tender point of the foot arch. Visual analog scale (VAS) and pressure pain threshold (PPT) were measured to evaluate the efficacy of BTX-A injections. Real-time, high-resolution ultrasonographic findings of the plantar fascia after BTX-A injections were also used for serial follow-ups. After BTX-A injection, decreased VAS values were reported and increased PPT was observed. In ultrasonographic studies, the thickness of the plantar fascia and the hypoechogenicity of the fascia were reduced. Decreased plantar fascia thickness was observed on the first and third week after BTX-A injections. The findings were compatible with the changes in pain assessed by VAS and PPT. Ultrasonographic findings also indicated a progressive decrease in the thickness of the underlying muscle belly. Ultrasonography seems to be a valuable, noninvasive diagnostic tool for the evaluation of plantar fasciitis treated with BTX-A injections. It can offer objective measurements of therapeutic effects and is feasible for serial follow-ups.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 147,
                "text": "heel pain"
            }
        },
        {
            "context": "Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells. Telomerase is required for the unlimited lifespan of cancer cells. The vast majority of pancreatic adenocarcinomas overexpress telomerase activity and blocking telomerase could limit their lifespan. GRN163L (Imetelstat) is a lipid-conjugated N3'→P5' thio-phosphoramidate oligonucleotide that blocks the template region of telomerase. The aim of this study was to define the effects of long-term GRN163L exposure on the maintenance of telomeres and lifespan of pancreatic cancer cells. Telomere size, telomerase activity, and telomerase inhibition response to GRN163L were measured in a panel of 10 pancreatic cancer cell lines. The cell lines exhibited large differences in levels of telomerase activity (46-fold variation), but most lines had very short telomeres (2-3 kb in size). GRN163L inhibited telomerase in all 10 pancreatic cancer cell lines, with IC50 ranging from 50 nM to 200 nM. Continuous GRN163L exposure of CAPAN1 (IC50 = 75 nM) and CD18 cells (IC50 = 204 nM) resulted in an initial rapid shortening of the telomeres followed by the maintenance of extremely short but stable telomeres. Continuous exposure to the drug eventually led to crisis and to a complete loss of viability after 47 (CAPAN1) and 69 (CD18) doublings. Crisis In these cells was accompanied by activation of a DNA damage response (γ-H2AX) and evidence of both senescence (SA-β-galactosidase activity) and apoptosis (sub-G1 DNA content, PARP cleavage). Removal of the drug after long-term GRN163L exposure led to a reactivation of telomerase and re-elongation of telomeres in the third week of cultivation without GRN163L. These findings show that the lifespan of pancreatic cancer cells can be limited by continuous telomerase inhibition. These results should facilitate the design of future clinical trials of GRN163L in patients with pancreatic cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 418,
                "text": "telomerase"
            }
        },
        {
            "context": "Detection of K-ras mutations in mucinous pancreatic duct hyperplasia from a patient with a family history of pancreatic carcinoma. Mutations in the K-ras oncogene and in the p53 tumor suppressor gene are commonly identified in sporadic cases of pancreatic adenocarcinoma. Although these genes might serve as useful markers for early diagnosis of pancreatic carcinoma in patients at risk for the development of this disease, familial pancreatic carcinomas have not been studied for these mutations. We recently had the opportunity to examine a pancreas prophylactically removed from a patient with a strong family history of pancreatic carcinoma. This gave us the unique opportunity to study the early events in the development of familial adenocarcinoma of the pancreas. Histopathological examination of the pancreas revealed multifocal papillary and nonpapillary mucinous duct hyperplasia. Seven of these foci were microdissected and analyzed for K-ras and p53 mutations. The K-ras mutations were detected by combined mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. Five of the seven duct lesions harbored activating point mutations in codon 12 of K-ras; a G to A transition was found in four and a G to C transversion in one. In contrast, these lesions did not harbor detectable p53 mutations as determined by denaturing gradient gel electrophoresis of exons 5 to 8, nor was there overexpression of the p53 protein as determined by immunohistochemistry. These findings suggest that mutations in K-ras represent an early event in the pathogenesis of pancreatic carcinoma. In addition, monitoring of patients with a strong family history of pancreatic carcinoma for K-ras mutations may identify patients at risk for the development of invasive carcinoma.",
            "question": "Which is the molecular mechanism underlying K-ras alterations in carcinomas?",
            "answers": {
                "answer_start": 1238,
                "text": "point mutations"
            }
        },
        {
            "context": "Calpain cleavage regulates the protein stability of p73. The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 724,
                "text": "7"
            }
        },
        {
            "context": "Analysis of protein profile of tomato root infected with Fusarium oxysporum f. sp lycopersici. Fusarium wilt caused by Fusarium oxysporum f. sp lycopersici (Fol) is one of the main diseases affecting tomatoes. The BHRS 2,3 genotype of tomato is, however, resistant to this disease. A proteomic approach was used to understand the defense mechanisms of this genotype using the tomato root, the first tissue that interacts with the fungus, as a target. Protein was extracted and separated by two-dimensional electrophoresis followed by staining with Coomassie brilliant blue. The proteins were identified by MALDI-TOF/TOF mass spectrometry. A total of 22 proteins were identified, 21 of which showed differential expression with 12 proteins being upregulated and nine being downregulated. Plants responded to the pathogen with increased expression of pathogenesis-related proteins. We noted the induction of proteins involved in hypersensitivity reaction and other defense mechanisms. The expression of proteins of primary metabolism related to energy production, however, decreased, as did the expression of two proteins related to defense against abiotic stress. These results demonstrate the presence of important mechanisms for defense against Fol in the tomato genotype BHRS 2,3.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 200,
                "text": "tomato"
            }
        },
        {
            "context": "Defective secretion of recombinant fragments of fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Fibrillin-1 is a large modular glycoprotein that assembles to form 10-12 nm microfibrils in the extracellular matrix. Mutations in the fibrillin-1 gene (FBN1) cause Marfan syndrome and related connective tissue disorders (fibrillinopathies) that show autosomal dominant inheritance. The pathogenic mechanism is thought to be a dominant negative effect of a mutant protein on microfibril assembly, although direct evidence is lacking. A significant group of disease-causing FBN1 mutations are cysteine substitutions within EGF domains that are predicted to cause misfolding by removal of disulphide bonds that stabilize the native domain fold. We have studied three missense mutations (C1117Y, C1129Y and G1127S) to investigate the effect of misfolding on the trafficking of fibrillin-1 from fibroblast cells. We demonstrate that both C1117Y and C1129Y, expressed as recombinant fragments of fibrillin-1, are retained and accumulate within the cell. Both undergo core glycosylation but lack the complex glycosylation observed in the secreted wild-type fragment, suggesting retention in the endoplasmic reticulum (ER). In addition, co-immunoprecipitation experiments show association with the ER chaperone calreticulin, but not calnexin, 78 kDa glucose-regulated protein (Grp78/BiP) or protein disulfide isomerase. In contrast, G1127S, which causes a moderate change in the EGF domain fold, shows a pattern of glycosylation and trafficking profile indistinguishable from the wild-type fragment. Since expression of the recombinant fragments does not disrupt the secretion of endogenous fibrillin-1 by the cell, we propose that G1127S causes disease via an extracellular dominant negative effect. In contrast, the observed ER retention of C1117Y and C1129Y suggests that disease associated with these missense mutations is caused either by an intracellular dominant negative effect or haploinsufficiency.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 312,
                "text": "FBN1"
            }
        },
        {
            "context": "Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease development and progression. In this light, new therapies that specifically target signaling molecules downstream of the BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton's tyrosine kinase (Btk), Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior, these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ CLL mouse model, which is based on sporadic expression of the simian oncovirus SV40 T-antigen in mature B cells. To this end, we crossed IgH.ETμ mice on a Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and that leukemias formed in Btk haplo-insufficient mice selectively expressed the wild-type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together, these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for malignant transformation.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 473,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "A highly efficient form of the selenocysteine insertion sequence element in protozoan parasites and its use in mammalian cells. Selenoproteins are an elite group of proteins containing a rare amino acid, selenocysteine (Sec), encoded by the codon, UGA. In eukaryotes, incorporation of Sec requires a Sec insertion sequence (SECIS) element, a stem-loop structure located in the 3'-untranslated regions of selenoprotein mRNAs. Here we report identification of a noncanonical form of SECIS element in Toxoplasma gondii and Neospora canine, single-celled apicomplexan parasites of humans and domestic animals. This SECIS has a GGGA sequence in the SBP2-binding site in place of AUGA previously considered invariant. Using a combination of computational and molecular techniques, we show that Toxoplasma and Neospora possess both canonical and noncanonical SECIS elements. The GGGA-type SECIS element supported Sec insertion in mammalian HEK 293 and NIH 3T3 cells and did so more efficiently than the natural mammalian SECIS elements tested. In addition, mammalian type I and type II SECIS elements mutated into the GGGA forms were functional but manifested decreased Sec insertion efficiency. We carried out computational searches for both AUGA and GGGA forms of SECIS elements in Toxoplasma and detected five selenoprotein genes, including one coding for a previously undescribed selenoprotein, designated SelQ, and two containing the GGGA form of the SECIS element. In contrast, the GGGA-type SECIS elements were not detected in mammals and nematodes. As a practical outcome of the study, we developed pSelExpress1, a vector for convenient expression of selenoproteins in mammalian cells. It contains an SBP2 gene and the most efficient tested SECIS element: an AUGA mutant of the GGGA-type Toxoplasma SelT structure.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 324,
                "text": "SECIS"
            }
        },
        {
            "context": "[Chemotherapy-free treatment of chronic lymphocytic leukemia?]. Treatment of CLL patients with conventional cytotoxic agents is often combined with significant toxicity that prevents broad application especially in elderly patients. In addition, relapse frequently occurs after application of conventional chemotherapy in CLL. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab obinutuzumab, although in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Lenalidomide as monotherapy has demonstrated clinical efficacy in patients with relapsed disease and first data within clinical trials have been generated in the front-line setting. A promising class of novel agents has been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL are the BH3-mimetic inhibitors of the Bcl-2 family of pro-survival proteins. Other interesting candidate drugs that are currently explored for CLL patients include small modular immunopharmaceutical (SMIP) proteins (e. g. TRU-016), CDK inhibitors (e. g. dinaciclib), HDAC inhibitors and others. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 995,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 831,
                "text": "CD38"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 745,
                "text": "early"
            }
        },
        {
            "context": "H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast. The histone variant H2A.Z is a universal mark of gene promoters, enhancers, and regulatory elements in eukaryotic chromatin. The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer. Binding of both substrates, the canonical nucleosome and the H2A.Z-H2B dimer, is essential for activation of SWR1. We found that SWR1 primarily recognizes key residues within the α2 helix in the histone-fold of nucleosomal histone H2A, a region not previously known to influence remodeler activity. Moreover, SWR1 interacts preferentially with nucleosomal DNA at superhelix location 2 on the nucleosome face distal to its linker-binding site. Our findings provide new molecular insights on recognition of the canonical nucleosome by a chromatin remodeler and have implications for ATP-driven mechanisms of histone eviction and deposition.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 57,
                "text": "SWR1"
            }
        },
        {
            "context": "H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast. The histone variant H2A.Z is a universal mark of gene promoters, enhancers, and regulatory elements in eukaryotic chromatin. The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer. Binding of both substrates, the canonical nucleosome and the H2A.Z-H2B dimer, is essential for activation of SWR1. We found that SWR1 primarily recognizes key residues within the α2 helix in the histone-fold of nucleosomal histone H2A, a region not previously known to influence remodeler activity. Moreover, SWR1 interacts preferentially with nucleosomal DNA at superhelix location 2 on the nucleosome face distal to its linker-binding site. Our findings provide new molecular insights on recognition of the canonical nucleosome by a chromatin remodeler and have implications for ATP-driven mechanisms of histone eviction and deposition.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 256,
                "text": "SWR1"
            }
        },
        {
            "context": "Novel therapies in benign and malignant bone diseases. With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 504,
                "text": "RANKL"
            }
        },
        {
            "context": "Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924. Cullin-RING ubiquitin ligases (CRLs) are responsible for the ubiquitination of many cellular proteins, thereby targeting them for proteasomal degradation. In most cases the substrates of the CRLs have not been identified, although many of those that are known have cancer relevance. MLN4924, an investigational small molecule that is a potent and selective inhibitor of the Nedd8-activating enzyme (NAE), is currently being explored in Phase I clinical trials. Inhibition of Nedd8-activating enzyme by MLN4924 prevents the conjugation of cullin proteins with NEDD8, resulting in inactivation of the entire family of CRLs. We have performed stable isotope labeling with amino acids in cell culture analysis of A375 melanoma cells treated with MLN4924 to identify new CRL substrates, confidently identifying and quantitating 5122-6012 proteins per time point. Proteins such as MLX, EID1, KLF5, ORC6L, MAGEA6, MORF4L2, MRFAP1, MORF4L1, and TAX1BP1 are rapidly stabilized by MLN4924, suggesting that they are novel CRL substrates. Proteins up-regulated at later times were also identified and siRNA against their corresponding genes were used to evaluate their influence on MLN4924-induced cell death. Thirty-eight proteins were identified as being particularly important for the cytotoxicity of MLN4924. Strikingly, these proteins had roles in cell cycle, DNA damage repair, and ubiquitin transfer. Therefore, the combination of RNAi with stable isotope labeling with amino acids in cell culture provides a paradigm for understanding the mechanism of action of novel agents affecting the ubiquitin proteasome system and a path to identifying mechanistic biomarkers.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 86,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Sonic hedgehog-induced histone deacetylase activation is required for cerebellar granule precursor hyperplasia in medulloblastoma. Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 131,
                "text": "Medulloblastoma"
            }
        },
        {
            "context": "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well-ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 375,
                "text": "SET domain"
            }
        },
        {
            "context": "p16Ink4a suppression of lung adenocarcinoma by Bmi-1 in the presence of p38 activation. PURPOSE: Because evasion of tumor suppression is a critical step in cancer development, cancer cells have developed a variety of mechanisms to circumvent the influence of tumor suppressive pathways. Thus, genes that negatively regulate tumor suppressors could be considered novel types of oncogenes such as Bmi-1 repressing p16Ink4a and inhibiting p53 and were found to be frequently up-regulated in a variety of cancers. p38 mitogen-activated protein kinase (MAPK), which reportedly plays a crucial role as a tumor suppressor, is activated in number of lung adenocarcinomas, which is seemingly at odds with its role as a tumor suppressor. METHODS: We examined 10 lung adenocarcinomas and corresponding normal tissues and determined the expression levels of a variety of tumor suppressor proteins through real-time polymerase chain reaction and immunohistochemistry and measured p38 MAPK activity by immunoblotting or immunohistochemistry analysis. In the in vitro cellular model, p38 activation by H-Ras and consequent senescence induction was achieved through retro-viral gene transduction. Similarly, the suppression of p16Ink4a by Bmi-1 after the introduction of H-Ras was achieved through transient transfection with cationic liposome. RESULTS: We detected several lung adenocarcinomas that were positive for activated p38 MAPK but evidenced reduced levels of p16Ink4a expression. The suppression of p16Ink4a occurred in parallel with an increase in Bmi-1 and/or p16Ink4a promoter hypermethylation. Consistent with these observations, the H-Ras-stimulated induction of p16Ink4a was suppressed significantly through the coexpression of Bmi-1 in vitro. DISCUSSION: These results demonstrate that the suppression of p16Ink4a by either the induction of Bmi-1 or the hypermethylation of p16Ink4 may be an important step in avoiding tumor surveillance by p38 MAPK during the development of lung cancer.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 1493,
                "text": "p16Ink4"
            }
        },
        {
            "context": "Transsphenoidal surgery for a life-threatening prolactinoma apoplexy during pregnancy. Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility. Currently the treatment of choice is pharmacotherapy with dopamine agonists, whereas surgical treatment is reserved for a selected group of patients. Pituitary-tumor apoplexy is a rare, life-threatening condition associated with significant morbidity and mortality. The authors present the case of a 25-year-old woman with prolactinoma treated with dopamine agonist. In course of such a treatment the patient became pregnant. The bromocriptine was gradually withdrawn. In the 14th week of pregnancy she was admitted for symptoms suggesting pituitary tumor apoplexy. The treatment with bromocriptine was reinitiated. In the 20th week of pregnancy further deterioration of the patient's neurological condition and visual-field abnormalities were observed. The patient was qualified for surgical treatment - selective transsphenoidal adenomectomy. The successful surgery led to improvement of neurological condition. The early postoperative PRL level decreased significantly and hormonal function of the pituitary was preserved. The pregnancy ended in 38th week with a caesarean section. Endocrinological evaluation conducted after the uneventful delivery confirmed normal function of the pituitary. Magnetic resonance imaging (MRI) did not reveal tumor re-growth. The patient is kept under constant medical care. In this case study the authors discussed therapeutic management and reviewed literature regarding gestational pituitary-tumor apoplexy with particular emphasis on surgical treatment.",
            "question": "Which pituitary adenoma is common cause of infertility is women?",
            "answers": {
                "answer_start": 87,
                "text": "Prolactinoma"
            }
        },
        {
            "context": "Treatment of chronic myeloid leukemia with imatinib mesylate. Philadelphia (Ph) chromosome is the cytogenetic hallmark of chronic myeloid leukemia (CML). The translocation forms a chimeric gene, bcr-abl, which generates BCR-ABL. This fusion protein constitutively activate ABL tyrosine kinase and causes CML. Imatinib mesylate is a selective tyrosine kinase inhibitor on ABL, c-Kit and PGDF-receptor, and functions through competitive inhibition at the ATP-binding site of the enzyme, which leads to growth arrest or apoptosis in cells that express BCR-ABL. Imatinib has revolutionized the management of patients with CML, and at a dose of 400 mg daily has become the current standard therapy for newly diagnosed patients with CML even when they have HLA-matched family donors. Although imatinib therapy has only a 5-year history, it is hoped that CML will be cured with this drug and with forthcoming second-generation tyrosine kinase inhibitors as well as by allogeneic stem cell transplantation in patients who have become resistant to these drugs.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 195,
                "text": "bcr-abl"
            }
        },
        {
            "context": "Nonhematological benefits of iron. Iron deficiency anemia is common in people with chronic kidney disease (CKD) and its importance in supporting erythropoiesis is unquestioned especially in those patients treated with erythropoietin. Clinical symptomatology such as fatigability, cold intolerance, failure to concentrate and poor effort intolerance is often attributed to anemia or uremia. That iron deficiency, per se, can cause these symptoms is poorly recognized. Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 524,
                "text": "iron"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 997,
                "text": "xa"
            }
        },
        {
            "context": "Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies. PURPOSE: Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies. METHODS: In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed. RESULTS: A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed. CONCLUSIONS: This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 166,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Association of restless legs syndrome variants in Korean patients with restless legs syndrome. STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS. DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci. MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters. CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 255,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 305,
                "text": "CD38"
            }
        },
        {
            "context": "SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 415,
                "text": "NCX"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 14,
                "text": "ZEB2"
            }
        },
        {
            "context": "Regulation of NOXO1 activity through reversible interactions with p22 and NOXA1. Reactive oxygen species (ROS) have been known for a long time to play important roles in host defense against microbial infections. In addition, it has become apparent that they also perform regulatory roles in signal transduction and cell proliferation. The source of these chemicals are members of the NOX family of NADPH oxidases that are found in a variety of tissues. NOX1, an NADPH oxidase homologue that is most abundantly expressed in colon epithelial cells, requires the regulatory subunits NOXO1 (NOX organizing protein 1) and NOXA1 (NOX activating protein 1), as well as the flavocytochrome component p22(phox) for maximal activity. Unlike NOX2, the phagocytic NADPH oxidase whose activity is tightly repressed in the resting state, NOX1 produces superoxide constitutively at low levels. These levels can be further increased in a stimulus-dependent manner, yet the molecular details regulating this activity are not fully understood. Here we present the first quantitative characterization of the interactions made between the cytosolic regulators NOXO1 and NOXA1 and membrane-bound p22(phox). Using isothermal titration calorimetry we show that the isolated tandem SH3 domains of NOXO1 bind to p22(phox) with high affinity, most likely adopting a superSH3 domain conformation. In contrast, complex formation is severely inhibited in the presence of the C-terminal tail of NOXO1, suggesting that this region competes for binding to p22(phox) and thereby contributes to the regulation of superoxide production. Furthermore, we provide data indicating that the molecular details of the interaction between NOXO1 and NOXA1 is significantly different from that between the homologous proteins of the phagocytic oxidase, suggesting that there are important functional differences between the two systems. Taken together, this study provides clear evidence that the assembly of the NOX1 oxidase complex can be regulated through reversible protein-protein interactions.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 454,
                "text": "NOX1"
            }
        },
        {
            "context": "[Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis]. Dermatitis herpetiformis is an autoimmune blistering disease that appears as a cutaneous manifestation of gluten intolerance. It is one of a group of disorders that have gluten sensitivity in common, including celiac disease and gluten ataxia. Patients with dermatitis herpetiformis present with a pruritic papulovesicular rash on extensor surfaces and on the buttocks. Immunological studies demonstrate the presence of specific immunoglobulin (Ig) A anti-endomysial and anti-transglutaminase antibodies. The finding of granular deposits of IgA along the dermal-epidermal junction is pathognomonic of dermatitis herpetiformis. Treatment of dermatitis herpetiformis is based on a life-long, strict gluten-free diet, which improves all clinical aspects of gluten sensitivity, and dapsone, a drug that is only effective for the skin manifestations.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 723,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Partial lumbosacral transitional vertebra resection for contralateral facetogenic pain. STUDY DESIGN: Case report of surgically treated mechanical low back pain from the facet joint contralateral to a unilateral anomalous lumbosacral articulation (Bertolotti's syndrome). OBJECTIVES: To describe the clinical presentation, diagnostic evaluation, and management of facet-related low back pain in a 17-year-old cheerleader and its successful surgical treatment with resection of a contralateral anomalous articulation. SUMMARY OF BACKGROUND DATA: Lumbosacral transitional vertebrae are common in the general population. Bertolotti's syndrome is mechanical low back pain associated with these transitional segments. Little is known about the pathophysiology and mechanics of these vertebral segments and their propensity to be pain generators. Treatment of this syndrome is controversial, and surgical intervention has been infrequently reported. METHOD: A retrospective chart analysis and radiographic review were performed. RESULTS: Repeated fluoroscopically guided injections implicated a symptomatic L6-S1 facet joint contralateral to an anomalous lumbosacral articulation. Eventually, a successful surgical outcome was achieved with resection of the anomalous articulation. CONCLUSION: Clinicians should consider the possibility that mechanical low back pain may occur from a facet contralateral to a unilateral anomalous lumbosacral articulation, even in a young patient. Although reports of surgical treatment of Bertolotti's syndrome are infrequent, resection of the anomalous articulation provided excellent results in this patient, presumably because of reduced stresses on the symptomatic facet.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 1149,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 733,
                "text": "Xa"
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: the last 100 years. Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 737,
                "text": "tyr"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 363,
                "text": "stroke"
            }
        },
        {
            "context": "Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 251,
                "text": "malaria"
            }
        },
        {
            "context": "Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. BACKGROUND: Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS: In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS: The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 407,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Thyroid hormone transporters and resistance. Cellular entry is an important step preceding intracellular metabolism and action of thyroid hormone (TH). Transport of TH across the plasma membrane does not take place by simple diffusion but requires transporter proteins. One of the most effective and specific TH transporters identified to date is monocarboxylate transporter 8 (MCT8), the gene of which is located on the X chromosome. Although MCT8 is expressed in many tissues, its function appears to be most critical in the brain. Hemizygous MCT8 mutations in males cause severe psychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS), and abnormal serum TH levels. AHDS thus represents a type of TH resistance caused by a defect in cellular TH transport.",
            "question": "Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome?",
            "answers": {
                "answer_start": 545,
                "text": "MCT8"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 395,
                "text": "CD38"
            }
        },
        {
            "context": "First detection of Nosema ceranae, a microsporidian parasite of European honey bees (Apis mellifera), in Canada and central USA. Nosema ceranae is an emerging microsporidian parasite of European honey bees, Apis mellifera, but its distribution is not well known. Six Nosema-positive samples (determined from light microscopy of spores) of adult worker bees from Canada (two each from Nova Scotia, New Brunswick, and Prince Edward Island) and two from USA (Minnesota) were tested to determine Nosema species using previously-developed PCR primers of the 16S rRNA gene. We detected for the first time N. ceranae in Canada and central USA. One haplotype of N. ceranae was identified; its virulence may differ from that of other haplotypes.",
            "question": "What is the genus for the common European honey bee?",
            "answers": {
                "answer_start": 207,
                "text": "Apis"
            }
        },
        {
            "context": "Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. New treatment options are urgently needed for patients with relapsed chronic lymphocytic leukemia (CLL) who fail to respond to currently available therapies or cannot achieve a sustained response. Moreover, targeted agents with less myelotoxicity are necessary to treat patients with multiple comorbidities who would otherwise be unable to tolerate standard regimens. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown highly encouraging results in phase I/II trials in patients with treatment-naive, relapsed and refractory CLL even in the presence of high risk disease or poor prognostic markers. In phase I/II trials, ibrutinib 420 mg or 840 mg - given continuously as single agent or at a dose of 420 mg daily in combination with a monoclonal antibody or chemoimmunotherapy - has been associated with high response rates and durable clinical remissions. Phase II and III trials are currently under way for treatment-naive patients, relapsed/refractory patients, and for those patients harboring a 17p deletion.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 496,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 297,
                "text": "MITF"
            }
        },
        {
            "context": "Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti-tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25- T cells in a dose-dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down-regulation of the transcription factor forkhead box P3, glucocorticoid-induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor kappaB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25- T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft-versus-leukaemia effect but also the graft-versus-host-disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib.",
            "question": "Does dasatinib promote or inhibit T-cell proliferation?",
            "answers": {
                "answer_start": 10,
                "text": "inhibits"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 135,
                "text": "Xa"
            }
        },
        {
            "context": "Extraction of proteins from the large subunit of bovine mitochondrial ribosomes under nondenaturing conditions. The 55 S mammalian mitochondrial ribosome (referred to hereafter as \"mitoribosome\") is protein-rich, containing nearly twice as much protein as the Escherichia coli ribosome. In order to produce soluble mitochondrial proteins and protein-deficient subribosomal particles for use in functional and structural studies, the proteins of bovine mitoribosomes were extracted by washing in a series of buffers containing increasing concentrations of LiCl as the only chaotropic agent. LiCl disruption is used in order to preserve the solubilized proteins in a substantially \"native\" configuration. The extraction mixtures were characterized by sucrose density gradient analysis and the compositions of the stripped protein and residual pellet fractions were determined by two-dimensional polyacrylamide gel electrophoresis. In order to analyze the behavior or individual proteins, the intensity of Coomassie blue stain for each protein was normalized against the intensity of stain for the same protein in a control sample. Buffers with 1, 2, and 4 M LiCl each extract a specific subset of mitoribosomal proteins, while another group of proteins remains in the residual pellet fraction. Although very few proteins are detected in only one condition, most proteins are specifically enriched in one fraction. This LiCl procedure, therefore, produces fractionated groups of mitoribosomal proteins which can be used directly as a source for those proteins in which they are enriched, or they can be used as a starting point in further purification procedures. In contrast to results with E. coli ribosomes, several mitoribosomal proteins remain core-associated, indicating a different structural organization in these ribosomes.",
            "question": "What is the sedimentation coefficient of the mammalian mitoribosome?",
            "answers": {
                "answer_start": 116,
                "text": "55 S"
            }
        },
        {
            "context": "Applying the Milwaukee protocol to treat canine rabies in Equatorial Guinea. In this first report of rabies in Equatorial Guinea, problems accompanying the application of the Milwaukee Protocol are described. With its apparent success, and despite a subsequent death from complications of malnutrition, we sound a note of optimism that canine as well as bat rabies may be treatable.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 101,
                "text": "rabies"
            }
        },
        {
            "context": "p73 plays a role in erythroid differentiation through GATA1 induction. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. Although TAp73alpha and -beta proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, DeltaNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or DeltaN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73alpha. Furthermore, TAp73alpha induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and DeltaNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 123,
                "text": "7"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "Tyr"
            }
        },
        {
            "context": "Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. PDS5B is a sister chromatid cohesion protein that is crucial for faithful segregation of duplicated chromosomes in lower organisms. Mutations in cohesion proteins are associated with the developmental disorder Cornelia de Lange syndrome (CdLS) in humans. To delineate the physiological roles of PDS5B in mammals, we generated mice lacking PDS5B (APRIN). Pds5B-deficient mice died shortly after birth. They exhibited multiple congenital anomalies, including heart defects, cleft palate, fusion of the ribs, short limbs, distal colon aganglionosis, abnormal migration and axonal projections of sympathetic neurons, and germ cell depletion, many of which are similar to abnormalities found in humans with CdLS. Unexpectedly, we found no cohesion defects in Pds5B(-/-) cells and detected high PDS5B expression in post-mitotic neurons in the brain. These results, along with the developmental anomalies of Pds5B(-/-) mice, the presence of a DNA-binding domain in PDS5B in vertebrates and its nucleolar localization, suggest that PDS5B and the cohesin complex have important functions beyond their role in chromosomal dynamics.",
            "question": "Which syndrome is caused by deletion of Pds5b in mice?",
            "answers": {
                "answer_start": 104,
                "text": "Cornelia de Lange syndrome."
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: the last 100 years. Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 737,
                "text": "tyr"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 35,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Nucleolin binds to a subset of selenoprotein mRNAs and regulates their expression. Selenium, an essential trace element, is incorporated into selenoproteins as selenocysteine (Sec), the 21st amino acid. In order to synthesize selenoproteins, a translational reprogramming event must occur since Sec is encoded by the UGA stop codon. In mammals, the recoding of UGA as Sec depends on the selenocysteine insertion sequence (SECIS) element, a stem-loop structure in the 3' untranslated region of the transcript. The SECIS acts as a platform for RNA-binding proteins, which mediate or regulate the recoding mechanism. Using UV crosslinking, we identified a 110 kDa protein, which binds with high affinity to SECIS elements from a subset of selenoprotein mRNAs. The crosslinking activity was purified by RNA affinity chromatography and identified as nucleolin by mass spectrometry analysis. In vitro binding assays showed that purified nucleolin discriminates among SECIS elements in the absence of other factors. Based on siRNA experiments, nucleolin is required for the optimal expression of certain selenoproteins. There was a good correlation between the affinity of nucleolin for a SECIS and its effect on selenoprotein expression. As selenoprotein transcript levels and localization did not change in siRNA-treated cells, our results suggest that nucleolin selectively enhances the expression of a subset of selenoproteins at the translational level.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 422,
                "text": "SECIS"
            }
        },
        {
            "context": "Benzodiazepine intoxication treated with flumazenil (Anexate, RO 15-1788). The efficacy and safety of flumazenil were assessed in comparison to placebo in a double-blind randomised study of 31 adults intoxicated with benzodiazepines. The criteria of efficacy were the degree of sedation, and orientation in time and space. Patients who received flumazenil awoke within minutes but central depression returned partly one hour later, which reflects the short elimination half-life of the drug. Side effects were few and the results indicate that flumazenil is effective in the primary management of benzodiazepine overdose and in states where benzodiazepines have been taken with other drugs.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 345,
                "text": "flumazenil"
            }
        },
        {
            "context": "Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. Robinow syndrome (RS) is a phenotypically and genetically heterogeneous condition that can be caused by mutations in genes encoding components of the non-canonical Wnt signaling pathway. In contrast, germline mutations that act to increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes. Here, we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals. The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic sequence. We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation. In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic phenotype, revealed that the mutant allele was less active than the wild-type allele in the canonical Wnt signaling pathway. However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone. This work establishes that DVL1 mutations cause a specific RS subtype, RS-OS, and that the osteosclerosis associated with this subtype might be the result of an interaction between the wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling.",
            "question": "Which syndrome is associated with mutant DVL1?",
            "answers": {
                "answer_start": 50,
                "text": "Robinow syndrome"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 499,
                "text": "CD38"
            }
        },
        {
            "context": "Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism. BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. This response requires the presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To better understand the genetic basis of this response, we utilized a controlled in vitro system and Next Generation sequencing to determine and compare RNA expression profiles of the parental strain and an isogenic AtxA-deficient strain in a 2 × 2 factorial design with growth environments containing or lacking carbon dioxide. RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were strongly regulated by the separate or synergistic actions of AtxA and carbon dioxide. The majority of the regulated genes responded to both AtxA and carbon dioxide rather than to just one of these factors. Interestingly, we identified two previously unrecognized small RNAs that are highly expressed under physiological carbon dioxide concentrations in an AtxA-dependent manner. Expression levels of the two small RNAs were found to be higher than that of any other gene differentially expressed in response to these conditions. Secondary structure and small RNA-mRNA binding predictions for the two small RNAs suggest that they may perform important functions in regulating B. anthracis virulence. CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are regulated by the presence of either CO2 or AtxA separately are also regulated synergistically in the presence of both. These results also elucidate novel pXO1-encoded small RNAs that are associated with virulence conditions.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 75,
                "text": "CO2"
            }
        },
        {
            "context": "Possible site of action of CGRP antagonists in migraine. BACKGROUND: The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagonists behind the blood-brain barrier (BBB), i.e. in the central nervous system (CNS). METHODS: Comparison of doses needed for CGRP blocking effect in vitro with dose needed in vivo in man and monkeys. Discussion of these doses in relation to doses needed for anti-migraine activity. RESULTS: In vivo studies in monkeys and man showed that high doses compared to doses needed in vitro are needed to block capsaicin-induced in skin blood flow, a CGRP-mediated reaction. These doses are close to those needed for anti-migraine activity. CONCLUSION: The apparently high doses of CGRP receptor antagonists, olcegepant and telcagepant needed for anti-migraine effect are not so high after all. They do not allow a conclusion as to whether CGRP antagonists act on peripheral sites or central sites in migraine.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 73,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1β-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 279,
                "text": "IL-1β"
            }
        },
        {
            "context": "Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome. BACKGROUND: Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. METHODS: Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3±4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. RESULTS: The mean preoperative Cobb angle was 102.8±16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49±16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. CONCLUSIONS: Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. LEVEL OF EVIDENCE: Level IV.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 147,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 529,
                "text": "INCA"
            }
        },
        {
            "context": "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 52,
                "text": "MC1R"
            }
        },
        {
            "context": "Optimizing therapy of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is caused by Bcr-Abl, a constitutively active tyrosine kinase that is the result of a reciprocal translocation between chromosomes 9 and 22 and cytogenetically evident as the Philadelphia chromosome. Imatinib (Glivec, Gleevec), a specific small molecule inhibitor of Bcr-Abl, has become the standard drug therapy for CML, and has dramatically diminished the use of allogeneic stem cell transplantation. Despite unprecedented rates of complete cytogenetic response, residual disease remains detectable in the majority of patients, suggesting that imatinib fails to eradicate leukemic stem cells. In this publication, the current perspectives for CML patients treated with imatinib are reviewed, focusing on the results of both standard and high-dose therapy. Monitoring of time-dependent prognostic factors is reviewed. The reasons imatinib may not be able to eradicate the disease are discussed, and potential strategies to achieve disease elimination are presented. Lastly, resistance to imatinib and the potential of second-generation Abl kinase inhibitors in the setting of clinical resistance are considered.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 346,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Unusual volume reduction of Galassi grade III arachnoid cyst following head trauma. We report the case of a 36-year-old woman with a Sylvian fissure arachnoid cyst, which diminished after head trauma and minor hemorrhage into the cyst. We discuss the relationship between the cyst volume reduction and the head trauma to determine the main mechanism of this self-healing process.",
            "question": "Galassi classification is used for which disorder?",
            "answers": {
                "answer_start": 46,
                "text": "arachnoid cyst"
            }
        },
        {
            "context": "Molecular analysis and genotype-phenotype correlation of Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 665,
                "text": "DBA"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 797,
                "text": "IL-1β"
            }
        },
        {
            "context": "Molecular basis of congenital hypopigmentary disorders in humans: a review. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 1734,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease. Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent.",
            "question": "What is the administration route of IVIG in Alzheimer's disease patients?",
            "answers": {
                "answer_start": 139,
                "text": "Intravenous"
            }
        },
        {
            "context": "Regulation of neuronal differentiation by proteins associated with nuclear bodies. Nuclear bodies are large sub-nuclear structures composed of RNA and protein molecules. The Survival of Motor Neuron (SMN) protein localizes to Cajal bodies (CBs) and nuclear gems. Diminished cellular concentration of SMN is associated with the neurodegenerative disease Spinal Muscular Atrophy (SMA). How nuclear body architecture and its structural components influence neuronal differentiation remains elusive. In this study, we analyzed the effects of SMN and two of its interaction partners in cellular models of neuronal differentiation. The nuclear 23 kDa isoform of Fibroblast Growth Factor - 2 (FGF-2(23)) is one of these interacting proteins - and was previously observed to influence nuclear bodies by destabilizing nuclear gems and mobilizing SMN from Cajal bodies (CBs). Here we demonstrate that FGF-2(23) blocks SMN-promoted neurite outgrowth, and also show that SMN disrupts FGF-2(23)-dependent transcription. Our results indicate that FGF-2(23) and SMN form an inactive complex that interferes with neuronal differentiation by mutually antagonizing nuclear functions. Coilin is another nuclear SMN binding partner and a marker protein for Cajal bodies (CBs). In addition, coilin is essential for CB function in maturation of small nuclear ribonucleoprotein particles (snRNPs). The role of coilin outside of Cajal bodies and its putative impacts in tissue differentiation are poorly defined. The present study shows that protein levels of nucleoplasmic coilin outside of CBs decrease during neuronal differentiation. Overexpression of coilin has an inhibitory effect on neurite outgrowth. Furthermore, we find that nucleoplasmic coilin inhibits neurite outgrowth independent of SMN binding revealing a new function for coilin in neuronal differentiation.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1166,
                "text": "Coilin"
            }
        },
        {
            "context": "Molecular analysis of Gaucher disease: distribution of eight mutations and the complete gene deletion in 27 patients from Germany. Gaucher disease is the most common lysosomal storage disease with a high prevalence in the Ashkenazi Jewish population but it is also present in other populations. The presence of eight mutations (1226G, 1448C, IVS2+1. 84GG, 1504T, 1604T, 1342C and 1297T) and the complete deletion of the beta-glucocerebrosidase gene was investigated in 25 unrelated non-Jewish patients with Gaucher's disease in Germany. In the Jewish population, three of these mutations account for more than 90% of all mutated alleles. In addition, relatives of two patients were included in our study. Restriction fragment length polymorphism analysis and sequencing of PCR products obtained from DNA of peripheral blood leukocytes was performed for mutation analysis. Gene deletion was detected by comparison of radioactively labelled PCR fragments of both the functional beta-glucocerebrosidase gene and the pseudogene. Among the unrelated patients, 50 alleles were investigated and the mutations identified in 35 alleles (70%), whereas 15 alleles (30%) remained unidentified. The most prevalent mutation in our group of patients was the 1226G (370Asn-->Ser) mutation, accounting for 18 alleles (36%), followed by the 1448C (444Lcu-->Pro) mutation, that was found in 12 alleles (24%). A complete gene deletion was present in two alleles (4%). The IVS1+2 (splicing mutation), the 1504T (463Arg-->Cys) as well as the 1342C (409Asp-->His) mutations were each present in one allele (2%). None of the alleles carried the 84GG (frame-shift), 1604A (496Arg-->His) or the 1297T (394Val-->Leu) mutation. This distribution is different from the Ashkenazi Jewish population but is similar to other Caucasian groups like the Spanish and Portuguese populations. Our results confirm the variability of mutation patterns in Gaucher patients of different ethnic origin. All patients were divided into nine groups according to their genotype and their clinical status was related to the individual genotype. Genotype/phenotype characteristics of the 1226G, 1448C, and 1342C mutations of previous studies were confirmed by our results.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 425,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, DeltaNp73, is upregulated in breast and gynecological cancers. We further showed that DeltaNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of DeltaNp73, this can only be directly shown in primary cells. We report here that DeltaNp73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. DeltaNp73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, DeltaNp73 rescues Ras-induced senescence. Moreover, DeltaNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of DeltaNp73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of DeltaNp73. Taken together, DeltaNp73 behaves as an oncogene that targets p53 that might explain why DeltaNp73 upregulation may be selected for during tumorigenesis of human cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 472,
                "text": "7"
            }
        },
        {
            "context": "Use of dialectical behavior therapy in borderline personality disorder: a view from residency. OBJECTIVE: The authors describe the use of dialectical behavior therapy (DBT) in treating borderline personality disorder during psychiatry residency, and assess the status of DBT education within psychiatry residencies in the United States. METHOD: The authors present a patient with borderline personality disorder treated by a resident using DBT, along with perspectives from the resident's supervisors. Additionally, self-report surveys inquiring about the attitudes and experiences of residency directors and PGY-4 residents regarding DBT were sent to program directors with available e-mail addresses on FREIDA online. RESULTS: The DBT method employed by the resident had to be modified to fit the constraints of a residency program. The patient in therapy had a tumultuous course, ultimately resulting in the discontinuation of treatment. Survey results suggested an underemphasis on the education and use of DBT during residency, though the strength of this conclusion is limited by the small proportion of surveys returned. CONCLUSIONS: Achieving the efficacy of DBT-based treatment of borderline personality disorder reported in the literature in the setting of a residency program is challenging. Greater exposure to DBT during residency may increase residents' skills in using the technique and the likelihood that they will use it after residency.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 39,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 394,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1283,
                "text": "xa"
            }
        },
        {
            "context": "Allan-Herndon-Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels. Allan-Herndon-Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels. Mutation was also detected, although in the heterozygous state, in three females showing thyroid hormone levels in the normal range. Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 1470,
                "text": "thyroid"
            }
        },
        {
            "context": "A single heterozygous nucleotide substitution displays two different altered mechanisms in the FBN1 gene of five Italian Marfan patients. The Fibrillin-1 gene (FBN1; chromosome 15q21.1) encodes a major glycoprotein component of the extracellular matrix. Mutations in FBN1, TGFBR1, TGFBR2 are known to cause Marfan syndrome (MIM 154700), a pleiotropic disorder. In the present study, we describe five novel missense FBN1 mutations in five Marfan patients that have the peculiarity to activate two contemporary mutational mechanisms: a missense mutation and exon skipping.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 267,
                "text": "FBN1"
            }
        },
        {
            "context": "The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene. Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 676,
                "text": "7"
            }
        },
        {
            "context": "Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome. Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32_-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 6,
                "text": "FBN1"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 461,
                "text": "xa"
            }
        },
        {
            "context": "The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes. Nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase (JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured astrocytes. In view of the previous observation that NO stimulates the activity of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 582,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 222,
                "text": "MRSA"
            }
        },
        {
            "context": "Antigenotoxic effects of p53 on spontaneous and ultraviolet light B--induced deletions in the epidermis of gpt delta transgenic mice. Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as \"the guardian of the genome.\" To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(+/+) mice. However, no increase of such large deletions was observed in irradiated p53(-/-) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 250,
                "text": "p53"
            }
        },
        {
            "context": "Imatinib mesylate for the treatment of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion--the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene is formed on the 22q- derivative (traditionally known as the Philadelphia chromosome) and the deregulated tyrosine kinase activity of the protein encoded by this gene has been shown to be both necessary and sufficient for initiation and maintenance of the disease. Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl, entered clinical evaluation in 1998. Its efficacy surpassed almost everyone's predictions, and the observation of high response rates and favorable toxicity profile associated with imatinib therapy led to its approval as first-line treatment for all newly diagnosed CML patients over an exceptionally short period of time. The 6-year results of the Phase III trial have recently been reported and confirm durability of responses and declining incidence of adverse events over time, although, at present, occurrence of unexpected side effects in the long term cannot be excluded. Although imatinib does not 'cure' CML and has to be administered chronically to patients, it has revolutionized both outcome and quality of life of CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 325,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 581,
                "text": "xa"
            }
        },
        {
            "context": "An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 982,
                "text": "H3K4"
            }
        },
        {
            "context": "Clinical Inquiry: What's the best test for underlying osteomyelitis in patients with diabetic foot ulcers? Magnetic resonance imaging (MRI) has a higher sensitivity and specificity (90% and 79%) than plain radiography (54% and 68%) for diagnosing diabetic foot osteomyelitis. MRI performs somewhat better than any of several common tests--probe to bone (PTB), erythrocyte sedimentation rate (ESR) >70 mm/hr, C-reactive protein (CRP) >14 mg/L, procalcitonin >0.3 ng/mL, and ulcer size >2 cm²--although PTB has the highest specificity of any test and is commonly used together with MRI. No studies have directly compared MRI with a combination of these tests, which may assist in diagnosis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 247,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "A highly sensitive genetic protocol to detect NF1 mutations. Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene. Detecting mutation in NF1 is hindered by the gene's large size, the lack of mutation hotspots, the presence of pseudogenes, and the wide variety of possible lesions. We developed a method for detecting germline mutations by combining an original RNA-based cDNA-PCR mutation detection method and denaturing high-performance liquid chromatography (DHPLC) with multiplex ligation-dependent probe amplification (MLPA). The protocol was validated in a cohort of 56 blood samples from NF1 patients who fulfilled NIH diagnostic criteria, identifying the germline mutation in 53 cases (95% sensitivity). The efficiency and reliability of this approach facilitated detection of different types of mutations, including single-base substitutions, deletions or insertions of one to several nucleotides, microdeletions, and changes in intragenic copy number. Because mutational screening for minor lesions was performed using cDNA and the characterization of mutated alleles was performed at both the RNA and genomic DNA level, the analysis provided insight into the nature of the different mutations and their effect on NF1 mRNA splicing. After validation, we implemented the protocol as a routine test. Here we present the overall unbiased spectrum of NF1 mutations identified in 93 patients in a cohort of 105. The results indicate that this protocol is a powerful new tool for the molecular diagnosis of NF1.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 144,
                "text": "NF1"
            }
        },
        {
            "context": "Yeast DNA topoisomerase II is encoded by a single-copy, essential gene. The gene TOP2 encoding yeast topoisomerase II has been cloned by immunological screening of a yeast genomic library constructed in the phage lambda expression vector, lambda gt11. The ends of the message encoded by the cloned DNA fragment were delimited by the Berk and Sharp procedure (S1 nuclease mapping) for the 5' end and mapping of the polyA tail portion of a cDNA fragment for the 3' end. The predicted size of the message agrees with the length of the message as determined by Northern blot hybridization analysis. The identity of the gene was confirmed by expressing the gene in E. coli from the E. coli promoter lac UV5 to give catalytically active yeast DNA topoisomerase II. Disruption of one copy of the gene in a diploid yeast creates a recessive lethal mutation, indicating that the single DNA topoisomerase II gene of yeast has an essential function.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 10,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1435,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "OCA1 in different ethnic groups of india is primarily due to founder mutations in the tyrosinase gene. Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 371,
                "text": "TYR"
            }
        },
        {
            "context": "Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. PURPOSE OF REVIEW: Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy. RECENT FINDINGS: Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase. SUMMARY: Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1237,
                "text": "xa"
            }
        },
        {
            "context": "In vivo Mn-enhanced MRI for early tumor detection and growth rate analysis in a mouse medulloblastoma model. Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm(3). Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain.",
            "question": "Which is the most common type of pediatric cerebellar tumor?",
            "answers": {
                "answer_start": 178,
                "text": "medulloblastoma"
            }
        },
        {
            "context": "A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS: We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS: Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 128,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. OBJECTIVE: In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). METHODS: The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED. RESULTS: Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions. CONCLUSIONS: These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 221,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila, many messenger RNAs involved in neuro-transmission are re-coded at the RNA level by the RNA-editing enzyme, dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto-regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto-editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviours. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re-coding events in fine-tuning brain function and organismal behaviour.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 313,
                "text": "ADAR"
            }
        },
        {
            "context": "Bacillus anthracis virulence regulator AtxA: oligomeric state, function and CO(2) -signalling. AtxA, a unique regulatory protein of unknown molecular function, positively controls expression of the major virulence genes of Bacillus anthracis. The 475 amino acid sequence of AtxA reveals DNA binding motifs and regions similar to proteins associated with the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS). We used strains producing native and functional epitope-tagged AtxA proteins to examine protein-protein interactions in cell lysates and in solutions of purified protein. Co-affinity purification, non-denaturing polyacrylamide gel electrophoresis and bis(maleimido)hexane (BMH) cross-linking experiments revealed AtxA homo-multimers. Dimers were the most abundant species. BMH cross-links available cysteines within 13 Å. To localize interaction sites, six AtxA mutants containing distinct Cys→Ser substitutions were tested for multimerization and cross-linking. All mutants multimerized, but one mutation, C402S, prevented cross-linking. Thus, BMH uses C402 to make the inter-molecular bond between AtxA proteins, but C402 is not required for protein-protein interaction. C402 is in a region bearing amino acid similarity to Enzyme IIB proteins of the PTS. The AtxA EIIB motif may function in protein oligomerization. Finally, cultures grown with elevated CO(2) /bicarbonate exhibited increased AtxA dimer/monomer ratios and increased AtxA activity, relative to cultures grown without added CO(2) /bicarbonate, suggesting that this host-associated signal enhances AtxA function by shifting the dimer/monomer equilibrium towards the dimeric state.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1524,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Dissecting the regulatory switches of development: lessons from enhancer evolution in Drosophila. Cis-regulatory modules are non-protein-coding regions of DNA essential for the control of gene expression. One class of regulatory modules is embryonic enhancers, which drive gene expression during development as a result of transcription factor protein binding at the enhancer sequences. Recent comparative studies have begun to investigate the evolution of the sequence architecture within enhancers. These analyses are illuminating the way that developmental biologists think about enhancers by revealing their molecular mechanism of function.",
            "question": "Are human enhancers or promoters evolving faster?",
            "answers": {
                "answer_start": 490,
                "text": "enhancers"
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: the last 100 years. Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 737,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 13,
                "text": "Poly(ADP-ribose) Polymerase"
            }
        },
        {
            "context": "The pattern and evolution of looped gene bendability. Gene looping, defined as the physical interaction between the promoter and terminator regions of a RNA polymerase II-transcribed gene, is widespread in yeast and mammalian cells. Gene looping has been shown to play important roles in transcription. Gene-loop formation is dependent on regulatory proteins localized at the 5' and 3' ends of genes, such as TFIIB. However, whether other factors contribute to gene looping remains to be elucidated. Here, we investigated the contribution of intrinsic DNA and chromatin structures to gene looping. We found that Saccharomyces cerevisiae looped genes show high DNA bendability around middle and 3/4 regions in open reading frames (ORFs). This bendability pattern is conserved between yeast species, whereas the position of bendability peak varies substantially among species. Looped genes in human cells also show high DNA bendability. Nucleosome positioning around looped ORF middle regions is unstable. We also present evidence indicating that this unstable nucleosome positioning is involved in gene looping. These results suggest a mechanism by which DNA bendability and unstable nucleosome positioning could assist in the formation of gene loops.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 409,
                "text": "TFIIB"
            }
        },
        {
            "context": "Simpson Grade I-III Resection of Spinal Atypical (World Health Organization Grade II) Meningiomas is Associated With Symptom Resolution and Low Recurrence. BACKGROUND: Because of their rarity, outcomes regarding spinal atypical meningiomas (AMs) remain unclear. OBJECTIVE: To describe the recurrence rate and postoperative outcomes after resection of spinal AMs, and to discuss an appropriate resection strategy and adjuvant therapy for spinal AMs. METHODS: Data from all patients who presented with spinal AMs to 2 tertiary referral centers between 1998 and 2013 were obtained by chart review. RESULTS: From 102 patients with spinal meningioma, 20 AM tumors (7 cervical, 11 thoracic, 2 thoracolumbar) were identified in 18 patients (median age, 50 years [range, 19-75] at time of resection; 11% male; median follow-up, 32 months [range, 1-179] after resection). Before resection, patients had sensory deficits (70%), pain (70%), weakness (60%), ataxia (50%), spasticity (65%), and incontinence (35%). One tumor presented asymptomatically. Simpson grade I, II, III, and IV resection were achieved in 3 (15%), 13 (65%), 2 (10%), and 2 (10%) tumors, respectively. One patient that underwent Simpson grade III resection received adjuvant radiation therapy. After Simpson grade I-III or gross total resection, no tumors recurred (0%; confidence interval, 0%-17.6%). After Simpson grade IV resection, 1 tumor recurred (50%; confidence interval, 1.3%-98.7%). With the exception of 1 patient who had bilateral paraplegia perioperatively, all other patients experienced improvement of preoperative symptoms after surgery (median time, 3.6 months [range, 1-13] after resection). CONCLUSION: Despite published cases suggesting an aggressive clinical course for spinal AMs, this series of spinal AMs reports that gross total resection without adjuvant radiation therapy resulted in symptom resolution and low recurrence.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 86,
                "text": "Meningioma"
            }
        },
        {
            "context": "Imatinib and nilotinib inhibit hematopoietic progenitor cell growth, but do not prevent adhesion, migration and engraftment of human cord blood CD34+ cells. BACKGROUND: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34(+) cells. DESIGN AND METHODS: After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice. RESULTS: TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34(+) cell cycle entry. Adhesion of CD34(+) cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. CONCLUSIONS: These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 313,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "SeqArray-a storage-efficient high-performance data format for WGS variant calls. Motivation: Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Results: Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. Availability and Implementation: http://www.bioconductor.org/packages/SeqArray. Contact: zhengx@u.washington.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm has been proposed for efficient storage of WGS variant calls?",
            "answers": {
                "answer_start": 550,
                "text": "SeqArray"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 73,
                "text": "RADAR"
            }
        },
        {
            "context": "Comparison of the BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay and the BD GeneOhm MRSA achromopeptidase assay with direct- and enriched-culture techniques using clinical specimens for detection of MRSA. We evaluated the new, fully automated molecular BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay for detection of methicillin-resistant S. aureus in a low-prevalence (4.1%) setting. Sensitivity, specificity, and positive and negative predictive values were 93.9%, 99.2%, 83.8%, and 99.7%, respectively. The assay reported fewer unresolved results than the BD GeneOhm MRSA ACP assay.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 70,
                "text": "MRSA"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 511,
                "text": "xa"
            }
        },
        {
            "context": "Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. OBJECTIVE: In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). METHODS: The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED. RESULTS: Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions. CONCLUSIONS: These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 221,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Size matters: versatile use of PiggyBac transposons as a genetic manipulation tool. Transposons have been promising elements for gene integration, and the Sleeping Beauty (SB) system has been the major one for many years, although there have been several other transposon systems available, for example, Tol2. However, recently another system known as PiggyBac (PB) has been introduced and developed for fulfilling the same purposes, for example, mutagenesis, transgenesis and gene therapy and in some cases with improved transposition efficiency and advantages over the Sleeping Beauty transposon system, although improved hyperactive transposase has highly increased the transposition efficacy for SB. The PB systems have been used in many different scientific research fields; therefore, the purpose of this review is to describe some of these versatile uses of the PiggyBac system to give readers an overview on the usage of PiggyBac system.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 352,
                "text": "PiggyBac"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 667,
                "text": "7"
            }
        },
        {
            "context": "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease. BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 695,
                "text": "AD"
            }
        },
        {
            "context": "Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation. Lipin 2 is a phosphatidic acid phosphatase (PAP) responsible for the penultimate step of triglyceride synthesis and dephosphorylation of phosphatidic acid (PA) to generate diacylglycerol. The lipin family of PA phosphatases is composed of lipins 1-3, which are members of the conserved haloacid dehalogenase superfamily. Although genetic alteration of LPIN2 in humans is known to cause Majeed syndrome, little is known about the biochemical regulation of its PAP activity. Here, in an attempt to gain a better general understanding of the biochemical nature of lipin 2, we have performed kinetic and phosphorylation analyses. We provide evidence that lipin 2, like lipin 1, binds PA via the electrostatic hydrogen bond switch mechanism but has a lower rate of catalysis. Like lipin 1, lipin 2 is highly phosphorylated, and we identified 15 phosphosites. However, unlike lipin 1, the phosphorylation of lipin 2 is not induced by insulin signaling nor is it sensitive to inhibition of the mammalian target of rapamycin. Importantly, phosphorylation of lipin 2 does not negatively regulate either membrane binding or PAP activity. This suggests that lipin 2 functions as a constitutively active PA phosphatase in stark contrast to the high degree of phosphorylation-mediated regulation of lipin 1. This knowledge of lipin 2 regulation is important for a deeper understanding of how the lipin family functions with respect to lipid synthesis and, more generally, as an example of how the membrane environment around PA can influence its effector proteins.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 468,
                "text": "LPIN2"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1043,
                "text": "xa"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 403,
                "text": "calcineurin"
            }
        },
        {
            "context": "Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Multiple endocrine neoplasia type 2 (MEN2) is an inherited, autosomal-dominant disorder caused by deleterious mutations within the RET protooncogene. MEN2 RET mutations are mainly heterozygous, missense sequence changes found in RET exons 10, 11, and 13-16. Our group has developed the publicly available, searchable MEN2 RET database to aid in genotype/phenotype correlations, using Human Genome Variation Society recommendations for sequence variation nomenclature and database content. The MEN2 RET database catalogs all RET sequence variation relevant to the MEN2 syndromes, with associated clinical information. Each database entry lists a RET sequence variation's location within the RET gene, genotype, pathogenicity classification, MEN2 phenotype, first literature reference, and comments (which may contain information on other clinical features, complex genotypes, and additional literature references). The MEN2 phenotype definitions were derived from the International RET Mutation Consortium guidelines for classification of MEN2 disease phenotypes. Although nearly all of the 132 RET sequence variation entries initially cataloged in the database were from literature reports, novel sequence variation and updated phenotypic information for any existing database entry can be submitted electronically on the database website. The database website also contains links to selected MEN2 literature reviews, gene and protein information, and RET reference sequences. The MEN2 RET database (www.arup.utah.edu/database/MEN2/MEN2_welcome.php) will serve as a repository for MEN2-associated RET sequence variation and reference for RET genotype/MEN2 phenotype correlations.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 397,
                "text": "RET"
            }
        },
        {
            "context": "Monitoring plasma levels of factor Xa inhibitors: how, why and when? New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed. Several available anti-FXa assays are used for monitoring anticoagulant activity of heparins and fondaparinux. They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). The use of calibrators (lyophilized plasma with a known concentration of drug) allows an expression of the results in ng per ml of plasma. Two categories of assays - endogenous and exogenous assays are available. Endogenous assays are useful in pharmaceutical research, while exogenous assays are used in clinical laboratories. The preferred anti-FXa assay is a specific method in contrast to prothrombin time and activated partial thromboplastin time, but it is not available everywhere at any time. A specific measurement of direct FXa inhibitors is feasible with the use of a new test developed by the authors' group. The physicians must be aware of the possibility to measure the plasma concentration of FXa inhibitors in patients at high risk of bleeding and in several other special clinical situations.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 625,
                "text": "Xa"
            }
        },
        {
            "context": "NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 233,
                "text": "thyroid transcription factor 1"
            }
        },
        {
            "context": "Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 212,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "PPADS, a P2X receptor antagonist, as a novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger in guinea pig airway smooth muscle. The Na(+)/Ca(2+)exchanger (NCX) principal function is taking 1 Ca(2+) out of the cytoplasm and introducing 3 Na(+). The increase of cytoplasmic Na(+) concentration induces the NCX reverse mode (NCX(REV)), favoring Ca(2+) influx. NCX(REV) can be inhibited by: KB-R7943 a non-specific compound that blocks voltage-dependent and store-operated Ca(2+) channels; SEA0400 that appears to be selective for NCX(REV), but difficult to obtain and SN-6, which efficacy has been shown only in cardiomyocytes. We found that PPADS, a P2X receptor antagonist, acts as a NCX(REV) inhibitor in guinea pig tracheal myocytes. In these cells, we characterized the NCX(REV) by substituting NaCl and NaHCO(3) with LiCl, resulting in the increase of the intracellular Ca(2+) concentration ([Ca(2+)]i) using fura 2-AM. We analyzed 5 consecutive responses of the NCX(REV) every 10 min, finding no differences among them. To evaluate the effect of different NCX(REV) blockers, concentration response curves to KB-R7943 (1, 3.2 and 10 μM), and SN-6 (3.2, 10 and 30 μM) were constructed, whereas PPADS effect was characterized as time- and concentration-dependent (1, 3.2, 10 and 30 μM). PPADS had similar potency and efficacy as KB-R7943, whereas SN-6 was the least effective. Furthermore, KCl-induced contraction, sensitive to D600 and nifedipine, was blocked by KB-R7943, but not by PPADS. KCl-induced [Ca(2+)]i increment in myocytes was also significantly decreased by KBR-7943 (10 μM). Our results demonstrate that PPADS can be used as a reliable pharmacological tool to inhibit NCX(REV), with the advantage that it is more specific than KB-R7943 because it does not affect L-type Ca(2+) channels.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 164,
                "text": "NCX"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1140,
                "text": "XK"
            }
        },
        {
            "context": "Mammalian selenoprotein in which selenocysteine (Sec) incorporation is supported by a new form of Sec insertion sequence element. Selenocysteine (Sec), the 21st amino acid in protein, is encoded by UGA. The Sec insertion sequence (SECIS) element, which is the stem-loop structure present in 3' untranslated regions (UTRs) of eukaryotic selenoprotein-encoding genes, is essential for recognition of UGA as a codon for Sec rather than as a stop signal. We now report the identification of a new eukaryotic selenoprotein, designated selenoprotein M (SelM). The 3-kb human SelM-encoding gene has five exons and is located on chromosome 22 but has not been correctly identified by either Celera or the public Human Genome Project. We characterized human and mouse SelM cDNA sequences and expressed the selenoprotein in various mammalian cell lines. The 3\" UTR of the human, mouse, and rat SelM-encoding genes lacks a canonical SECIS element. Instead, Sec is incorporated in response to a conserved mRNA structure, in which cytidines are present in place of the adenosines previously considered invariant. Substitution of adenosines for cytidines did not alter Sec incorporation; however, other mutant structures did not support selenoprotein synthesis, demonstrating that this new form of SECIS element is functional. SelM is expressed in a variety of tissues, with increased levels in the brain. It is localized to the perinuclear structures, and its N-terminal signal peptide is necessary for protein translocation.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 231,
                "text": "SECIS"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 430,
                "text": "Xa"
            }
        },
        {
            "context": "Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region. BACKGROUND: Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). FINDINGS: We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. CONCLUSIONS: Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 1571,
                "text": "FOXP2"
            }
        },
        {
            "context": "SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 552,
                "text": "NCX"
            }
        },
        {
            "context": "Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle? BACKGROUND: The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy. OBJECTIVE: We describe controversies regarding the use of idarucizumab therapy in patients with dabigatran-associated bleeding. DISCUSSION: Although existing clinical studies show a rapid reversal of coagulation assays, these studies did not describe a corresponding improvement in mortality or rapid cessation of hemorrhage. It is questionable how heavily clinicians can rely upon the use of the surrogate endpoints in clinical studies, such as ecarin clotting time and dilute thrombin time. Another issue is whether patients exhibiting re-elevation of coagulation assays would benefit from an additional dose of idarucizumab, because this has not been studied. It is currently unclear if blood products must be given in addition to idarucizumab can be used as monotherapy. CONCLUSIONS: The initial data suggest a definite role for idarucizumab in treatment of bleeding associated with dabigatran. As more clinical practice experience is gained with the agent and the remaining data on its use are released, clinicians can better guide the clinical use of idarucizumab. At present, there is currently not enough evidence for idarucizumab to be used as monotherapy.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1447,
                "text": "dabigatran"
            }
        },
        {
            "context": "Clonal size-variation of rDNA cluster region on chromosome XII of Saccharomyces cerevisiae. Using pulsed-field gel electrophoresis (PFGE), we have demonstrated clonal variation in the size of chromosome XII in a diploid strain of Saccharomyces cerevisiae X2180-2D. The sizes of the two chromosome XII homologues were very different: 2600 (L-type) and 1450 kb (S-type). The frequency with which we detected clonal size variation in the diploid, compared to that of the parental clones, was about 15-50% of the progeny clones and the range of the size variation of the homologues was 2580-2680 kb (L-type) and 1340-1500 kb (S-type), respectively. The homologue of the L-type appeared to be more frequently variable than that of the S-type. The size variation was shown to be derived from size changes in the rDNA cluster region, which is present in chromosome XII, by digesting the chromosome with XhoI, whose cutting site is not present in a rDNA repeat unit, and hybridizing to rDNA probes. The clonal size variation was also investigated in haploids from spores after meiosis. The L-type and S-type chromosomes segregated 2:2 in an ascus and the sizes of all the S-type chromosomes were shifted up, compared to the original diploid, though the L-type ones were stable. The S-type sizes of 1340, 1450 and 1780 kb in the original diploids changed into the ranges of 1475-1610 kb, 1520-1680 kb and 1820-2010 kb, respectively, in the segregants. Furthermore, we observed that the size of S-type chromosomes in haploid cells was gradually increasing in mitosis during successive subcultures.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 286,
                "text": "chromosome XII"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 462,
                "text": "CO2"
            }
        },
        {
            "context": "Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 859,
                "text": "Xa"
            }
        },
        {
            "context": "Restricted motion of the median nerve in carpal tunnel syndrome. Motion of the median nerve was compared on an axial ultrasonographic image in the mid-carpal tunnel in 30 wrists of 15 women with bilateral idiopathic carpal tunnel syndrome and 30 wrists of 15 healthy women. During passive flexion and extension of the index finger, the control wrists had transverse sliding of the nerve beneath the flexor retinaculum (1.75 +/- 0.49 mm), which was regarded as a physiological phenomenon. In contrast, the wrists of patients with carpal tunnel syndrome had significantly less sliding (0.37 +/- 0.34 mm; P = 0.0001), which indicates that physiological motion of the nerve is restricted. This decrease in nerve mobility may be of significance in the pathophysiology of carpal tunnel syndrome.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 25,
                "text": "median"
            }
        },
        {
            "context": "Correlation between the Wells score and the Quanadli index in patients with pulmonary embolism. BACKGROUND AND AIMS: Determining clinical probability of pulmonary embolism (PE) with Wells scoring system is the first step towards diagnosis of PE. Definitive diagnosis of PE is confirmed by computed tomography pulmonary angiography (CTPA). METHODS: This was a prospective study on 80 patients referred to the Institute for Pulmonary Diseases of Vojvodina with suspected PE between April 2010 and August 2012. Clinical probability of PE was determined according to the Wells and modified Wells scoring system. CTPA was performed in 60 patients. The degree of pulmonary vascular obstruction was quantified by the Qanadli index. RESULTS: Low clinical probability of PE was present in one patient (1.6%), moderate in 43 (71.6%) and high in 16 (26.6%) patients. PE was confirmed in 50 (83.3%) patients. There were 21 patients (42%) whose Quanadli index was <25%, 18 (36%) between 25%-50%, while Quanadli index was > 50 in 11 patients (22%). When compared to CTPA findings, modified Wells scoring system showed 90% sensitivity [95% confidence interval (CI) 78.2%-96.6%], and 20% specificity (95% CI 3.11%-55.6%), positive predictive value (PPV) 84.9% (95% CI 72.4%-93.2%) and negative predictive value (NPV) 28.6% (95% CI 4.5%-70.7%). There was weak positive correlation between Wells score and Quanadli index (r = 0.14; P = 0.29), without statistical significance. Wells score was significantly higher in haemodynamically unstable than in haemodynamically stable patients (6.8 vs 5.6, P = 0.014). There was no statistically significant difference between the values of Quanadli index in these two groups (31.33% vs 26.64%, P = 0.062). CONCLUSION: Modified Wells criteria have high sensitivity but low specificity in PE diagnostics. The Wells score does not correlate well with the Quanadli index.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 153,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers. Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 474,
                "text": "chordomas"
            }
        },
        {
            "context": "Mouse Xist expression begins at zygotic genome activation and is timed by a zygotic clock. The imprinted mouse Xist (X-inactive specific transcript) gene is involved in the initiation of X-chromosome inactivation. Only the paternal Xist is expressed in preimplantation development beginning from the 4-cell stage, preceding and in correlation with paternal X-inactivation in the extraembryonic lineage of the blastocyst. To better understand the mechanisms regulating Xist expression in early development, we investigated the precise timing of its onset. We set up a single-cell RT-PCR for the simultaneous analysis on single embryos of Xist and Hprt (internal control) cDNAs and a Y-chromosome specific DNA sequence, Zfy (for embryo sexing). Applying this procedure, we demonstrate that Xist expression begins at the G2-phase of 2-cell female embryos, earlier than previously reported and at the same time of the major wave of zygotic genome activation (ZGA). We then examined, if Xist expression at the 2-cell stage is dependent on the lapse of time spent since fertilization, as previously reported for zygotic genes. One-cell embryos at the G2-phase of the first cell-cycle were cultured with cytochalasin D (inhibitor of cytokinesis but not of DNA synthesis or nuclear progression) for a time equivalent to the 4-cell stage in control, untreated embryos. We show that Xist activation occurs at a scheduled time following fertilization despite the embryos being blocked at the 1-cell stage, suggesting the existence of a zygotic clock involved in the regulation of the transcription of this imprinted gene.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 111,
                "text": "Xist"
            }
        },
        {
            "context": "A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke. INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence. METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance. RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2). CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 395,
                "text": "acute ischemic stroke"
            }
        },
        {
            "context": "Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme. Celldex Therapeutics is developing rindopepimut (CDX-110), a 14-mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme (GBM). Rindopepimut specifically targets a novel junctional epitope of the EGFR deletion mutant EGFRvIII, which is a constitutively active receptor that is expressed in approximately 60 to 70% of patients with GBM. EGFRvIII expression is correlated with worse prognosis and reduced overall survival. Importantly, EGFRvIII is not expressed in normal brain tissue, making it an excellent therapeutic target. Preclinical studies demonstrated lasting tumor regression and increased survival times, as well as efficient generation of EGFRvIII-specific humoral and cellular immune responses, in animals expressing EGFRvIII and vaccinated with rindopepimut. Phase I and II clinical trials in patients with GBM demonstrated significantly increased median time to progression and overall survival time in those vaccinated with rindopepimut compared with matched historical controls. Only limited side effects have been observed in patients. Given these results, rindopepimut is an extremely promising therapy for patients with GBM. Phase I and II clinical trials in patients with GBM were ongoing at the time of publication. In the future, it may be beneficial to combine rindopepimut with other treatment modalities to further prolong survival.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 58,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a new therapeutic strategy for disorders of lipid metabolism.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 355,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Fibrillin-1 gene (FBN1) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium-binding epidermal growth factor-like domains. We found preferential associations between The Cys-missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1-10 and 59-65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 136,
                "text": "FBN1"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 656,
                "text": "SERCA"
            }
        },
        {
            "context": "Mechanism of start site selection by RNA polymerase II: interplay between TFIIB and Ssl2/XPB helicase subunit of TFIIH. TFIIB is essential for transcription initiation by RNA polymerase II. TFIIB also cross-links to terminator regions and is required for gene loops that juxtapose promoter-terminator elements in a transcription-dependent manner. The Saccharomyces cerevisiae sua7-1 mutation encodes an altered form of TFIIB (E62K) that is defective for both start site selection and gene looping. Here we report the isolation of an ssl2 mutant, encoding an altered form of TFIIH, as a suppressor of the cold-sensitive growth defect of the sua7-1 mutation. Ssl2 (Rad25) is orthologous to human XPB and is a member of the SF2 family of ATP-dependent DNA helicases. The ssl2 suppressor allele encodes an arginine replacement of the conserved histidine residue (H508R) located within the DEVH-containing helicase domain. In addition to suppressing the TFIIB E62K growth defect, Ssl2 H508R partially restores both normal start site selection and gene looping. Moreover, Ssl2, like TFIIB, associates with promoter and terminator regions, and the diminished association of TFIIB E62K with the PMA1 terminator is restored by the Ssl2 H508R suppressor. These results define a novel, functional interaction between TFIIB and Ssl2 that affects start site selection and gene looping.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 190,
                "text": "TFIIB"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 250,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 293,
                "text": "NCX"
            }
        },
        {
            "context": "The genomic stability of induced pluripotent stem cells. With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of human patients with defined factors, hold promise for regenerative medicine because they can provide a renewable source of autologous cells for cell therapy without the concern for immune rejection. In addition, iPSCs provide a unique opportunity to model human diseases with complex genetic traits, and a panel of human diseases have been successfully modeled in vitro by patient-specific iPSCs. Despite these progresses, recent studies have raised the concern for genetic and epigenetic abnormalities of iPSCs that could contribute to the immunogenicity of some cells differentiated from iPSCs. The oncogenic potential of iPSCs is further underscored by the findings that the critical tumor suppressor p53, known as the guardian of the genome, suppresses induced pluripotency. Therefore, the clinic application of iPSCs will require the optimization of the reprogramming technology to minimize the genetic and epigenetic abnormalities associated with induced pluripotency.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 946,
                "text": "p53"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist. PURPOSE: The incidence of sudden death appears to be 20 times higher in patients with epilepsy compared with the general population. Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is still underestimated by healthcare professionals and this may reflect the mistaken belief that epilepsy is a benign condition. The risk of death associated with epilepsy appeared rarely to have been discussed with patients or their families. It appears the decision to discuss SUDEP and also to peg SUDEP risk is arbitrary and clinical. Unfortunately there is no structured evidenced mechanism at present to represent person centered risk of SUDEP and there is currently no easy manner or template to have this discussion with the family and the patient. METHODS: We conducted a detailed literature review in Medline, Embase and Psychinfo databases to extract the common risk factors as evidenced from literature till date. Research into risk factors has identified a number of risk factors for SUDEP, some of which are potentially modifiable. RESULTS: Based on the literature review, we believe that the ascertained risk factors could be employed in clinical practice as a checklist to reduce an individual patient's risk of SUDEP. The SUDEP safety checklist may be of practical use in reducing risks in some individuals and is definitely of use in helping communication. CONCLUSIONS: An evidence based checklist identifying the major risk factors can help both clinicians and patients to focus on minimizing certain risk factors and promote safety by focusing on the modifiable factors and guide treatment. It can be a tool to open a person centered discussion with patients and to outline how individual behaviors could impact on risk.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 250,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Coeliac disease presenting as dermatitis herpetiformis in infancy. The incidence of reporting and diagnosis of coeliac disease (CD) in children is increasing with the improvement in sensitivity and specificity of screening markers. This in turn has led to an increasing awareness of gluten-sensitive enteropathy and associated disorders. We report the unusual case of an 8-month-old child presenting to his general practitioner with pruritic skin lesions, subsequently proven to be dermatitis herpetiformis (DH) as the first sign of gluten-sensitive disease. This infant is the youngest child presenting with DH who could be identified from published report dating from 1966 onwards. Dermatitis herpetiformis is the commonest associated pathology of CD, although rare in infancy, it should be considered in any child presenting with failure to thrive and atypical, chronic rash not responding to simple measures.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 482,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 424,
                "text": "XK"
            }
        },
        {
            "context": "EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 674,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 647,
                "text": "L-dopa"
            }
        },
        {
            "context": "SERMs in the prevention and treatment of postmenopausal osteoporosis: an update. Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently under clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 81,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for studying multiple sclerosis (MS). Calpain has been implicated in many inflammatory and neurodegenerative events that lead to disability in EAE and MS. Thus, treating EAE animals with calpain inhibitors may block these events and ameliorate disability. To test this hypothesis, acute EAE Lewis rats were treated dose dependently with the calpain inhibitor calpeptin (50-250 microg/kg). Calpain activity, gliosis, loss of myelin, and axonal damage were attenuated by calpeptin therapy, leading to improved clinical scores. Neuronal and oligodendrocyte death were also decreased, with down-regulation of proapoptotic proteins, suggesting that decreases in cell death were due to decreases in the expression or activity of proapoptotic proteins. These results indicate that calpain inhibition may offer a novel therapeutic avenue for treating EAE and MS.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 104,
                "text": "Experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 115,
                "text": "FSHD"
            }
        },
        {
            "context": "Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 9,
                "text": "EGFR"
            }
        },
        {
            "context": "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in approximately 30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 0,
                "text": "Ribosomal protein genes"
            }
        },
        {
            "context": "Spermidine protects against α-synuclein neurotoxicity. As our society ages, neurodegenerative disorders like Parkinson`s disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human α-synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued α-synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.",
            "question": "What is the association of spermidine with α-synuclein neurotoxicity?",
            "answers": {
                "answer_start": 0,
                "text": "Spermidine protects against α-synuclein neurotoxicity"
            }
        },
        {
            "context": "Characterisation of inflammatory response, coagulation, and radiological findings in Katayama fever: a report of three cases at the Medical University of Vienna, Austria. BACKGROUND: Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp. infection. It is predominantly reported in travellers from non-endemic regions. Whereas the immunological response to Schistosoma infection is well characterised, alterations in inflammatory markers and coagulation in response to acute infection are poorly understood. METHODS: Here we report the clinical, laboratory and radiological characteristics of three returning travellers with Katayama fever. Inflammatory markers and coagulation status were assessed repeatedly during follow-up to characterise the host response to infection. Radiographic findings were correlated with clinical and laboratory markers. RESULTS: Clinical symptoms were suggestive of a significant inflammatory response in all patients including high fever (>39°C), cough, and general malaise. Classical inflammatory markers including blood sedimentation rate, C-reactive protein, and serum amyloid A were only moderately elevated. Marked eosinophilia (33-42% of white blood cells) was observed and persisted despite anti-inflammatory and anthelminthic treatment for up to 32 weeks. Analysis of blood coagulation markers indicated increased coagulability reflected by elevated D-dimer values (0.57-1.17 μg/ml) and high thrombin generating potentials (peak thrombin activity: 311-384 nM). One patient showed particularly high levels of microparticle-associated tissue factor activity at initial presentation (1.64 pg/ml). Multiple pulmonary and hepatic opacities demonstrated by computed tomography (CT) scanning were associated with raised inflammatory markers in one patient. CONCLUSIONS: The characterisation of the inflammatory response, blood coagulation parameters and radiological findings in three patients adds to our current understanding of Katayama fever and serves as a starting point for further systematic investigations of the pathophysiology of this acute helminthic infection.",
            "question": "What causes Katayama Fever?",
            "answers": {
                "answer_start": 311,
                "text": "Schistosoma spp"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1551,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Cell-cycle regulation of cohesin stability along fission yeast chromosomes. Sister chromatid cohesion is mediated by cohesin, but the process of cohesion establishment during S-phase is still enigmatic. In mammalian cells, cohesin binding to chromatin is dynamic in G1, but becomes stabilized during S-phase. Whether the regulation of cohesin stability is integral to the process of cohesion establishment is unknown. Here, we provide evidence that fission yeast cohesin also displays dynamic behavior. Cohesin association with G1 chromosomes requires continued activity of the cohesin loader Mis4/Ssl3, suggesting that repeated loading cycles maintain cohesin binding. Cohesin instability in G1 depends on wpl1, the fission yeast ortholog of mammalian Wapl, suggestive of a conserved mechanism that controls cohesin stability on chromosomes. wpl1 is nonessential, indicating that a change in wpl1-dependent cohesin dynamics is dispensable for cohesion establishment. Instead, we find that cohesin stability increases at the time of S-phase in a reaction that can be uncoupled from DNA replication. Hence, cohesin stabilization might be a pre-requisite for cohesion establishment rather than its consequence.",
            "question": "During which stage of the cell cycle is cohesin deposited on the yeast genome?",
            "answers": {
                "answer_start": 175,
                "text": "S-phase"
            }
        },
        {
            "context": "The potential for crizotinib in non-small cell lung cancer: a perspective review. Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 527,
                "text": "cancer"
            }
        },
        {
            "context": "Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype. Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early-onset CHS with a homozygous missense mutation (c.11362 G>A, p.G3725R) in the LYST/CHS1 gene. This molecular change results in a reduction at the CHS1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T>C, p.C258R, which seemed to have minor effect on the structure of the CHS1/LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 119,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 62,
                "text": "interleukin-5"
            }
        },
        {
            "context": "The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. OBJECTIVE: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. METHODS: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. RESULTS: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. CONCLUSIONS: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 126,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "Simpson grade: an opportunity to reassess the need for complete resection of meningiomas. BACKGROUND: The relevance of the Simpson grading system as a predictor of meningioma progression or recurrence in modern neurosurgical practice has recently been called into question. The aim of our study was to compare the risk of progression/recurrence of tumours that had been treated with different Simpson grade resections in a contemporary population of benign (WHO grade I) meningioma patients. METHOD: One hundred eighty-three patients with histologically confirmed WHO grade I meningioma were retrospectively analysed. All patients underwent first-time craniotomy as their initial therapy between 2004 and 2012. Univariate analysis was performed using log-rank testing and Kaplan-Meier analysis for progression/recurrence-free survival. Multivariate analysis was performed using Cox proportional hazards regression modelling. RESULTS: The three-year progression/recurrence-free survival rates for patients receiving Simpson grade 1, 2 or 4 resections were 95 %, 87 % and 67 %, respectively. Simpson grade 4 resections progressed/recurred at a significantly greater rate than Simpson grade 1 resections (hazard ratio [HR] = 3.26, P = 0.04), whereas Simpson grade 2 resections did not progress/recur at a significantly greater rate than Simpson grade 1 resections (HR = 1.78, P = 0.29). Subtotal resections progressed/recurred at a significantly greater rate than gross-total resections (HR = 2.47, P = 0.03). CONCLUSIONS: Tumours that undergo subtotal resection are at a significantly greater risk of progression/recurrence than tumours that undergo gross-total resection. Gross-total resection should therefore be the aim of surgery. However, given modern access to follow-up imaging and stereotactic radiosurgery, these results should not be used to justify overly 'heroic' tumour resection.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 164,
                "text": "meningioma"
            }
        },
        {
            "context": "Drug-induced lupus in anti-TNF-alpha therapy and its treatment with rituximab. We report three patients with rheumatoid arthritis (RA) who were treated with anti-TNF-α agents and who developed drug-induced lupus (DIL). Two of them received etanercept and the remainder adalimumab. We also present the favorable response observed with the withdrawal of the anti-TNF-alpha agents and the introduction of rituximab. Through this intervention, we observed a very good control of the activity of both DIL and RA without additional adverse reactions.",
            "question": "Which is the most widely used anti-TNF drug?",
            "answers": {
                "answer_start": 240,
                "text": "etanercept"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1352,
                "text": "Xa"
            }
        },
        {
            "context": "Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 12,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast. The histone variant H2A.Z is a universal mark of gene promoters, enhancers, and regulatory elements in eukaryotic chromatin. The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer. Binding of both substrates, the canonical nucleosome and the H2A.Z-H2B dimer, is essential for activation of SWR1. We found that SWR1 primarily recognizes key residues within the α2 helix in the histone-fold of nucleosomal histone H2A, a region not previously known to influence remodeler activity. Moreover, SWR1 interacts preferentially with nucleosomal DNA at superhelix location 2 on the nucleosome face distal to its linker-binding site. Our findings provide new molecular insights on recognition of the canonical nucleosome by a chromatin remodeler and have implications for ATP-driven mechanisms of histone eviction and deposition.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 256,
                "text": "SWR1"
            }
        },
        {
            "context": "Role of the Q-tip test in evaluating stress urinary incontinence. The Q-tip test was applied on 105 patients. Fifty-one had stress urinary incontinency (SUI), 28 had bladder instability by clinical and urodynamic criteria, and 36 had mild or moderate pelvic relaxation without urinary pathology. More than 90% of the patients with SUI and no previous surgery had a positive Q-tip test, with 90% test sensitivity in this group. More than one-third of the patients with bladder instability and almost one-half of the patients with pelvic relaxation and no urinary incontinence had a positive Q-tip test, for low test specificity. The Q-tip test is a simple clinical tool for diagnosing pelvic relaxation, which at times leads to SUI. Almost all patients with primary SUI have pelvic relaxation. The Q-tip test alone does not stand as a diagnostic test. When it is positive, the diagnosis of genuine stress incontinence is possible although not absolute. A negative test should cause one to question the diagnosis of genuine stress incontinence, and sophisticated and more expensive tests should be ordered before establishing a final diagnosis.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 37,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Increased Need for Gastrointestinal Surgery and Increased Risk of Surgery-Related Complications in Patients with Ehlers-Danlos Syndrome: A Systematic Review. BACKGROUND/AIMS: Ehlers-Danlos syndromes (EDSs) constitute a rare group of inherited connective tissue diseases, characterized by multisystemic manifestations and general tissue fragility. Most severe complications include vascular and gastrointestinal (GI) emergencies requiring acute surgery. The purpose of this systematic review was to assess the causes of GI-related surgery and related mortality and morbidity in patients with EDSs. METHODS: A systematic search was conducted in PubMed, Embase, and Scopus to identify relevant studies. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for systematic reviews were followed. According to eligibility criteria, data were extracted and systematically screened by 2 authors. RESULTS: Screening process identified 11 studies with a total of 1,567 patients. Findings indicated that patients with EDSs had a higher occurrence of surgery demanding GI manifestations, including perforation, hemorrhage, rupture of intra-abdominal organs, and rectal prolapse. Most affected was the vascular subtype, of which up to 33% underwent GI surgery and suffered from a lowered average life expectancy of 48 years (range 6-78). Secondary complications of surgery were common in all patients with EDSs. CONCLUSION: Studies suggested that patients with EDSs present an increased need for GI surgery, but also an increased risk of surgery-related complications, most predominantly seen in the vascular subtype.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 243,
                "text": "connective tissue"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 226,
                "text": "7"
            }
        },
        {
            "context": "Transcriptional regulator PRDM12 is essential for human pain perception. Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.",
            "question": "What is the phenotype of people carrying mutations in the gene PRDM12?",
            "answers": {
                "answer_start": 468,
                "text": "CIP"
            }
        },
        {
            "context": "The atxA gene product activates transcription of the anthrax toxin genes and is essential for virulence. Bacillus anthracis plasmid pXO1 carries the structural genes for the three anthrax toxin proteins, cya (edema factor), lef (lethal factor), and pag (protective antigen). Expression of the toxin genes by B. anthracis is enhanced during growth under elevated levels of CO2. This CO2 effect is observed only in the presence of another pXO1 gene, atxA, which encodes a transactivator of anthrax toxin synthesis. Here we show that transcription of atxA does not appear to differ in cells grown in 5% CO2 compared with cells grown in air. Using a new efficient method for gene replacement in B. anthracis, we constructed an atxA-null mutant in which the atxA-coding sequence on pXO1 is replaced with an omega km-2 cassette. Transcription of all three toxin genes is decreased in the absence of atxA. The pag gene possesses two apparent transcription start sites, P1 and P2; only transcripts with 5' ends mapping to P1 are decreased in the atxA-null mutant. Deletion analysis of the pag promoter region indicates that the 111 bp region upstream of the P1 site is sufficient for atxA-mediated activation of this transcript. The cya and lef genes each have one apparent start site for transcription. Transcripts with 5' ends mapping to these sites are not detected in the atxA-null mutant. The atxA-null mutant is avirulent in mice. Moreover, the antibody response to all three toxin proteins is decreased significantly in atxA-null mutant-infected mice. These data suggest that the atxA gene product also regulates toxin gene expression during infection.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 372,
                "text": "CO2"
            }
        },
        {
            "context": "Regulation of hTERT by BCR-ABL at multiple levels in K562 cells. BACKGROUND: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells. METHODS: Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels. RESULTS: Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. CONCLUSIONS: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 204,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Calcineurin signaling has been implicated in a broad spectrum of developmental processes in a variety of organ systems. Calcineurin is a calmodulin-dependent, calcium-activated protein phosphatase composed of catalytic and regulatory subunits. The serine/threonine-specific phosphatase functions within a signal transduction pathway that regulates gene expression and biological responses in many developmentally important cell types. Calcineurin signaling was first defined in T lymphocytes as a regulator of nuclear factor of activated T cells (NFAT) transcription factor nuclear translocation and activation. Recent studies have demonstrated the vital nature of calcium/calcineurin/NFAT signaling in cardiovascular and skeletal muscle development in vertebrates. Inhibition, mutation, or forced expression of calcineurin pathway genes result in defects or alterations in cardiomyocyte maturation, heart valve formation, vascular development, skeletal muscle differentiation and fiber-type switching, and cardiac and skeletal muscle hypertrophy. Conserved calcineurin genes are found in invertebrates such as Drosophila and Caenorhabditis elegans, and genetic studies have demonstrated specific myogenic functions for the phosphatase in their development. The ability to investigate calcineurin signaling pathways in vertebrates and model genetic organisms provides a great potential to more fully comprehend the functions of calcineurin and its interacting genes in heart, blood vessel, and muscle development.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 528,
                "text": "Calcineurin"
            }
        },
        {
            "context": "Tofacitinib: The First Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy and safety, dosage administration, and adverse effects of tofacitinib for rheumatoid arthritis (RA) treatment. DATA SOURCES: Primary sources of information were obtained from clinical studies, which were identified through PubMed (1966 to June 2013) and International Pharmaceutical Abstracts (1970 to March 2013) using terms: tofacitinib, tasocitinib, CP-690550, and CP-690,550. Information was used from tofacitinib package insert, guidelines, and published abstracts from the American College of Rheumatology (ACR) and the European League Against Rheumatism. STUDY SELECTION AND DATA EXTRACTION: Data search was limited to include publications in English language and from human subjects. DATA SYNTHESIS: Tofacitinib is the first oral Janus kinase inhibitor indicated for treatment of moderate to severe RA. Tofacitinib demonstrated efficacy and safety comparable to other disease-modifying antirheumatic drugs (DMARDs). Tofacitinib was efficacious in RA patients, indicated by achievements of ACR20, ACR50, and ACR70 criteria. Similar improvements were observed in patients who met remission criteria based on the Disease Activity Scores 28 criteria and quality of life as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Tofacitinib was associated with infections and malignancies; and elevations in serum creatinine and lipids were observed. Drug interactions with inducers and inhibitors of the cytochrome P-450 3A4 and 2C9 isoenzymes were reported. CONCLUSIONS: Tofacitinib is an oral treatment option for RA patients who have inadequate response or intolerance to methotrexate. Postmarket surveillance will provide further insight to tofacitinib's role in RA therapy, especially in patients who may require different types of combination therapy with DMARDS.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 0,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34). Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.",
            "question": "What is a potential side effect for Tymlos?",
            "answers": {
                "answer_start": 1467,
                "text": "osteosarcoma"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2392,
                "text": "CYP17A1"
            }
        },
        {
            "context": "A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family. Giant axonal neuropathy is a severe autosomal recessive neurodegenerative disorder of childhood that affects both the peripheral and central nervous systems. It is caused by mutations in the GAN gene linked to chromosome 16q24.1 At least 45 distinct disease-causing mutations have been identified throughout the gene in families of various ethnic origins, with different symptomatologies and different clinical courses. To date, no characteristic mutation or phenotype-genotype correlation has been established. We describe a novel missense mutation in four siblings born to consanguineous parents of Arab original with clinical and molecular features compatible with giant axonal neuropathy. The phenotype was characterized by a predominant motor and sensory peripheral neuropathies and severe skeletal deformities.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 24,
                "text": "GAN gene"
            }
        },
        {
            "context": "The Saccharomyces cerevisiae Dna2 can function as a sole nuclease in the processing of Okazaki fragments in DNA replication. During DNA replication, synthesis of the lagging strand occurs in stretches termed Okazaki fragments. Before adjacent fragments are ligated, any flaps resulting from the displacement of the 5' DNA end of the Okazaki fragment must be cleaved. Previously, Dna2 was implicated to function upstream of flap endonuclease 1 (Fen1 or Rad27) in the processing of long flaps bound by the replication protein A (RPA). Here we show that Dna2 efficiently cleaves long DNA flaps exactly at or directly adjacent to the base. A fraction of the flaps cleaved by Dna2 can be immediately ligated. When coupled with DNA replication, the flap processing activity of Dna2 leads to a nearly complete Okazaki fragment maturation at sub-nanomolar Dna2 concentrations. Our results indicate that a subsequent nucleolytic activity of Fen1 is not required in most cases. In contrast Dna2 is completely incapable to cleave short flaps. We show that also Dna2, like Fen1, interacts with proliferating cell nuclear antigen (PCNA). We propose a model where Dna2 alone is responsible for cleaving of RPA-bound long flaps, while Fen1 or exonuclease 1 (Exo1) cleave short flaps. Our results argue that Dna2 can function in a separate, rather than in a Fen1-dependent pathway.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 132,
                "text": "DNA replication"
            }
        },
        {
            "context": "UV-enhanced reactivation of a UV-damaged reporter gene suggests transcription-coupled repair is UV-inducible in human cells. The genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS) exhibit deficiencies in the repair of UV-induced DNA damage. CS fibroblasts retain proficient nucleotide excision repair (NER) of inactive (or bulk) DNA, but are deficient in the transcription-coupled repair (TCR) of active genes. In contrast, XP complementation group C (XP-C) fibroblasts retain proficient TCR, but are deficient in bulk DNA repair. The remaining NER-deficient XP groups exhibit deficiencies in both repair pathways. Ad5HCMVsp1lacZ is a recombinant adenovirus vector that is unable to replicate in human fibroblasts, but can efficiently infect and express the beta-galactosidase reporter gene in these cells. We have examined the host cell reactivation (HCR) of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ in non-irradiated and UV-irradiated normal, XP-B, XP-C, XP-D, XP-F, XP-G, CS-A and CS-B fibroblasts. HCR of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ was reduced in non-irradiated cells from each of the repair-deficient groups examined (including XP-C) relative to that in non-irradiated normal cells. Prior irradiation of cells with low UV fluences resulted in an enhancement of HCR for normal and XP-C strains, but not for the remaining XP and CS strains. HCR of the UV-damaged reporter gene in UV-irradiated XP and CS strains was similar to measurements of TCR reported previously for these cells. These results suggest that UV treatment results in an induced repair of UV-damaged DNA in the transcribed strand of an active gene in XP-C and normal cells through an enhancement of TCR or a mechanism which involves the TCR pathway.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 1652,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 846,
                "text": "Genomiser"
            }
        },
        {
            "context": "Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan anemia. Mutations in the ribosomal protein (RP)S19 gene have been found in about 25% of the cases of Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia that includes variable physical malformations. Various mutations have been identified in the RPS19 gene, but no investigations regarding the effect of these alterations on RPS19 mRNA levels have been performed. It is well established that mutated mRNA containing a premature stop codon (PTC) or lacking a stop codon can be rapidly degraded by specific mechanisms called nonsense mediated decay (NMD) and nonstop decay. To study the involvement of such mechanisms in DBA, we analyzed immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. We found that RPS19 mRNA levels are decreased in the cells with allelic deletion and, to a variable extent, also in all the cell lines with PTC or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA. Our findings indicate that NMD and nonstop decay affect the expression of mutated RPS19 genes; this may help to clarify genotype-phenotype correlations in DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 69,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "Mechanistic insight into the relationship between N-terminal acetylation of α-synuclein and fibril formation rates by NMR and fluorescence. Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body inclusions of patients with Parkinson's disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylation on fibrillation by first establishing a quantitative relationship between monomer secondary structural propensity and fibril assembly kinetics, and secondly by demonstrating in the N-terminal acetylated form of the early onset A53T mutation, that N-terminal transient helices formed and/or inhibited by N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical shifts and fluorescence experiments, we report that secondary structural propensity in residues 5-8, 14-31, and 50-57 are highly correlated to fibril growth rate. A four-way comparison of secondary structure propensity and fibril growth rates of N-terminally acetylated A53T and WT αSyn with non-acetylated A53T and WT αSyn present novel mechanistic insight into the role of N-terminal acetylation in amyloid fibril formation. We show that N-terminal acetylation inhibits the formation of the \"fibrillation promoting\" transient helix at residues 14-31 resulting from the A53T mutation in the non-acetylated variant and supports the formation of the \"fibrillation inhibiting\" transient helix in residues 1-12 thereby resulting in slower fibrillation rates relative to the previously studied non-acetylated A53T variant. Our results highlight the critical interplay of the region-specific transient secondary structure of the N-terminal region with fibrillation, and the inhibitory role of the N-terminal acetyl group in fibril formation.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 155,
                "text": "α-synuclein"
            }
        },
        {
            "context": "New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome. The authors report a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, \"coarse\" face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high (>50 microU/ml; normal value 0.2-4 microU/ml), while serum free T(3) (FT3) and free T(4) (FT4) levels were normal (FT3 3.6 pg/ml, normal value 2.8-5.6 pg/ml; FT4 11.6 pg/ml, normal value 6.6-14 pg/ml); antithyroid autoantibodies were absent. Thyroid scintigraphy with sodium 99m Tc pertechnetate showed a small ectopic thyroid located in sublingual position, so treatment with L-thyroxine 37.5 microg/24 hr was started with rapid improvement of the clinical picture. At 17 months of age the patient developed the complete characteristic phenotype of Williams syndrome (WS); the clinical diagnosis was proven by fluorescent in situ hybridization (FISH) analysis which showed hemizygous deletion of the elastin gene on chromosome 7. Recently a case of thyroid hemiagenesis in a child with WS has been reported; our patient underscores the association of hypothyroidism and WS. Moreover, our case shows that clinical manifestations of hypothyroidism may be present and the treatment may be necessary as it is in isolated congenital hypothyroidism.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1401,
                "text": "thyroid"
            }
        },
        {
            "context": "Localization of DNA methyltransferase-1 during oocyte differentiation, in vitro maturation and early embryonic development in cow. DNA methyltransferase-1 (Dnmt1) is involved in the maintenance of DNA methylation patterns and is crucial for normal mammalian development. The aim of the present study was to assess the localization of Dnmt1 in cow, during the latest phases of oocyte differentiation and during the early stages of segmentation. Dnmt1 expression and localization were assessed in oocytes according to the chromatin configuration, which in turn provides an important epigenetic mechanism for the control of global gene expression and represents a morphological marker of oocyte differentiation. We found that the initial chromatin condensation was accompanied by a slight increase in the level of global DNA methylation, as assessed by 5-methyl-cytosine immunostaining followed by laser scanning confocal microscopy analysis (LSCM). RT-PCR confirmed the presence of Dnmt1 transcripts throughout this phase of oocyte differentiation. Analogously, Dnmt1 immunodetection and LSCM indicated that the protein was always present and localized in the cytoplasm, regardless the chromatin configuration and the level of global DNA methylation. Moreover, our data indicate that while Dnmt1 is retained in the cytoplasm in metaphase II stage oocytes and zygotes, it enters the nuclei of 8-16 cell stage embryos. As suggested in mouse, the functional meaning of the presence of Dnmt1 in the bovine embryo nuclei could be the maintainement of the methylation pattern of imprinted genes. In conclusion, the present work provides useful elements for the study of Dnmt1 function during the late stage of oocyte differentiation, maturation and early embryonic development in mammals.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 156,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study. We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 40,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 464,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "N terminus of Swr1 binds to histone H2AZ and provides a platform for subunit assembly in the chromatin remodeling complex. Variant histone H2AZ-containing nucleosomes are involved in the regulation of gene expression. In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Previous work defined the role of seven SWR1 subunits (Swr1 ATPase, Swc2, Swc3, Arp6, Swc5, Yaf9, and Swc6) in maintaining complex integrity and H2AZ histone replacement activity. Here we examined the function of three additional SWR1 subunits, bromodomain containing Bdf1, actin-related protein Arp4 and Swc7, by analyzing affinity-purified mutant SWR1 complexes. We observed that depletion of Arp4 (arp4-td) substantially impaired the association of Bdf1, Yaf9, and Swc4. In contrast, loss of either Bdf1 or Swc7 had minimal effects on overall complex integrity. Furthermore, the basic H2AZ histone replacement activity of SWR1 in vitro required Arp4, but not Bdf1 or Swc7. Thus, three out of fourteen SWR1 subunits, Bdf1, Swc7, and previously noted Swc3, appear to have roles auxiliary to the basic histone replacement activity. The N-terminal region of the Swr1 ATPase subunit is necessary and sufficient to direct association of Bdf1 and Swc7, as well as Arp4, Act1, Yaf9 and Swc4. This same region contains an additional H2AZ-H2B specific binding site, distinct from the previously identified Swc2 subunit. These findings suggest that one SWR1 enzyme might be capable of binding two H2AZ-H2B dimers, and provide further insight on the hierarchy and interdependency of molecular interactions within the SWR1 complex.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 320,
                "text": "SWR1"
            }
        },
        {
            "context": "A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 1017,
                "text": "LPIN2"
            }
        },
        {
            "context": "A case of color-taste synesthesia. This is a report on a case of color-taste synesthesia exhibited by an artist painter. This case is unique in that it is not common for color to appear as an inducer or taste as a concurrent. A comprehensive description of this particular case of synesthesia is provided first. The application and results of consistency, psychophysical, and Stroop tests are presented later. Finally, the difficulties encountered with the application of such tests are discussed.",
            "question": "Which test is used to diagnose colour synesthesia?",
            "answers": {
                "answer_start": 376,
                "text": "Stroop test"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Netherton syndrome and its multifaceted defective protein LEKTI. Netherton syndrome (NS, OMIM 256500) is a rare autosomal recessive disorder manifesting with congenital ichthyosis, a specific hair shaft abnormality named trichorrhexis invaginata, and atopic manifestations. Because of severe complications frequently occurring in the neonatal period, NS prognosis can be poor in infancy. NS is due to loss-of-function mutations in the SPINK5 gene and to the consequent lack of expression of its encoded protein LEKTI in the skin and all stratified epithelial tissues. Following the identification of the NS causative gene and protein, specific diagnostic tools have been developed, thus breaking up the challenge of distinguishing NS from other congenital ichthyoses with overlapping features, and from severe, early-onset forms of atopic dermatitis or psoriasis. Intensive efforts to extend the knowledge into the pathomechanisms of NS have also been made. However, NS management is still problematic due to the lack of specific treatment and unmet needs. This overview summarizes the current state of the art in NS research with an emphasis on the progress made toward disease-specific innovative therapy development.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 511,
                "text": "LEKTI"
            }
        },
        {
            "context": "A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 208,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Success evaluation of the biological control of Fusarium wilts of cucumber, banana, and tomato since 2000 and future research strategies. The Fusarium wilt caused by Fusarium oxysporum strains is the most devastating disease of cucumber, banana, and tomato. The biological control of this disease has become an attractive alternative to the chemical fungicides and other conventional control methods. In this review, the research trends and biological control efficiencies (BCE) of different microbial strains since 2000 are reviewed in detail, considering types of microbial genera, inoculum application methods, plant growth medium and conditions, inoculum application with amendments, and co-inoculation of different microbial strains and how those affect the BCE of Fusarium wilt. The data evaluation showed that the BCE of biocontrol agents was higher against the Fusarium wilt of cucumber compared to the Fusarium wilts of banana and tomato. Several biocontrol agents mainly Bacillus, Trichoderma, Pseudomonas, nonpathogenic Fusarium, and Penicillium strains were evaluated to control Fusarium wilt, but still this lethal disease could not be controlled completely. We have discussed different reasons of inconsistent results and recommendations for the betterment of BCE in the future. This review provides knowledge of the biotechnology of biological control of Fusarium wilt of cucumber, banana, and tomato in a nut shell that will provide researchers a beginning line to start and to organize and plan research for the future studies.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 250,
                "text": "tomato"
            }
        },
        {
            "context": "Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.",
            "question": "What is the role of eteplirsen in DMD patients?",
            "answers": {
                "answer_start": 325,
                "text": "skipping of dystrophin exon 51"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 0,
                "text": "MethPed"
            }
        },
        {
            "context": "Evaluation of brain apoptosis in a CADASIL postmortem case. OBJECTIVE: To evaluate the role of apoptosis in the pathogenesis of brain lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary microangiopathy leading to cognitive decline and dementia, caused by mutations in the NOTCH3 gene. MATERIALS AND METHODS: Detection of apoptotic nuclei in temporal lobe, brain stem, medulla oblongata, hippocampus and basal ganglia from one young CADASIL patient was performed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL). RESULTS: Our results showed a great involvement of glial cells in apoptotic cell death in the majority of the brain regions examined; neuronal apoptosis was significantly present only in the brain stem region. CONCLUSIONS: We hypothesized that in the early stages of the disease neuronal involvement of apoptosis is limited to the cells of the brain stem, sparing the cortical area which is involved in neuronal apoptosis and cognitive decline later.",
            "question": "Which gene is involved in CADASIL?",
            "answers": {
                "answer_start": 346,
                "text": "NOTCH3 gene"
            }
        },
        {
            "context": "Sequestration of p53 in the cytoplasm by adenovirus type 12 E1B 55-kilodalton oncoprotein is required for inhibition of p53-mediated apoptosis. The adenovirus E1B 55-kDa protein is a potent inhibitor of p53-mediated transactivation and apoptosis. The proposed mechanisms include tethering the E1B repression domain to p53-responsive promoters via direct E1B-p53 interaction. Cytoplasmic sequestration of p53 by the 55-kDa protein would impose additional inhibition on p53-mediated effects. To investigate further the role of cytoplasmic sequestration of p53 in its inhibition by the E1B 55-kDa protein we systematically examined domains in both the Ad12 55-kDa protein and p53 that underpin their colocalization in the cytoplasmic body and show that the N-terminal transactivation domain (TAD) of p53 is essential for retaining p53 in the cytoplasmic body. Deletion of amino acids 11 to 27 or even point mutation L22Q/W23S abolished the localization of p53 to the cytoplasmic body, whereas other parts of TAD and the C-terminal domain of p53 are dispensable. This cytoplasmic body is distinct from aggresome associated with overexpression of some proteins, since it neither altered vimentin intermediate filaments nor associated with centrosome or ubiquitin. Formation of this structure is sensitive to mutation of the Ad12 55-kDa protein. Strikingly, mutation S476/477A near the C terminus of the Ad12 55-kDa protein eliminated the formation of the cytoplasmic body. The equivalent residues in the Ad5 55-kDa protein were shown to be critical for its ability to inhibit p53. Indeed, Ad12 55-kDa mutants that cannot form a cytoplasmic body can no longer inhibit p53-mediated effects. Conversely, the Ad12 55-kDa protein does not suppress p53 mutant L22Q/W23S-mediated apoptosis. Finally, we show that E1B can still sequester p53 that contains the mitochondrial import sequence, thereby potentially preventing the localization of p53 to mitochondria. Thus, cytoplasmic sequestration of p53 by the E1B 55-kDa protein plays an important role in restricting p53 activities.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 765,
                "text": "transactivation domain"
            }
        },
        {
            "context": "Management of animal botulism outbreaks: from clinical suspicion to practical countermeasures to prevent or minimize outbreaks. Botulism is a severe neuroparalytic disease that affects humans, all warm-blooded animals, and some fishes. The disease is caused by exposure to toxins produced by Clostridium botulinum and other botulinum toxin-producing clostridia. Botulism in animals represents a severe environmental and economic concern because of its high mortality rate. Moreover, meat or other products from affected animals entering the food chain may result in a public health problem. To this end, early diagnosis is crucial to define and apply appropriate veterinary public health measures. Clinical diagnosis is based on clinical findings eliminating other causes of neuromuscular disorders and on the absence of internal lesions observed during postmortem examination. Since clinical signs alone are often insufficient to make a definitive diagnosis, laboratory confirmation is required. Botulinum antitoxin administration and supportive therapies are used to treat sick animals. Once the diagnosis has been made, euthanasia is frequently advisable. Vaccine administration is subject to health authorities' permission, and it is restricted to a small number of animal species. Several measures can be adopted to prevent or minimize outbreaks. In this article we outline all phases of management of animal botulism outbreaks occurring in wet wild birds, poultry, cattle, horses, and fur farm animals.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 292,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 501,
                "text": "RET"
            }
        },
        {
            "context": "Transcription domain-associated repair in human cells. Nucleotide excision repair (NER), which is arguably the most versatile DNA repair system, is strongly attenuated in human cells of the monocytic lineage when they differentiate into macrophages. Within active genes, however, both DNA strands continue to be proficiently repaired. The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes. We now report that the previously termed differentiation-associated repair (DAR) depends upon transcription, but not simply upon RNA polymerase II (RNAPII) encountering a lesion: proficient repair of both DNA strands can occur in a part of a gene that the polymerase never reaches, and even if the translocation of RNAPII is blocked with transcription inhibitors. This suggests that DAR may be a subset of global NER, restricted to the subnuclear compartments or chromatin domains within which transcription occurs. Downregulation of selected NER genes with small interfering RNA has confirmed that DAR relies upon the same genes as global genome repair, rather than upon TCR-specific genes. Our findings support the general view that the genomic domains within which transcription is active are more accessible than the bulk of the genome to the recognition and repair of lesions through the global pathway and that TCR is superimposed upon that pathway of NER.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 494,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Possible involvement of SINEs in mammalian-specific brain formation. Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 1525,
                "text": "development"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 2056,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Splicing-dependent RNA polymerase pausing in yeast. In eukaryotic cells, there is evidence for functional coupling between transcription and processing of pre-mRNAs. To better understand this coupling, we performed a high-resolution kinetic analysis of transcription and splicing in budding yeast. This revealed that shortly after induction of transcription, RNA polymerase accumulates transiently around the 3' end of the intron on two reporter genes. This apparent transcriptional pause coincides with splicing factor recruitment and with the first detection of spliced mRNA and is repeated periodically thereafter. Pausing requires productive splicing, as it is lost upon mutation of the intron and restored by suppressing the splicing defect. The carboxy-terminal domain of the paused polymerase large subunit is hyperphosphorylated on serine 5, and phosphorylation of serine 2 is first detected here. Phosphorylated polymerase also accumulates around the 3' splice sites of constitutively expressed, endogenous yeast genes. We propose that transcriptional pausing is imposed by a checkpoint associated with cotranscriptional splicing.",
            "question": "Which is the phosphorylated residue in the promoter paused form of RNA polymerase II?",
            "answers": {
                "answer_start": 840,
                "text": "serine 5"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 938,
                "text": "Xa"
            }
        },
        {
            "context": "[Heterogeneity of GTPase-activating proteins for Ras in the regulation of Ras signal transduction pathway]. The proto-oncogene ras is an essential gene for the growth and the differentiation for various types of cells. Ras, ras gene product, is a GTP binding protein which controls the signal transduction by GTP hydrolysis. The ras gene is frequently activated by point mutations in various types of human cancers, which results in a decrease in the GTPase activity of its product. A GTPase-activating protein p120 (p120GAP) was identified as a factor which stimulates the GTPase of normal ras gene product p21 but not of the mutated. An NF1 gene was identified as a gene whose loss of function causes an onset of human disorder, neurofibromatosis type I. The NF1 gene encodes a protein which contains a region with a similarity to the catalytic domain of p120GAP. We recently purified a novel Ras GAP whose molecular weight and immunogenecity are different from those of p120GAP and NF1. We named the novel mammalian Ras GAP as Gap1m. Isolation and sequencing of Gap1m cDNA revealed that Gap1m is indeed a novel Ras GAP. We also succeeded in isolation of another novel Ras GAP gene, GapIII/Gap1IP4BP, which is closely related to Gap1m. Recently, it is shown that GapIII/Gap1IP4BP binds inositol-tetrakis phosphate compounds. The overview of these Ras GAP molecules is described.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 639,
                "text": "NF1"
            }
        },
        {
            "context": "Okazaki fragment maturation: nucleases take centre stage. Completion of lagging strand DNA synthesis requires processing of up to 50 million Okazaki fragments per cell cycle in mammalian cells. Even in yeast, the Okazaki fragment maturation happens approximately a million times during a single round of DNA replication. Therefore, efficient processing of Okazaki fragments is vital for DNA replication and cell proliferation. During this process, primase-synthesized RNA/DNA primers are removed, and Okazaki fragments are joined into an intact lagging strand DNA. The processing of RNA/DNA primers requires a group of structure-specific nucleases typified by flap endonuclease 1 (FEN1). Here, we summarize the distinct roles of these nucleases in different pathways for removal of RNA/DNA primers. Recent findings reveal that Okazaki fragment maturation is highly coordinated. The dynamic interactions of polymerase δ, FEN1 and DNA ligase I with proliferating cell nuclear antigen allow these enzymes to act sequentially during Okazaki fragment maturation. Such protein-protein interactions may be regulated by post-translational modifications. We also discuss studies using mutant mouse models that suggest two distinct cancer etiological mechanisms arising from defects in different steps of Okazaki fragment maturation. Mutations that affect the efficiency of RNA primer removal may result in accumulation of unligated nicks and DNA double-strand breaks. These DNA strand breaks can cause varying forms of chromosome aberrations, contributing to development of cancer that associates with aneuploidy and gross chromosomal rearrangement. On the other hand, mutations that impair editing out of polymerase α incorporation errors result in cancer displaying a strong mutator phenotype.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 387,
                "text": "DNA replication"
            }
        },
        {
            "context": "TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. RESULTS: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. CONCLUSIONS: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. ©2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 60,
                "text": "Neuroblastoma"
            }
        },
        {
            "context": "Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait. We report a case of fulminant liver failure resulting in emergent liver transplantation following 3 weeks of nausea, vomiting, and malaise from Jamaican Vomiting Sickness. Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks. It is characterized by acute gastrointestinal illness and hypoglycemia. In severe cases, central nervous system depression can occur. In previous studies, histologic sections taken from patients with Jamaican Vomiting Sickness have shown hepatotoxicity similar to that seen in Reye syndrome and/or acetaminophen toxicity. We highlight macroscopic and microscopic changes in the liver secondary to hepatoxicity of Ackee fruit versus those caused by a previously unknown sickle cell trait. We discuss the clinical variables and the synergistic hepatotoxic effect of Ackee fruit and ischemic injury from sickled red blood cells, causing massive hepatic necrosis in this patient.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 348,
                "text": "Ackee fruit"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2853,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy (SUDEP): what do patients think? OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in epilepsy. Despite its devastating consequences, SUDEP appears to be poorly discussed with patients by health professionals. The risk of causing psychological distress to the patient is highlighted as a reason for not discussing SUDEP. However, no studies have assessed the adult patients' views on this important question. We conducted this cross-sectional study to evaluate the awareness and perspectives on SUDEP among adult patients with epilepsy. METHODS: One hundred five consecutive adult patients with epilepsy, referred to the Epilepsy Clinic of a tertiary hospital between October 2012 and November 2013, were surveyed to ascertain their views and understanding of SUDEP. The data were analyzed using logistic regression to explore the association between patients' awareness of SUDEP and characteristics such as age, gender, duration of epilepsy, level of education, and employment. RESULTS: Awareness of SUDEP among adult patients with epilepsy was poor (14.3%). However, the vast majority (89.5%) wished to be informed about SUDEP, and 59% requested detailed information. The treating neurologist was considered to be the most appropriate source of SUDEP information by 85.6% of patients. Multivariable analysis of the data showed no association between characteristics of patients (age, gender, duration of epilepsy, level of education, and employment) and their awareness of SUDEP or desire to get SUDEP-related information. CONCLUSIONS: Our study suggests that the majority of adult patients wish to be informed about SUDEP. This is in contrast to the general reluctance of medical professionals to inform all patients routinely about this condition.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 81,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 561,
                "text": "CD38"
            }
        },
        {
            "context": "Two cases of Sotos syndrome with novel mutations of the NSD1 gene. Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome. Fluorescent in situ hybridization analysis (FISH), MLPA or multiplex quantitative PCR allow detection of total/partial NSD1 deletions and direct sequencing allows detection of NSD1 mutations. We describe two boys with Sotos syndrome in whom PCR amplification and direct sequencing of the NSD1 gene identified two novel mutations not previously described: c.4736dupG in exon 12 and c.3938_3939insT in exon 7. In addition to the cardinal and major features of the syndrome (abnormal facial appearance, overgrowth, cardiac anomalies, renal anomalies, hypotonia, neonatal jaundice, seizures and brain MRI abnormalities) in both patients, one boy also had cryptorchidism and vertebral anomalies, features considered not common. Despite the wide range of possible combinations of phenotypic features, molecular analysis can correctly identify Sotos syndrome.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 98,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1345,
                "text": "factor Xa"
            }
        },
        {
            "context": "Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi. BACKGROUND: Microsporidia is one of the taxa that have experienced the most dramatic taxonomic reclassifications. Once thought to be among the earliest diverging eukaryotes, the fungal nature of this group of intracellular pathogens is now widely accepted. However, the specific position of microsporidia within the fungal tree of life is still debated. Due to the presence of accelerated evolutionary rates, phylogenetic analyses involving microsporidia are prone to methodological artifacts, such as long-branch attraction, especially when taxon sampling is limited. RESULTS: Here we exploit the recent availability of six complete microsporidian genomes to re-assess the long-standing question of their phylogenetic position. We show that microsporidians have a similar low level of conservation of gene neighborhood with other groups of fungi when controlling for the confounding effects of recent segmental duplications. A combined analysis of thousands of gene trees supports a topology in which microsporidia is a sister group to all other sequenced fungi. Moreover, this topology received increased support when less informative trees were discarded. This position of microsporidia was also strongly supported based on the combined analysis of 53 concatenated genes, and was robust to filters controlling for rate heterogeneity, compositional bias, long branch attraction and heterotachy. CONCLUSIONS: Altogether, our data strongly support a scenario in which microsporidia is the earliest-diverging clade of sequenced fungi.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1616,
                "text": "fungi"
            }
        },
        {
            "context": "Schwann cell involvement in the peripheral neuropathy of spinocerebellar ataxia type 3. AIMS: Spinocerebellar ataxia type 3 (SCA3) is an inherited spinocerebellar ataxia caused by the expansion of trinucleotide CAG repeats in the gene encoding ataxin-3. The clinical manifestations of SCA3 include peripheral neuropathy, which is an important cause of disability in a subset of patients. Although the loss of neurones in the dorsal root ganglion (DRG) has been postulated to be the cause of this neuropathy, the precise mechanism remains to be elucidated. METHODS: To clarify the clinicopathological characteristics of SCA3-associated peripheral neuropathy, we performed nerve conduction studies and histopathological analyses. Nerve conduction studies were carried out in 18 SCA3 patients. Immunohistochemical analyses of the anterior and posterior roots of the spinal cord and peripheral nerves were performed in five SCA3 patients. We also employed immunohistochemistry and immunoelectron microscopy analyses with an anti-polyglutamine antibody. RESULTS: The mean sensory nerve action potentials of the SCA3 patients were half of the normal values. The motor conduction velocities were decreased, and the distal latencies were also significantly prolonged in the nerves studied relative to the those in normal controls. Histopathological analyses detected axonal sprouting and myelin thinning in all cases. Ataxin-3 aggregates were found in the cytoplasm of Schwann cells in all of the SCA3 patients examined but not in control subjects. CONCLUSIONS: In addition to the previously reported neuronopathy, the results of the present study indicate that Schwann cells are involved in the formation of the pathogenic intracytoplasmic ataxin-3 protein aggregates in patients with SCA3-associated neuropathy.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 244,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P-bodies. Argonaute proteins are effectors of RNA interference that function in the context of cytoplasmic ribonucleoprotein complexes to regulate gene expression. Processing bodies (PBs) and stress granules (SGs) are the two main types of ribonucleoprotein complexes with which Argonautes are associated. Targeting of Argonautes to these structures seems to be regulated by different factors. In the present study, we show that heat-shock protein (Hsp) 90 activity is required for efficient targeting of hAgo2 to PBs and SGs. Furthermore, pharmacological inhibition of Hsp90 was associated with reduced microRNA- and short interfering RNA-dependent gene silencing. Neither Dicer nor its cofactor TAR RNA binding protein (TRBP) associates with PBs or SGs, but interestingly, protein activator of the double-stranded RNA-activated protein kinase (PACT), another Dicer cofactor, is recruited to SGs. Formation of PBs and recruitment of hAgo2 to SGs were not dependent upon PACT (or TRBP) expression. Together, our data suggest that Hsp90 is a critical modulator of Argonaute function. Moreover, we propose that Ago2 and PACT form a complex that functions at the level of SGs.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 0,
                "text": "Hsp90"
            }
        },
        {
            "context": "CSEQ-SIMULATOR: A DATA SIMULATOR FOR CLIP-SEQ EXPERIMENTS. CLIP-Seq protocols such as PAR-CLIP, HITS-CLIP or iCLIP allow a genome-wide analysis of protein-RNA interactions. For the processing of the resulting short read data, various tools are utilized. Some of these tools were specifically developed for CLIP-Seq data, whereas others were designed for the analysis of RNA-Seq data. To this date, however, it has not been assessed which of the available tools are most appropriate for the analysis of CLIP-Seq data. This is because an experimental gold standard dataset on which methods can be accessed and compared, is still not available. To address this lack of a gold-standard dataset, we here present Cseq-Simulator, a simulator for PAR-CLIP, HITS-CLIP and iCLIP-data. This simulator can be applied to generate realistic datasets that can serve as surrogates for experimental gold standard dataset. In this work, we also show how Cseq-Simulator can be used to perform a comparison of steps of typical CLIP-Seq analysis pipelines, such as the read alignment or the peak calling. These comparisons show which tools are useful in different settings and also allow identifying pitfalls in the data analysis.",
            "question": "Which data simulator is available for CLIP-SEQ experiments?",
            "answers": {
                "answer_start": 936,
                "text": "Cseq-Simulator"
            }
        },
        {
            "context": "SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1393,
                "text": "NCX"
            }
        },
        {
            "context": "White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 257,
                "text": "thyroid"
            }
        },
        {
            "context": "Centromere Destiny in Dicentric Chromosomes: New Insights from the Evolution of Human Chromosome 2 Ancestral Centromeric Region. Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing, and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 863,
                "text": "chromosome 2"
            }
        },
        {
            "context": "The physiological target for LeuRS translational quality control is norvaline. The fidelity of protein synthesis depends on the capacity of aminoacyl-tRNA synthetases (AARSs) to couple only cognate amino acid-tRNA pairs. If amino acid selectivity is compromised, fidelity can be ensured by an inherent AARS editing activity that hydrolyses mischarged tRNAs. Here, we show that the editing activity of Escherichia coli leucyl-tRNA synthetase (EcLeuRS) is not required to prevent incorrect isoleucine incorporation. Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline. This conclusion follows from a reassessment of the discriminatory power of LeuRS against isoleucine and the demonstration that a LeuRS editing-deficient E. coli strain grows normally in high concentrations of isoleucine but not under oxygen deprivation conditions when norvaline accumulates to substantial levels. Thus, AARS-based translational quality control is a key feature for bacterial adaptive response to oxygen deprivation. The non-essential role for editing under normal bacterial growth has important implications for the development of resistance to antimicrobial agents targeting the LeuRS editing site.",
            "question": "Which is the physiological target for LeuRS translational quality control?",
            "answers": {
                "answer_start": 68,
                "text": "norvaline"
            }
        },
        {
            "context": "Patterns and prognostic indicators of response to CML treatment in a multi-country medical record review study. We conducted a review of patient medical records to assess treatment response patterns and prognostic indicators of response among chronic myeloid leukemia (CML) patients in the United States, the United Kingdom, Germany, and Japan. All 1,063 patients selected met the following inclusion criteria: aged 18 or older and in chronic phase at the time of diagnosis, Philadelphia chromosome and/or BCR-ABL positive, received first-line treatment with imatinib, and not enrolled in a randomized clinical trial during the period of retrospective review. Multivariable logistic regression models were used to evaluate prognostic indicators of complete hematological response (CHR), complete cytogenetic response (CCyR), and complete or major molecular response (C/MMR). Among patients treated with first-line imatinib, CHR at three months, CCyR at 12 months, and C/MMR at 18 months were observed in 53, 53.1, and 57.8 % of patients, respectively. Among patients treated with second-line dasatinib or nilotinib, CHR was achieved at three months in 49 and 42 %, CCyR at 12 months in 32 and 23 %, and MMR at 18 months in 30.5 and 26.1 % of patients, respectively. Prognostic indicators of first-line response included age, race, and Sokal score. For second-line treatment, duration of first-line hematological response and choice of drug used were also significant.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 506,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "tyrosinase"
            }
        },
        {
            "context": "A genome-wide study on the perception of the odorants androstenone and galaxolide. Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h (2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.",
            "question": "Which olfactory gene senses androsterone?",
            "answers": {
                "answer_start": 1255,
                "text": "OR7D4"
            }
        },
        {
            "context": "Viroids with hammerhead ribozymes: some unique structural and functional aspects with respect to other members of the group. Viroids, subviral pathogens of plants, are composed of a single-stranded circular RNA of 246-399 nucleotides. Within the 27 viroids sequenced, avocado sunblotch, peach latent mosaic and chrysanthemum chlorotic mottle viroids (ASBVd, PLMVd and CChMVd, respectively) can form hammerhead structures in both of their polarity strands. These ribozymes mediate self-cleavage of the oligomeric RNAs generated in the replication through a rolling circle mechanism, whose two other steps are catalyzed by an RNA polymerase and an RNA ligase. ASBVd, and presumably PLMVd and CChMVd, replicate and accumulate in the chloroplast, whereas typical viroids replicate and accumulate in the nucleus. PLMVd and CChMVd do not adopt a rod-like or quasi rod-like secondary structure as typical viroids do but have a highly branched conformation. A pathogenicity determinant has been mapped in a defined region of the CChMVd molecule.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 125,
                "text": "Viroids"
            }
        },
        {
            "context": "MicroRNAs and cancer. MicroRNAs (miRNAs) are a recently discovered group of small RNA molecules involved in the regulation of gene expression. Analogously to mRNAs, the non-protein-encoding pri-miRNAs are synthesized by RNA polymerase II and post-transcriptionally modified by addition of a 5'-cap and a 3'-poly (A) tail. Subsequently, the pri-miRNA undergoes a number of processing steps in the nucleus and cytoplasm, and ends up as a mature approximately 22 nt miRNA, which can exert its function by binding to the 3'-untranslated region of a subset of mRNAs. Binding of the miRNA to the mRNA results in a reduced translation rate and/or increased degradation of the mRNA. In this way a large number of cellular pathways, such as cellular proliferation, differentiation, and apoptosis, are regulated by mi-RNAs. As corruption of these pathways is the hallmark of many cancers, dysregulation of miRNA biogenesis or expression levels may lead to tumorigenesis. The mechanisms that alter the expression of miRNAs are similar to those that change the expression levels of mRNAs of tumor suppressor- and oncogenes, i.e. gross genomic aberrations, epigenetic changes, and minor mutations affecting the expression level, processing, or target-interaction potential of the miRNA. Furthermore, expression profiling of miRNAs has been found to be useful for classification of different tumor types. Taken together, miRNAs can be classified as onco-miRs or tumor suppressor-miRs, and may turn out to be potential targets for cancer therapy.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 220,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Pregabalin: a review of its use in fibromyalgia. Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.",
            "question": "Which drug is considered as the first line treatment of fibromyalgia?",
            "answers": {
                "answer_start": 54,
                "text": "pregabalin"
            }
        },
        {
            "context": "Familial isolated pituitary adenoma: evidence for genetic heterogeneity. The identification of mutations in the Aryl hydrocarbon receptor interacting protein (AIP) gene in a subset of familial isolated pituitary adenoma (FIPA) cases has recently expanded our understanding of the pathophysiology of inherited pituitary adenoma disorders. However, a genetic cause of has not yet been determined in the majority (85%) of FIPA families and half of the families with isolated familial somatotropinoma. Several studies and reviews have assessed the genetic and clinical features of AIP-mutated FIPA patients, which range from a complete lack of symptoms in adult/elderly individuals to large, aggressive early-onset pituitary tumors. In this study, we aimed to briefly revise the data available for the 11q13 locus and other additional loci that have been implicated in genetic susceptibility to FIPA: 2p16-12; 3q28; 4q32.3-4q33; chr 5, 8q12.1, chr 14, 19q13.4 and 21q22.1. These candidate regions may contain unidentified gene(s) that can be potentially disrupted in AIP-negative FIPA families. A better knowledge of these susceptibility loci may disclose modifier genes that are likely to play exacerbating or protective roles in the phenotypic diversity of AIP-mutated families.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 112,
                "text": "Aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1600,
                "text": "CD38"
            }
        },
        {
            "context": "LC-MS/MS determination of apixaban (BMS-562247) and its major metabolite in human plasma: an application of polarity switching and monolithic HPLC column. BACKGROUND: apixaban (BMS-562247) (Eliquis(®)) is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa (FXa). A sensitive and reliable method was developed and validated for the measurement of apixaban (BMS-562247) and its major circulating metabolite (BMS-730823) in human citrated plasma for use in clinical testing. METHODOLOGY/RESULTS: A 0.100 ml portion of citrated plasma sample was extracted and analyzed by LC-MS/MS. Run times were approximately 3 min. The lower limit of quantification (LLOQ) was 1.00 ng/ml for BMS-562247 and 5.00 ng/ml for BMS-730823. Intra- and inter-assay precision values for replicate QC control samples were within < 5.36% for both analytes ( < 7.52% at the LLOQ). The accuracy for both analytes was within ±9.00%. CONCLUSION: The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies.",
            "question": "What is the drug target for Eliquis (Apixaban)?",
            "answers": {
                "answer_start": 288,
                "text": "factor Xa"
            }
        },
        {
            "context": "The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice. OBJECTIVE: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet -induced monocytosis and inflammatory gene expression. CONCLUSIONS: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 9,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.",
            "question": "How is OCT3 associated with serotonin?",
            "answers": {
                "answer_start": 367,
                "text": "serotonin clearance"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 4,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype. Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 479,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "McEnhancer: predicting gene expression via semi-supervised assignment of enhancers to target genes. Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.",
            "question": "Which method has been developed for assignment of enhancers to target genes?",
            "answers": {
                "answer_start": 0,
                "text": "McEnhancer"
            }
        },
        {
            "context": "[Expression and structure of BNIP3L in lung cancer]. BACKGROUND & OBJECTIVE: Bcl-2/E1B 19kDa interacting protein3-like (BNIP3L) gene is a tumor suppressor gene cloned from a human fetal liver cDNA library, which is located at 8p21, one of the high frequent regions of loss of heterozygosity (LOH) in lung carcinoma. BNIP3L protein can interact with antiapoptotic proteins, such as Bcl-2, Bcl-x(L), E1B19K, which promotes apoptosis. This study was designed to explore the correlation of alteration of expression and structure of BNIP3L gene with the progression of lung cancer. METHODS: The expression and structure of BNIP3L gene in 4 lung cancer cell strains and 30 tissues were determined by SP immunohistochemistry, immunoblot, semi-quantitative reverse transcription-PCR (RT-PCR), PCR-single strain conformation polymorphism (PCR-SSCP). RESULTS: (1) In 4 lung cancer cell strains, BNIP3L protein was not detected in A549, NCI-H460, NCI-H446, except for NCI-H520, in which the protein expression level was slightly lower than that in immortal bronchial epithelial cell strain HBE4-E6/E7. BNIP3L protein was observed in 46.7% (14/30) lung cancer tissues, while 100% (12/12) in normal lung tissues. The difference was significant in statistics (P< 0.05). (2) BNIP3L mRNA was detected in 4 lung cancer cell strains; and there existed no obvious discrepancy of the amount between these cell strains and HBE4-E6/E7. Absence or decrease of BNIP3L mRNA was observed in 26.7%(8/30) of lung cancer tissues. The average quantity of BNIP3L mRNA was 0.404+/-0.070 in lung cancer tissues, while 0.575+/-0.065 in paired normal lung tissues. The difference was significant in statistics (P< 0.05). In all the cancerous cell strains and tissues with BNIP3L mRNA, the products of RT-PCR were as long as those from their control samples in size, including the entire coding region, and no variation of BNIP3L gene structure such as absence, rearrangement, aberrant splicing were detected.(3) No point mutation was detected in all 6 exons of BNIP3L gene in 4 lung cancer cell strains and 30 tissues. CONCLUSION: BNIP3L protein expression was down-regulated in lung cancer, which might be involved in the occurrence and/or development of lung cancer. The down-regulation of BNIP3L protein expression in lung cancer was partly caused by the down-regulation of its transcription. The variation of gene structure may be not the reason of BNIP3L inactivity in lung cancer.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 859,
                "text": "lung"
            }
        },
        {
            "context": "Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1. Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 746,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "Structural ramification for acetyl-lysine recognition by the bromodomain of human BRG1 protein, a central ATPase of the SWI/SNF remodeling complex. Bromodomains represent an extensive family of evolutionarily conserved domains that are found in many chromatin-associated proteins such as histone acetyltransferases (HAT) and subunits of ATP-dependent chromatin-remodeling complexes. These domains are associated with acetylated lysine residues that bind both in vivo and in vitro; for example, they bind to the N-acetylated lysines of the histone tail of nucleosomes. In this report, we determined the structure of the bromodomain from human brahma-related gene 1 (BRG1) protein, a subunit of an ATP-dependent switching/sucrose nonfermenting (SWI/SNF) remodeling complex, and have also characterized its in vitro interaction with N-acetylated lysine peptides from histones. In addition to a typical all-alpha-helical fold that was observed in the bromodomains, we observed for the first time a small beta-sheet in the ZA loop region of the BRG1 protein. The BRG1 bromodomain exhibited binding, albeit weak, to acetylated peptides that were derived from histones H3 and H4. We have compared the acetyl-lysine binding sites of BRG1 bromodomain with the yGCN5 (general control of amino acid biosynthesis). By modeling the acetylated-lysine peptide into the BRG1 bromodomain structure, we were able to explain the weak binding of acetylated-lysine peptides to this bromodomain.",
            "question": "What is the structural fold of bromodomain proteins?",
            "answers": {
                "answer_start": 899,
                "text": "all-alpha-helical fold"
            }
        },
        {
            "context": "Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. New treatment options are urgently needed for patients with relapsed chronic lymphocytic leukemia (CLL) who fail to respond to currently available therapies or cannot achieve a sustained response. Moreover, targeted agents with less myelotoxicity are necessary to treat patients with multiple comorbidities who would otherwise be unable to tolerate standard regimens. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown highly encouraging results in phase I/II trials in patients with treatment-naive, relapsed and refractory CLL even in the presence of high risk disease or poor prognostic markers. In phase I/II trials, ibrutinib 420 mg or 840 mg - given continuously as single agent or at a dose of 420 mg daily in combination with a monoclonal antibody or chemoimmunotherapy - has been associated with high response rates and durable clinical remissions. Phase II and III trials are currently under way for treatment-naive patients, relapsed/refractory patients, and for those patients harboring a 17p deletion.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 0,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "Comment on \"Protein sequences from mastodon and Tyrannosaurus rex revealed by mass spectrometry\". We used authentication tests developed for ancient DNA to evaluate claims by Asara et al. (Reports, 13 April 2007, p. 280) of collagen peptide sequences recovered from mastodon and Tyrannosaurus rex fossils. Although the mastodon samples pass these tests, absence of amino acid composition data, lack of evidence for peptide deamidation, and association of alpha1(I) collagen sequences with amphibians rather than birds suggest that T. rex does not.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 224,
                "text": "collagen"
            }
        },
        {
            "context": "The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase. The mechanistic target of rapamycin (mTOR) functions as a component of two large complexes, mTORC1 and mTORC2, which play crucial roles in regulating cell growth and homeostasis. However, the molecular mechanisms by which mTOR controls cell proliferation remain elusive. Here we show that the FoxO3a transcription factor is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in controlling cell proliferation. To dissect mTOR signaling, mTORC1 was specifically inactivated by depleting p18, an essential anchor of mTORC1 on lysosomes. mTORC1 inactivation caused a marked retardation of cell proliferation, which was associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs). Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation. Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation. Expression of FoxO3a mutated at Ser314 suppressed cell proliferation by inducing CDKI expression. SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation. These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.",
            "question": "Which protein pathway is regulating SGK1-mediated phosphorylation of FOXO3a to control cell proliferation?",
            "answers": {
                "answer_start": 0,
                "text": "The mTOR pathway"
            }
        },
        {
            "context": "Lack of association of variants previously associated with anti-TNF medication response in rheumatoid arthritis patients: results from a homogeneous Greek population. Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.",
            "question": "What percentage of rheumatoid arthritis patients are responsive to anti-TNF therapy?",
            "answers": {
                "answer_start": 346,
                "text": "50-60%"
            }
        },
        {
            "context": "The p73 tumor suppressor is targeted by Pirh2 RING finger E3 ubiquitin ligase for the proteasome-dependent degradation. The p73 gene, a homologue of the p53 tumor suppressor, is expressed as TA and ΔN isoforms. TAp73 has similar activity as p53 and functions as a tumor suppressor whereas ΔNp73 has both pro- and anti-survival functions. While p73 is rarely mutated in spontaneous tumors, the expression status of p73 is linked to the sensitivity of tumor cells to chemotherapy and prognosis for many types of human cancer. Thus, uncovering its regulators in tumors is of great interest. Here, we found that Pirh2, a RING finger E3 ubiquitin ligase, promotes the proteasome-dependent degradation of p73. Specifically, we showed that knockdown of Pirh2 up-regulates, whereas ectopic expression of Pirh2 down-regulates, expression of endogenous and exogenous p73. In addition, Pirh2 physically associates with and promotes TAp73 polyubiquitination both in vivo and in vitro. Moreover, we found that p73 can be degraded by both 20 S and 26 S proteasomes. Finally, we showed that Pirh2 knockdown leads to growth suppression in a TAp73-dependent manner. Taken together, our findings indicate that Pirh2 promotes the proteasomal turnover of TAp73, and thus targeting Pirh2 to restore TAp73-mediated growth suppression in p53-deficient tumors may be developed as a novel anti-cancer strategy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 214,
                "text": "7"
            }
        },
        {
            "context": "A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke. INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence. METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance. RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2). CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 395,
                "text": "acute ischemic stroke"
            }
        },
        {
            "context": "Ultrasound: a noninvasive screening test for detrusor instability. OBJECTIVE: To determine whether transvaginal ultrasound measurement of bladder wall thickness can be used as a screening test for detrusor instability in women with urinary symptoms. DESIGN: A blinded prospective study. SETTING: A London teaching hospital. PARTICIPANTS: One hundred and eight-four symptomatic women presenting to a urodynamic clinic. MAIN OUTCOME MEASURE: The detection of detrusor instability by means of videocystourethrography (VCU) and ambulatory urodynamics in women with a mean bladder wall thickness of greater than 5 mm measured by transvaginal ultrasound. RESULTS: One hundred and eight women had a mean bladder wall thickness of greater than 5 mm. Ninety-four percent (102) of these women had detrusor instability either when undergoing VCU or ambulatory urodynamics. Seventeen women had a bladder wall thickness of less than 3.5 mm of whom three were found to have detrusor instability on VCU. CONCLUSION: The measurement of a mean bladder wall thickness greater than 5 mm with transvaginal ultrasound is a sensitive screening method for diagnosing detrusor instability in symptomatic women without outflow obstruction.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 1086,
                "text": "ultrasound"
            }
        },
        {
            "context": "Efficacy and limitations of transarterial acrylic glue embolization for intracranial dural arteriovenous fistulas. The efficacy and limitations of transarterial acrylic glue embolization for the treatment of intracranial dural arteriovenous fistulas (DAVFs) were investigated. Thirty-four DAVFs treated by transarterial embolization using n-butyl cyanoacrylate were retrospectively reviewed. The locations of DAVFs were the transverse-sigmoid sinus in 11, tentorium in 10, cranial vault in 9, and superior sagittal sinus, jugular bulb, foramen magnum, and middle cranial fossa in 1 each. Borden classification was type I in 7, type II in 3, and type III in 24. Eight patients had undergone prior transvenous coil embolization. Complete obliteration rate was 56% immediately after embolization, 71% at follow-up angiography, and 85% after additional treatments (1 transvenous embolization and 4 direct surgery). Complications occurred in three patients, consisting of asymptomatic vessel perforations during cannulation in two patients and leakage of contrast medium resulting in medullary infarction in one patient. Transarterial glue embolization is highly effective for Borden type III DAVF with direct cortical venous drainage, but has limitations for Borden type I and II DAVFs in which the affected sinus is part of the normal venous circulation. Onyx is a new liquid embolic material and is becoming the treatment of choice for DAVF. The benefits of glue embolization compared to Onyx embolization are high thrombogenicity, and relatively low risks of cranial nerve palsies and of excessive migration into the draining veins of high flow fistula. Transarterial glue embolization continues to be useful for selected patients, and complete cure can be expected in most patients with fewer complications if combined with transvenous embolization or direct surgery.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 1188,
                "text": "DAVF"
            }
        },
        {
            "context": "Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 40,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS). Strongly expressed in the most differentiated epidermal layers, LEKTI is a serine protease inhibitor synthesized as three different high-molecular-weight precursors, which are rapidly processed into shorter fragments and secreted extracellularly. LEKTI polypeptides interact with several proteases to regulate skin barrier homeostasis as well as inflammatory and/or immunoallergic responses. Here, by combining antibody mapping, N-terminal sequencing, and site-specific mutagenesis, we defined the amino-acid sequence of most of the LEKTI polypeptides physiologically generated in human epidermis. We also identified three processing intermediates not described so far. Hence, a proteolytic cascade model for LEKTI activation is proposed. We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the KLK-mediated proteolysis of desmoglein-1. Finally, we quantified the individual LEKTI fragments in the uppermost epidermis, showing that the ratios between LEKTI polypeptides and active KLK5 are compatible with a fine-tuned inhibition. These findings are relevant both to the understanding of skin homeostasis regulation and to the design of novel therapeutic strategies for NS.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 184,
                "text": "LEKTI"
            }
        },
        {
            "context": "Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India. Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 37,
                "text": "HEXA"
            }
        },
        {
            "context": "A scaffold for X chromosome inactivation. X chromosome inactivation (XCI), the silencing of one of the two X chromosomes in XX female cells, equalises the dosage of X-linked genes relative to XY males. The process is mediated by the non-coding RNA X inactive specific transcript (Xist) that binds in cis and propagates along the inactive X chromosome elect, triggering chromosome-wide silencing. The mechanisms by which Xist RNA binds and spreads along the chromosome, and initiates Xist-mediated chromosome silencing remain poorly understood. Accumulating evidence suggests that chromosome and nuclear organisation are important in both processes. Notably, recent studies have identified specific factors, previously shown to be components of the nuclear matrix or scaffold, to play a role both in Xist RNA-binding and in Xist-mediated silencing. In this review we provide a perspective on these studies in the context of previous work on chromosome/nuclear architecture in XCI.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 280,
                "text": "Xist"
            }
        },
        {
            "context": "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 35,
                "text": "orexin"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 0,
                "text": "RADAR"
            }
        },
        {
            "context": "Development of a real-time fluorescence loop-mediated isothermal amplification assay for rapid and quantitative detection of Fusarium oxysporum f. sp. cubense tropical race 4 in soil. Fusarium oxysporum f. sp. cubense (Foc), the causal agent of Fusarium wilt (Panama disease), is one of the most devastating diseases of banana (Musa spp.). The Foc tropical race 4 (TR4) is currently known as a major concern in global banana production. No effective resistance is known in Musa to Foc, and no effective measures for controlling Foc once banana plants have been infected in place. Early and accurate detection of Foc TR4 is essential to protect banana industry and guide banana planting. A real-time fluorescence loop-mediated isothermal amplification assay (RealAmp) was developed for the rapid and quantitative detection of Foc TR4 in soil. The detection limit of the RealAmp assay was approximately 0.4 pg/µl plasmid DNA when mixed with extracted soil DNA or 10(3) spores/g of artificial infested soil, and no cross-reaction with other relative pathogens were observed. The RealAmp assay for quantifying genomic DNA of TR4 was confirmed by testing both artificially and naturally infested samples. Quantification of the soil-borne pathogen DNA of Foc TR4 in naturally infested samples was no significant difference compared to classic real-time PCR (P>0.05). Additionally, RealAmp assay was visual with an improved closed-tube visual detection system by adding SYBR Green I fluorescent dye to the inside of the lid prior to amplification, which avoided the inhibitory effects of the stain on DNA amplification and makes the assay more convenient in the field and could thus become a simple, rapid and effective technique that has potential as an alternative tool for the detection and monitoring of Foc TR4 in field, which would be a routine DNA-based testing service for the soil-borne pathogen in South China.",
            "question": "What is the causative agent of the \"Panama disease\" affecting bananas?",
            "answers": {
                "answer_start": 184,
                "text": "Fusarium oxysporum f. sp. cubense"
            }
        },
        {
            "context": "Targeting the molecular target of rapamycin (mTOR). PURPOSE OF REVIEW: The molecular target of rapamycin, which is a member of the phosphoinositide 3-kinase related kinase family and a central modulator of cell growth, is a unique and prime strategic target for anticancer therapeutic development. RECENT FINDINGS: The molecular target of rapamycin plays a critical role in transducing proliferative signals mediated through the phosphatidylinositol 3 kinase and protein kinase B signaling pathways, principally by activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of mRNAs of proteins that are essential for G1 to S phase traverse. By targeting the molecular target of rapamycin with high potency and specificity, the immunosuppressant and antiproliferative agent rapamycin inhibits signals required for cell cycle progression, cell growth, and proliferation. Both rapamycin and several rapamycin analogs with more favorable pharmaceutical properties have demonstrated impressive growth inhibitory effects against a broad range of human cancers in both preclinical and early clinical evaluations. SUMMARY: This review discusses recent findings regarding the principal mechanisms of action of the rapamycins, the potential utility of these agents as anticancer therapeutics, clinical results to date, and developmental challenges that lie ahead.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 45,
                "text": "mTOR"
            }
        },
        {
            "context": "Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. AIMS: Glucocorticoids, such as dexamethasone, enhance hepatic energy metabolism and gluconeogenesis partly through changes in mitochondrial function. Mitochondrial function is influenced by the balance between mitochondrial fusion and fission events. However, whether glucocorticoids modulate mitochondrial function through the regulation of mitochondrial dynamics is currently unknown. RESULTS: Here, we report that the effects of dexamethasone on mitochondrial function and gluconeogenesis in hepatoma cells are dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Dexamethasone increased routine oxygen consumption, maximal respiratory capacity, superoxide anion, proton leak, and gluconeogenesis in hepatoma cells. Under these conditions, dexamethasone altered mitochondrial morphology, which was paralleled by a large increase in Drp1 expression, and reduced mitofusin 1 (Mfn1) and Mfn2. In vivo dexamethasone treatment also enhanced Drp1 expression in mouse liver. On the basis of these observations, we analyzed the dependence on the Drp1 function of dexamethasone effects on mitochondrial respiration and gluconeogenesis. We show that the increase in mitochondrial respiration and gluconeogenesis induced by dexamethasone are hampered by the inhibition of Drp1 function. INNOVATION: Our findings provide the first evidence that the effects of glucocorticoids on hepatic metabolism require the mitochondrial fission protein Drp1. CONCLUSION: In summary, we demonstrate that the mitochondrial effects of dexamethasone both on mitochondrial respiration and on the gluconeogenic pathway depend on Drp1.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 83,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 830,
                "text": "xa"
            }
        },
        {
            "context": "Androgen dependent mammary gland virilism in rats given the selective estrogen receptor modulator LY2066948 hydrochloride. A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 125,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 987,
                "text": "53BP1"
            }
        },
        {
            "context": "The role of voxel-based morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy. PURPOSE: To determine whether voxel-based morphometry (VBM) might contribute to the detection of cortical dysplasia within the temporal pole in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS). METHODS: Eighteen patients with intractable MTLE/HS and 30 sex- and age-matched healthy controls were included in the study. All of the patients fulfilled the diagnostic criteria for MTLE/HS and underwent anteromedial temporal resection. VBM without a modulation step was applied to the magnetic resonance (MR) images of the brain. Statistical parametric maps were used to compare structural characteristics such as gray matter concentration (GMC) within the temporal pole among patients and controls separately. The acquired data were then statistically analyzed to determine the congruency between visually inspected MR imaging (MRI) scans and VBM results in the detection of morphologic abnormalities in the temporal pole compared to postoperative histopathologic findings of cortical dysplasia. KEY FINDINGS: Histopathologic examination revealed cortical dysplasia within the temporal pole in 11 patients. In detail, according to Palmini's classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. Some type of structural temporal pole abnormality was suggested by VBM in 14 patients and by visually inspected MRI scans in 11 patients. The results of VBM were in agreement with the presence/absence of cortical dysplasia in 13 patients (72.2%); this correspondence was significant (p = 0.047). In one case, VBM was false negative and in four cases it was false positive. There was congruence between the results of visual analysis and histologic proof in 55.6% of examined patients, which was not significant. SIGNIFICANCE: We found that VBM made a superior contribution to the detection of temporopolar structural malformations (cortical dysplasia) compared to visual inspection. The agreement with postoperative histopathologic proof was clearly significant for VBM results and nonsignificant for visual inspection.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1430,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 482,
                "text": "PD-L1"
            }
        },
        {
            "context": "Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: role of IL-6. Bach1 is a transcriptional repressor of the heme oxygenase (HO)-1 gene. Bach1-null (Bach1(-/-)) mice are reported to be protected from myocardial ischemia/reperfusion injury; however, the effect of Bach1 disruption on another oxidative stress model of hyperoxic lung injury has yet to be determined. To investigate the role of Bach1 in hyperoxic lung injury, Bach1(-/-) mice and wild-type (WT) mice were exposed to 90% O(2). During hyperoxic exposure, the survival of Bach1(-/-) mice was significantly longer than that of WT mice. However, the administration of zinc protoporphyrin, an inhibitor of HO-1 activity, did not change the mortality in either of the mice, thus suggesting that this protective effect was not mediated by an HO-1 overexpression in Bach1(-/-) mice. The indices of lung injury in the lungs of Bach1(-/-) mice were lower than those of WT mice; unexpectedly, however, the levels of IL-6 in bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly higher than those of WT mice. Interestingly, the intrapulmonary administration of small interfering RNA against IL-6 was shown to reduce the IL-6 levels in BAL fluids and shorten the survival in Bach1(-/-) mice during hyperoxic exposure. In addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL-6 promoter and its detachment after oxidative stress. Considering the previous observation that the transgenic mice overexpressing IL-6 are protected from hyperoxic lung injury, these results therefore indicate that IL-6 mediates an increased survival in Bach1(-/-) mice during hyperoxic exposure.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 115,
                "text": "repressor"
            }
        },
        {
            "context": "Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor. Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 757,
                "text": "telomerase"
            }
        },
        {
            "context": "Borderline oxacillin-resistant Staphylococcus aureus (BORSA) - a more common problem than expected? Borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a quite poorly understood and inadequately defined phenotype of methicillin resistance. BORSA strains show low, borderline resistance to penicillinase-resistant penicillins (PRPs), with oxacillin MICs typically equal to 1-8 µg ml, and in contrast to methicillin-resistant S. aureus (MRSA), do not have an altered penicillin-binding protein, PBP2a, encoded by the mecA or mecC gene. Their resistance is typically associated with hyperproduction of beta-lactamases or, in some cases, point mutations in PBP genes. BORSA cannot be classified as either truly methicillin-resistant or truly methicillin-susceptible strains. However, they are frequently misidentified, which poses an obvious epidemiological and therapeutic threat. BORSA strains are commonly isolated from humans and animals, and are found both in hospitals and in a community setting. The epidemiology and clinical presentation of BORSA infections seem to be similar to those for MRSA; these infections are usually more severe than those caused by methicillin-sensitive S. aureus (MSSA). Treatment of severe infections caused by BORSA may be ineffective, even with larger doses of oxacillin. The available evidence suggests that BORSA represent a frequently neglected problem, and their emergence in new environments implies that they need to be monitored and accurately distinguished from MSSA and MRSA.",
            "question": "What is BORSA?",
            "answers": {
                "answer_start": 0,
                "text": "Borderline oxacillin-resistant Staphylococcus aureus"
            }
        },
        {
            "context": "Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXalpha. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. Here we show that hypoxia represses HO-1 expression in three human cell types but induces it in rat, bovine, and monkey cells, indicating the inter-species difference in the hypoxic regulation of HO-1 expression. The hypoxia-mediated repression of HO-1 expression is consistently associated with the induction of Bach1, a heme-regulated transcriptional repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a heterodimer with a small Maf protein. Expression of HO-1 was also reduced in human cells when exposed to interferon-gamma or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl(2) is associated with reduced expression of Bach1 mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have identified a Maf recognition element in the human HO-1 gene that is required for repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1 functions as a hypoxia-inducible repressor for the HO-1 gene, thereby contributing to fine-tuning of oxygen homeostasis in human cells.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 705,
                "text": "repressor"
            }
        },
        {
            "context": "A polymorphism study of the human Agouti gene and its association with MC1R. To determine whether the Agouti Signalling Protein (ASP) gene is associated with skin and hair coloration in humans, the complete coding region of ASP was screened for polymorphisms. Analysis of ASP in Caucasian, African-American, Spanish Basque, Hispanic, Apache and Australian Aboriginal populations revealed no amino acid substitutions. A single polymorphism in the 3' untranslated region occurred at a frequency of 0.2 in African-Americans. Variants of the Melanocortin 1 Receptor (MC1R) gene have been found to be associated with red hair and fair skin in humans. Red hair individuals are usually compound heterozygotes or homozygous for one of a number of MC1R polymorphisms associated with red hair. Some individuals however are heterozygous for only one of these polymorphisms and dizygotic twins can be concordant for MC1R variants but discordant for hair colour. A recent study has also identified rare redheads carrying no MC1R variants indicating that polymorphisms of the human MC1R gene are required but not sufficient for the red hair phenotype. To address the question of whether ASP also contributes to the red hair phenotype, individuals previously identified as having unexpected MC1R genotypes were screened for polymorphisms at the ASP locus. No polymorphisms were found in any of these individuals. Results indicate that the human ASP gene is unlikely to function in normal human pigmentation in the same way as MC1R.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 538,
                "text": "Melanocortin 1 Receptor"
            }
        },
        {
            "context": "Interpreting gaze in Turner syndrome: impaired sensitivity to intention and emotion, but preservation of social cueing. Women with Turner's syndrome (TS), who lack a complete X-chromosome, show an impairment in remembering faces and in classifying \"fear\" in face images. Could their difficulties extend to the processing of gaze? Three tasks, all of which rely on the ability to make use of the eye-region of a pictured face, are reported. Women with TS were impaired at judging mental state from images of the upper face (\"reading the mind in the eyes\"). They were also specifically impaired at interpreting \"fear\" from displays of the eye-region of the face. However, they showed normal susceptibility to direction of gaze as an attentional cue (social cueing), since they were as sensitive as controls to the validity of the cue, under conditions where it should be ignored. In this task, unlike those of reading the upper face for intention or expression, PIQ accounted for a significant amount of individual variance in task performance. The processing of displays of the eye region affording social and affective information is specifically affected in TS. We speculate that amygdala dysfunction is likely to be implicated in this anomalous behaviour. The presence in the female karyotype of two complete X-chromosomes is protective for some socio-cognitive abilities related to the modulation of behaviour by the interpretation of gaze.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 175,
                "text": "X"
            }
        },
        {
            "context": "GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. Growth factor signaling results in dramatic phenotypic changes in cells, which require commensurate alterations in cellular metabolism. Mutations in SLC2A10/GLUT10, a member of the facilitative glucose transporter family, are associated with altered transforming growth factor-β (TGFβ) signaling in patients with arterial tortuosity syndrome (ATS). The objective of this work was to test whether SLC2A10/GLUT10 can serve as a link between TGFβ-related transcriptional regulation and metabolism during development. In zebrafish embryos, knockdown of slc2a10 using antisense morpholino oligonucleotide injection caused a wavy notochord and cardiovascular abnormalities with a reduced heart rate and blood flow, which was coupled with an incomplete and irregular vascular patterning. This was phenocopied by treatment with a small-molecule inhibitor of TGFβ receptor (tgfbr1/alk5). Array hybridization showed that the changes at the transcriptome level caused by the two treatments were highly correlated, revealing that a reduced tgfbr1 signaling is a key feature of ATS in early zebrafish development. Interestingly, a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function. Consistent with these results, slc2a10 morphants showed decreased respiration and reduced TGFβ reporter gene activity. Finally, co-injection of antisense morpholinos targeting slc2a10 and smad7 (a TGFβ inhibitor) resulted in a partial rescue of smad7 morphant phenotypes, suggesting scl2a10/glut10 functions downstream of smads. Taken together, glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFβ signaling.",
            "question": "Mutation of which gene causes arterial tortuosity syndrome?",
            "answers": {
                "answer_start": 290,
                "text": "SLC2A10"
            }
        },
        {
            "context": "Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome. INTRODUCTION: Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations. Therapeutic strategies, such as prophylactic aortic root surgery and pharmacological therapy, focus on the prevention of aortic dissection. Currently, the standard medicinal treatments targeting aortic dilatation and dissection consist of agents generally used to lower blood pressure and/or the inotropic state of the heart. By these means, the cyclic repetitive forces exerted on the aortic wall are diminished and thus the onset of aortic dilatation is potentially prevented. Although these pharmacological agents may offer some benefit in reduction of aortic aneurysm expansion rate, they do not target the underlying cause of the progressive aortic degradation. AREAS COVERED: This review discusses the effectiveness of frequently prescribed medications used to prevent and delay aortic complications in Marfan syndrome. New insights on the biochemical pathways leading to aortic disease are also discussed to highlight new targets for pharmacological therapy. EXPERT OPINION: Recent insights in the transforming growth factor beta signaling pathway and inflammatory mechanisms in a well-established mouse model of Marfan syndrome, have led to studies exploring new pharmacological treatment strategies with doxycycline, statins and angiotensin II receptor blockers. Pharmacological therapy is focused more on prevention than on delay of aortic wall pathology in Marfan syndrome. Of the new pharmacological treatment strategies targeting aortic pathology in Marfan syndrome, angiotensin receptor type 1 blockers are promising candidates, with several clinical trials currently ongoing.",
            "question": "What is the main symptom of Marfan syndrome patients?",
            "answers": {
                "answer_start": 416,
                "text": "aortic root dissection"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 1125,
                "text": "thyroid"
            }
        },
        {
            "context": "Pannexin2 oligomers localize in the membranes of endosomal vesicles in mammalian cells while Pannexin1 channels traffic to the plasma membrane. Pannexin2 (Panx2) is the largest of three members of the pannexin proteins. Pannexins are topologically related to connexins and innexins, but serve different functional roles than forming gap junctions. We previously showed that pannexins form oligomeric channels but unlike connexins and innexins, they form only single membrane channels. High levels of Panx2 mRNA and protein in the Central Nervous System (CNS) have been documented. Whereas Pannexin1 (Panx1) is fairly ubiquitous and Pannexin3 (Panx3) is found in skin and connective tissue, both are fully glycosylated, traffic to the plasma membrane and have functions correlated with extracellular ATP release. Here, we describe trafficking and subcellular localizations of exogenous Panx2 and Panx1 protein expression in MDCK, HeLa, and HEK 293T cells as well as endogenous Panx1 and Panx2 patterns in the CNS. Panx2 was found in intracellular localizations, was partially N-glycosylated, and localizations were non-overlapping with Panx1. Confocal images of hippocampal sections immunolabeled for the astrocytic protein GFAP, Panx1 and Panx2 demonstrated that the two isoforms, Panx1 and Panx2, localized at different subcellular compartments in both astrocytes and neurons. Using recombinant fusions of Panx2 with appended genetic tags developed for correlated light and electron microscopy and then expressed in different cell lines, we determined that Panx2 is localized in the membrane of intracellular vesicles and not in the endoplasmic reticulum as initially indicated by calnexin colocalization experiments. Dual immunofluorescence imaging with protein markers for specific vesicle compartments showed that Panx2 vesicles are early endosomal in origin. In electron tomographic volumes, cross-sections of these vesicles displayed fine structural details and close proximity to actin filaments. Thus, pannexins expressed at different subcellular compartments likely exert distinct functional roles, particularly in the nervous system.",
            "question": "Where is the protein Pannexin1 located?",
            "answers": {
                "answer_start": 127,
                "text": "plasma membrane"
            }
        },
        {
            "context": "PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 446,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 3384,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [(3)H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [(3)H]S107 per RyR1 tetramer with EC(50) ∼52 µM and Hillslope ∼2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 µM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 415,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 120,
                "text": "Nox1"
            }
        },
        {
            "context": "Role of ApoE in conformation-prone diseases and atherosclerosis. Three isoforms of human plasma apolipoprotein E (apoE) are ligands to lipoprotein receptors and influence in different manner the synthesis and catabolism of pro-atherogenic triglyceride-rich lipoproteins. Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD). The conformational transitions of beta-amyloid (Abeta) influenced by apoE and serum amyloid P (SAP) component are key events in AD development, the accumulation of intermediate diffusible and soluble oligomers of Abeta being of particular significance. SAP and apoE, in a different manner for the three isoforms, serve as \"pathological\" chaperones during the aggregation of Abeta considered as a conformation-prone process. In turn, apoE consisting of two domains self-associates in solution and intermediate structures differently populated for the three isoforms exist. The different structures of the three isoforms determine their different distribution among various plasma lipoproteins. The structural and metabolic consideration of the common apoE pathway(s) in two pathologies assumes four molecular targets for AD correction: (i) inhibition of the accumulation of diffusible soluble Abeta oligomers; (ii) inhibition of apoE synthesis and secretion by astrocytes, in particular, under lipid-lowering therapy; (iii) inhibition of the binding of apoE and/or SAP to Abeta; (iv) stimulation of the expression of cholesterol transporter ABCA1.",
            "question": "Which ApoE isoform is associated with atherosclerosis and Alzheimer's disease?",
            "answers": {
                "answer_start": 297,
                "text": "apoE4 isoform"
            }
        },
        {
            "context": "Modified Mallampati Score Improves Specificity of STOP-BANG Questionnaire for Obstructive Sleep Apnea. BACKGROUND: An accurate, clinical screening tool for obstructive sleep apnea (OSA) that identifies patients for further diagnostic testing would assist in the diagnosis of this comorbidity. One example, the STOP-BANG questionnaire (SBQ), has been validated as a screening tool with high sensitivity. However, its specificity may result in a high false-positive rate. The aim of this study to determine if addition of the Modified Mallampati score to the SBQ improves its specificity. METHODS: The authors studied 162 patients referred to the Sleep Disorders Clinic at Yedikule Chest Disease Education and Research Hospital. All patients were prospectively screened for risk of OSA using the SBQ, their oral anatomy was assessed by Modified Mallampati scoring, and sleep quality characterized by polysomnography. Polysomnography results were reviewed when available and the predictive performance of the SBQ and the modified SBQ scoring models were compared. RESULTS: In the authors' study an SBQ score > 3 yielded sensitivities of 0.85, 0.86, and 0.91 for Apnea-Hypopnea Index (AHI) > 5/h, AHI > 15/h, and AHI > 30/h, respectively, and specificities of 0.09, 0.10, and 0.18. The modified SBQ with a cutoff of > 4 (>3) points for AHI levels of >5, >15, and >30 yielded respective sensitivities of 0.84, 0.86, and 0.91 and specificities of 0.25, 0.26, and 0.27. CONCLUSIONS: The author's results from indicated the modified SBQ with a cutoff of >3 points in this study was more specific than the standard SBQ but no less sensitive, and may be used in identifying OSA patients for further diagnostic evaluation or avoiding unnecessary testing.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 156,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Antinociceptive mechanism of L-DOPA. The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 405,
                "text": "L-DOPA"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 784,
                "text": "traseR"
            }
        },
        {
            "context": "A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. Most nucleosomes are well-organized at the 5' ends of S. cerevisiae genes where \"-1\" and \"+1\" nucleosomes bracket a nucleosome-free promoter region (NFR). How nucleosomal organization is specified by the genome is less clear. Here we establish and inter-relate rules governing genomic nucleosome organization by sequencing DNA from more than one million immunopurified S. cerevisiae nucleosomes (displayed at http://atlas.bx.psu.edu/). Evidence is presented that the organization of nucleosomes throughout genes is largely a consequence of statistical packing principles. The genomic sequence specifies the location of the -1 and +1 nucleosomes. The +1 nucleosome forms a barrier against which nucleosomes are packed, resulting in uniform positioning, which decays at farther distances from the barrier. We present evidence for a novel 3' NFR that is present at >95% of all genes. 3' NFRs may be important for transcription termination and anti-sense initiation. We present a high-resolution genome-wide map of TFIIB locations that implicates 3' NFRs in gene looping.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 1110,
                "text": "TFIIB"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. AIMS: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR). RESULTS: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under the empagliflozin concentration-time curve (AUC0 -∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate, severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment. CONCLUSIONS: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 98,
                "text": "SGLT2"
            }
        },
        {
            "context": "[Hereditary hypomelanocytoses: the role of PAX3, SOX10, MITF, SNAI2, KIT, EDN3 and EDNRB genes]. Hypo- and hyperpigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function and melanocytoses connected with melanocyte development. The article presents some hereditary hypomelanocytoses, which are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by Waardenburg syndrome, piebaldism and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations. It has been demonstrated that mutations of the same gene may cause different hypopigmentation syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2A as well as Tietz syndrome. It has also been demonstrated that mutations of different genes may cause an identical syndrome. For example, mutations of MITF, SNAI2 and SOX10 genes are observed in Waardenburg syndrome type II and mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV. In turn, mutation of the KIT gene and/or heterozygous deletion of the SNAI2 gene result in piebaldism disease. The knowledge of the exact mechanisms of pigmentary disorders may be useful in the development of new therapeutic approaches to their treatment.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1080,
                "text": "MITF"
            }
        },
        {
            "context": "A novel compound RY10-4 induces apoptosis and inhibits invasion via inhibiting STAT3 through ERK-, p38-dependent pathways in human lung adenocarcinoma A549 cells. Previous reports suggested that protoapigenone showed remarkable antitumor activities against a broad spectrum of human cancer cell lines, but had no effect on human lung adenocarcinoma A549 cell. The lack of effective remedies had necessitated the application of new therapeutic scheme. A novel compound RY10-4 which has the similar structure close to protoapigenone showed better antitumor activity. Treatment with RY10-4 inhibited the expression of pro-caspase-3, pro-caspase-9, Bcl-2 as well as phosphorylation of signal transducer and activator of transcription-3 (p-STAT3). It also reduced the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and increases the expressions of reversion-inducing cysteine-rich protein with kazal motifs (RECK), as well as tissue inhibitor of metalloproteinase (TIMP) via inhibiting STAT3 by activating the mitogen-activated protein (MAP) kinases (the c-Jun N-terminal kinase (JNK), the p38 and extracellular signal-regulated kinase (ERK)) in A549 cells treated with RY10-4. Moreover, the cytotoxic effect of RY10-4 was induction of apoptosis in A549 cells by enhancing production of reactive oxygen species (ROS). Taken together, the observations suggested that RY10-4 had affected Bcl-2 family members, caspases, MMPs, TIMPs expressions and ROS production via inhibiting STAT3 activities through ERK and p38 pathways in A549 cells.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 1114,
                "text": "JNK"
            }
        },
        {
            "context": "Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. PURPOSE: To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery. METHODS: Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages. RESULTS: PEO-PCL NPs (180-200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days. CONCLUSIONS: Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 262,
                "text": "HIV"
            }
        },
        {
            "context": "Novel anticoagulants for stroke prevention in atrial fibrillation: current clinical evidence and future developments. Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 700,
                "text": "xa"
            }
        },
        {
            "context": "Phosphorylation of the C-terminal domain of yeast topoisomerase II by casein kinase II affects DNA-protein interaction. Eukaryotic DNA topoisomerase II is an abundant nuclear enzyme that is essential for cell proliferation. This homodimeric enzyme catalyzes the cleavage and re-ligation of double-stranded DNA required to separate replicated sister chromatids. Both biochemical and genetic studies show that its catalytic activity is required for chromosome condensation and segregation, and that its decatenation activity can be stimulated by a variety of protein kinases in vitro. In budding yeast, topoisomerase II is most highly phosphorylated in metaphase, and casein kinase II (CKII) was shown to be the major kinase modifying topoisomerase II. We have investigated the effects of phosphorylation of yeast topoisomerase II by CKII in vitro, by means of gel-retardation and filter binding assays. The phosphorylation of the C terminus of topoisomerase II by CKII appears to increase the stability of the complex formed with linear DNA fragments, while dephosphorylation has the opposite effect. Rephosphorylation of phosphatase-treated topoisomerase II by chicken casein kinase II restores a stable protein-DNA complex using a linear DNA fragment. The enhanced stability of the topoisomerase II-DNA complex is also observed with relaxed circular DNA, but not with supercoiled minicircles, in agreement with published results using topoisomerase II from Drosophila. Limited proteolysis and probing with domain-specific antibodies shows that, with the exception of a weakly modified residue between amino acid residues 660 and 1250, all residues modified by casein kinase II are in the last 180 amino acid residues of yeast topoisomerase II.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 135,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "A family with McLeod syndrome and calpainopathy with clinically overlapping diseases. The authors describe a family with six patients with muscular dystrophy with a variable course. One is a compound heterozygote for CAPN3 mutations (calpainopathy) and the others have a single CAPN3 mutation. Linkage analysis and sequencing revealed a XK gene mutation (McLeod syndrome). This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 337,
                "text": "XK"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 781,
                "text": "xa"
            }
        },
        {
            "context": "Molecular epidemiology and characteristic of virulence gene of community-acquired and hospital-acquired methicillin-resistant Staphylococcus aureus isolates in Sun Yat-sen Memorial hospital, Guangzhou, Southern China. BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of both hospital and community infections globally. It's important to illuminate the differences between community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA), but there have been confusions on the definition, especially for the MRSA isolates identified within 48 h of admission. This study aimed to determine the molecular characteristics and virulence genes profile of CA and HA-MRSA isolates identified less than 48 h after hospital admission in our region. METHODS: A total 62 MRSA isolates identified within 48 h after admission and the clinical data were collected. Antimicrobial susceptibility test (AST) of collected isolates were performed according to the guidelines of Clinical and Laboratory Standards Institute (CLSI) 2015, and staphylococcal cassette chromosome mec (SCCmec) typing, multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and virulence gene profiling were performed to explore the molecular diversity. RESULTS: SCCmec III and sequence type (ST) 239 were the most prevalent SCCmec type and ST in both CA and HA-MRSA groups. HA-MRSA group had higher prevalence of SCCmec III (87.2 %) and ST239 (79.5 %) compared with CA-MRSA (60.9 and 43.4 %, both P < 0.001), while the frequency of SCCmec IV (26.0 %) and ST59 (21.7 %) were higher in CA-MRSA than its counterpart (P < 0.001 and P = 0.003). MRSA-ST239-III was the predominant type in this study (61.3 %, 38/62), especially in HA-MRSA group (76.9 %, 30/39). However, CA-MRSA strains exhibited more diversity in genotypes in this study. Meanwhile, CA-MRSA tended to have lower resistant percentage to non-β-lactams antibiotics but more virulence genes carriage, especially the staphylococcal enterotoxins (SE) genes. Notably, seb gene was only detected in CA-MRSA isolates (52.2 %), likely a significant marker for CA-MRSA isolates. Panton-Valentine leukocidin gene (PVL) was highly detected in both groups, while appeared no significantly different between CA-MRSA (47.8 %) and HA-MRSA (43.6 %). CONCLUSIONS: Our findings support a difference in the molecular epidemiology and virulence genes profile of CA-MRSA and HA-MRSA. Furthermore, this study indicates a possible transmission from HA-MRSA to CA-MRSA, which may cause the overlap of the definition.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 275,
                "text": "MRSA"
            }
        },
        {
            "context": "Viroids: petite RNA pathogens with distinguished talents. Viroids are small, circular, single-stranded RNA molecules that cause several infectious plant diseases. Viroids do not encode any pathogen-specific peptides but nonetheless, the subviral pathogens replicate autonomously and spread in the plant by recruiting host proteins via functional motifs encoded in their RNA genome. During the past couple of years, considerable progress has been made towards comprehending how viroids interact with their hosts. Here, we summarize recent findings on the structure-function relationships of viroids, their strategies and mechanisms of replication and trafficking, and the identification and characterization of interacting host proteins. We also describe the impact of the RNA silencing machinery of plants on viroid RNAs and how this has started to influence our models of viroid replication and pathogenicity.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 58,
                "text": "Viroids"
            }
        },
        {
            "context": "Identification and characterization of polyadenylation signal (PAS) variants in human genomic sequences based on modified EST clustering. A large-scale analysis of human polyadenylation signals was carried out in silico. The most canonical AAUAAA hexamer and its 11 single-nucleotide variants that are most frequent in human genes were used to search for polyadenylation signals in the terminal sequences. Out of 18,277 poly(A) sites that were identified from 26,414 human genes, 82.5% of the sites were found to contain at least one of these 12 hexamers as a polyadenylation signal within 40 nucleotides upstream of the poly(A) site. The rest (17.5%) did not contain any of these hexamers, which suggests the existence of yet unknown signals. A total of 20,347 terminal sequences in close proximity to 12 polyadenylation signals were collected using modified EST clustering technique to establish a large-scale database of polyadenylation signals. To characterize the 12 hexamers, the locations of polyadenylation signals that were identified as \"authentic\" and the uracil contents of the downstream region of the signal were examined. Based on this analysis, the 11 variants of the canonical AAUAAA were identified as possibly forming \"functional\" signals as AAUAAA. Moreover, the observed frequency of 41.9% for AAUAAA was significantly lower than those of other reports, suggesting that the non-canonical variants are more important in the polyadenylation process than frequently recognized. Since the poly(A) sites processed by those non-canonical variants have not been generally annotated in major gene databases, it is important to determine whether the variant hexamers could work as polyadenylation signals that may be responsible for generating heterogeneity of mRNAs by alternative polyadenylation.",
            "question": "Which is the RNA sequence of the canonical polyadenylation signal?",
            "answers": {
                "answer_start": 240,
                "text": "AAUAAA"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 352,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Ser67-phosphorylated inhibitor 1 is a potent protein phosphatase 1 inhibitor. Inhibitor 1 (I-1) is a protein inhibitor of protein phosphatase 1 (PP1), a major eukaryotic Ser/Thr phosphatase. Nonphosphorylated I-1 is inactive, whereas phosphorylated I-1 is a potent PP1 inhibitor. I-1 is phosphorylated in vivo on Thr(35) and Ser(67). Thr(35) is phosphorylated by cAMP-dependent protein kinase (A kinase), and Thr(35)-phosphorylated I-1 inhibits PP1. Until now the kinase that phosphorylates Ser(67) had not been identified and the physiological role of Ser(67) phosphorylation was unknown. In this study we detected a high level of kinase activity in brain extract when a glutathione S-transferase (GST) fusion I-1 mutant containing an Ala substituted for Thr(35) [GST-I-1(T35A)] was used as the substrate. GST-I-1(T35A) kinase and neuronal cdc2-like protein kinase (NCLK) in the brain extract could not be separated from each other by a series of sequential chromatographies. GST-I-1(T35A) kinase immunoprecipitated with anti-NCLK antibody from kinase-active column fractions. Purified NCLK-phosphorylated GST-I-1(T35A) and I-1 (0.7 mole of phosphate per mole of I-1). HPLC phosphopeptide mapping, amino acid sequencing, and site-directed mutagenesis determined that NCLK phosphorylates Ser(67) of I-1. NCLK-phosphorylated I-1 and I-1(T35A) inhibited PP1 with IC(50) values approximately 9.5 and 13. 8 nM, respectively. When compared, A kinase-phosphorylated I-1 was only approximately 1.2 times more inhibitory than NCLK-phosphorylated I-1. Our data indicate that NCLK is a potential in vivo I-1 kinase and that Thr(35) and Ser(67) phosphorylation independently activate I-1.",
            "question": "Which protein is the main inhibitor of protein phosphatase 1 (PP1)?",
            "answers": {
                "answer_start": 78,
                "text": "Inhibitor 1"
            }
        },
        {
            "context": "Anaplastic Lymphoma Kinase as a Cancer Target in Pediatric Malignancies. In this era of more rational therapies, substantial efforts are being made to identify optimal targets. The discovery of translocations involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase in a subset of non-small cell lung cancers has become a paradigm for precision medicine. Notably, ALK was initially discovered as the fusion gene in anaplastic large cell non-Hodgkin lymphoma, a disease predominantly of childhood. The discovery of activating kinase domain mutations of the full-length ALK receptor as the major cause of hereditary neuroblastoma, and that somatically acquired mutations and amplification events often drive the malignant process in a subset of sporadic tumors, has established ALK as a tractable molecular target across histologically diverse tumors in which ALK is a critical mediator of oncogenesis. We are now uncovering the reexpression of this developmentally regulated protein in a broader subset of pediatric cancers, providing therapeutic targeting opportunities for diseases with shared molecular etiology. This review focuses on the role of ALK in pediatric malignancies, alongside the prospects and challenges associated with the development of effective ALK-inhibition strategies.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 316,
                "text": "cancer"
            }
        },
        {
            "context": "Two distinct SECIS structures capable of directing selenocysteine incorporation in eukaryotes. Translation of UGA as selenocysteine requires specific RNA secondary structures in the mRNAs of selenoproteins. These elements differ in sequence, structure, and location in the mRNA, that is, coding versus 3' untranslated region, in prokaryotes, eukaryotes, and archaea. Analyses of eukaryotic selenocysteine insertion sequence (SECIS) elements via computer folding programs, mutagenesis studies, and chemical and enzymatic probing has led to the derivation of a predicted consensus structural model for these elements. This model consists of a stem-loop or hairpin, with conserved nucleotides in the loop and in a non-Watson-Crick motif at the base of the stem. However, the sequences of a number of SECIS elements predict that they would diverge from the consensus structure in the loop region. Using site-directed mutagenesis to introduce mutations predicted to either disrupt or restore structure, or to manipulate loop size or stem length, we show that eukaryotic SECIS elements fall into two distinct classes, termed forms 1 and 2. Form 2 elements have additional secondary structures not present in form 1 elements. By either insertion or deletion of the sequences and structures distinguishing the two classes of elements while maintaining appropriate loop size, conversion of a form 1 element to a functional form 2-like element and of a form 2 to a functional form 1-like element was achieved. These results suggest commonality of function of the two classes. The information obtained regarding the existence of two classes of SECIS elements and the tolerances for manipulations of stem length and loop size should facilitate designing RNA molecules for obtaining high-resolution structural information about these elements.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 425,
                "text": "SECIS"
            }
        },
        {
            "context": "New antipsychotics in schizophrenia: the French experience. Since the beginning of the neuroleptics in 1952, French psychiatrists have proposed a classification of neuroleptics, taking into account the pharmacological and therapeutic differences between these drugs. They distinguished 3 different clinical effects of neuroleptics: sedative effects, effects on the positive symptoms of schizophrenia and effects on the negative symptoms. The effect of some neuroleptics on negative symptoms is recognized by the international community, which considers clozapine to be effective. In France, in most cases, the indication of clozapine is still refractory paranoid schizophrenia. The effect of this atypical neuroleptic on other types of schizophrenic patient is not well known. Remoxipride appears to be as effective in treating psychotic symptoms and to have fewer side effects than haloperidol. Remoxipride is effective for both positive and negative symptoms. Loxapine has been prescribed in France since 1980. Its pharmacological profile is close to that of clozapine: it has dopamine (D2), histamine (H1), serotonin (5-HT2) and adrenergic (alpha 1)-blocking activities. Its best indication seems to be paranoid schizophrenia, although some data suggest bipolar action. The bipolar action of some new neuroleptics is illustrated by amisulpride, a substitute benzamide derivative. The originality of this molecule lies in its two opposite actions at two distinct doses. Doses of 600-1200 mg/day are effective against positive symptoms; 50-150 mg/day improves negative symptoms. This latter effect could be mediated by activation of the dopamine system.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "What disease in Loxapine prominently used for?",
            "answers": {
                "answer_start": 1215,
                "text": "schizophrenia"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 695,
                "text": "naloxone"
            }
        },
        {
            "context": "Suvorexant, a dual orexin receptor antagonist for the management of insomnia. Suvorexant, a dual orexin receptor antagonist for the management of insomnia.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 19,
                "text": "orexin"
            }
        },
        {
            "context": "Is pulmonary arterial hypertension in neurofibromatosis type 1 secondary to a plexogenic arteriopathy? BACKGROUND: Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1. Pulmonary arterial hypertension (PAH) in patients with NF1 is hypothesized to be secondary to an underlying vasculopathy. METHODS: We describe the entity we term NF1-associated PAH (NF1-PAH) in four new patients and update the data on four previously published reports of patients with PAH and NF1. We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH. We report, for the first time, pathologic findings in the autopsy-obtained lung of one patient with NF1-PAH. RESULTS: Patients with NF1-PAH have a generally poor long-term prognosis. In four patients, we observed the mosaic pattern of lung attenuation on a CT scan of the chest, a radiographic finding that can be consistent with an underlying vasculopathy. No mutations or rearrangements in the BMPR2 gene were found. We observed complex plexiform lesions in the one available autopsy specimen. Similar lesions are a hallmark of plexogenic pulmonary arteriopathy and are associated with several severe types of PAH. (Plexiform lesions should not be confused with plexiform neurofibromas, which are distinctive tumors seen in NF1.) CONCLUSIONS: Our findings suggest that NF1 should be considered as being \"associated with PAH as outlined in the Revised Clinical Classification of Pulmonary Hypertension. Understanding the mechanism of PAH in NF1 may inform the pathogenesis of PAH, NF1-PAH itself, and other NF1-associated vasculopathies. The pulmonary vasculature should now be included among the arterial beds affected by NF1 vasculopathy.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 141,
                "text": "NF1"
            }
        },
        {
            "context": "A revised six-kingdom system of life. A revised six-kingdom system of life is presented, down to the level of infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi, Plantae and Chromista. Intermediate high level categories (superkingdom, subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are extensively used to avoid splitting organisms into an excessive number of kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms, Protozoa and Animalia, are subject to the International Code of Zoological Nomenclature, the kingdom Bacteria to the International Code of Bacteriological Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to the International Code of Botanical Nomenclature. Circumscriptions of the kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20 classes; fungal classification at the rank of subclass and above is comprehensively revised. The kingdoms Protozoa and Animalia are modified in the light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not Protozoa, and that mesozoans are related to bilaterian animals. Animalia are divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa, Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other phyla). Several new higher level groupings are made in the animal kingdom including three new phyla: Acanthognatha (rotifers, acanthocephalans, gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not as a separate kingdom. The recently revised phylum Rhizopoda is modified further by adding more flagellates and removing some 'rhizopods' and is therefore renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa and Archamoebae (both now infraphyla) as a new subphylum Conosa within the phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the (formerly microsporidian) metchnikovellids are now both placed within the phylum Sporozoa. These changes make a total of only 13 currently recognized protozoan phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is modified in circumscription by adding the Discicristata, a new infrakingdom comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in relation to the principles of megasystematics, here defined as systematics that concentrates on the higher levels of classes, phyla, and kingdoms. These principles also make it desirable to rank Archaebacteria as an infrakingdom of the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising all bacteria bounded by a single membrane. The bacterial subkingdom Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides in the outer leaflet of the outer membrane and phospholipids in its inner leaflet. (ABSTRACT TRUNCATED)",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 965,
                "text": "Fungi"
            }
        },
        {
            "context": "Biofoams and natural protein surfactants. Naturally occurring foam constituent and surfactant proteins with intriguing structures and functions are now being identified from a variety of biological sources. The ranaspumins from tropical frog foam nests comprise a range of proteins with a mixture of surfactant, carbohydrate binding and antimicrobial activities that together provide a stable, biocompatible, protective foam environment for developing eggs and embryos. Ranasmurfin, a blue protein from a different species of frog, displays a novel structure with a unique chromophoric crosslink. Latherin, primarily from horse sweat, but with similarities to salivary, oral and upper respiratory tract proteins, illustrates several potential roles for surfactant proteins in mammalian systems. These proteins, together with the previously discovered hydrophobins of fungi, throw new light on biomolecular processes at air-water and other interfaces. This review provides a perspective on these recent findings, focussing on structure and biophysical properties.",
            "question": "What is the color of the protein Ranasmurfin?",
            "answers": {
                "answer_start": 485,
                "text": "blue"
            }
        },
        {
            "context": "Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1104,
                "text": "XK"
            }
        },
        {
            "context": "Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas. BACKGROUND: Facial nerve preservation surgery for large vestibular schwannomas is a novel strategy for maintaining normal nerve function by allowing residual tumor adherent to this nerve or root-entry zone. OBJECTIVE: To report, in a retrospective study, outcomes for large Koos grade 3 and 4 vestibular schwannomas. METHODS: After surgical treatment for vestibular schwannomas in 52 patients (2004-2013), outcomes included extent of resection, postoperative hearing, and facial nerve function. Extent of resection defined as gross total, near total, or subtotal were 7 (39%), 3 (17%), and 8 (44%) in 18 patients after retrosigmoid approaches, respectively, and 10 (29.5%), 9 (26.5%), and 15 (44%) for 34 patients after translabyrinthine approaches, respectively. RESULTS: Hearing was preserved in 1 (20%) of 5 gross total, 0 of 2 near-total, and 1 (33%) of 3 subtotal resections. Good long-term facial nerve function (House-Brackmann grades of I and II) was achieved in 16 of 17 gross total (94%), 11 of 12 near-total (92%), and 21 of 23 subtotal (91%) resections. Long-term tumor control was 100% for gross total, 92% for near-total, and 83% for subtotal resections. Postoperative radiation therapy was delivered to 9 subtotal resection patients and 1 near-total resection patient. Follow-up averaged 33 months. CONCLUSION: Our findings support facial nerve preservation surgery in becoming the new standard for acoustic neuroma treatment. Maximizing resection and close postoperative radiographic follow-up enable early identification of tumors that will progress to radiosurgical treatment. This sequential approach can lead to combined optimal facial nerve function and effective tumor control rates.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 374,
                "text": "vestibular schwannoma"
            }
        },
        {
            "context": "Arf6-GEF BRAG1 regulates JNK-mediated synaptic removal of GluA1-containing AMPA receptors: a new mechanism for nonsyndromic X-linked mental disorder. Activity-dependent modifications of excitatory synapses contribute to synaptic maturation and plasticity, and are critical for learning and memory. Consequently, impairments in synapse formation or synaptic transmission are thought to be responsible for several types of mental disabilities. BRAG1 is a guanine nucleotide exchange factor for the small GTP-binding protein Arf6 that localizes to the postsynaptic density of excitatory synapses. Mutations in BRAG1 have been identified in families with X-linked intellectual disability (XLID). These mutations mapped to either the catalytic domain or an IQ-like motif; however, the pathophysiological basis of these mutations remains unknown. Here, we show that the BRAG1 IQ motif binds apo-calmodulin (CaM), and that calcium-induced CaM release triggers a reversible conformational change in human BRAG1. We demonstrate that BRAG1 activity, stimulated by activation of NMDA-sensitive glutamate receptors, depresses AMPA receptor (AMPA-R)-mediated transmission via JNK-mediated synaptic removal of GluA1-containing AMPA-Rs in rat hippocampal neurons. Importantly, a BRAG1 mutant that fails to activate Arf6 also fails to depress AMPA-R signaling, indicating that Arf6 activity is necessary for this process. Conversely, a mutation in the BRAG1 IQ-like motif that impairs CaM binding results in hyperactivation of Arf6 signaling and constitutive depression of AMPA transmission. Our findings reveal a role for BRAG1 in response to neuronal activity with possible clinical relevance to nonsyndromic XLID.",
            "question": "Which disease is linked to mutations within BRAG1?",
            "answers": {
                "answer_start": 651,
                "text": "X-linked intellectual disability"
            }
        },
        {
            "context": "Nascent RNA cleavage by purified ternary complexes of vaccinia RNA polymerase. Ternary complexes of vaccinia virus RNA polymerase containing 3'-OMeGMP-arrested transcripts were purified by native gel electrophoresis. These complexes resumed elongation in situ when gel slices were incubated with magnesium and NTPs. Elongation occurred in the absence of pyrophosphate, suggesting that the blocking 3'-OMeGMP residue was removed via a novel pathway. We show that purified elongation complexes contain an intrinsic nuclease activity that shortens nascent RNA from the 3'-end. RNA cleavage was absolutely dependent on a divalent cation and was stimulated by CTP. The initial 5' cleavage product remained associated with the ternary complex and could be elongated in the presence of NTPs. Multiple stepwise cleavages generated progressively shorter chains. Purified ternary complexes containing 3'-OH-terminated RNAs also displayed nuclease activity. Involvement of the vaccinia RNA polymerase subunit rpo30 in the transcript-shortening reaction is suggested based on sequence similarity of rpo30 to mammalian protein SII (TFIIS), an extrinsic transcription factor required for nascent RNA cleavage by RNA polymerase II (Reines, D. (1991) J. Biol. Chem. 267, 3795-3800).",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 1119,
                "text": "TFIIS"
            }
        },
        {
            "context": "Exosome enrichment by ultracentrifugation and size exclusion chromatography. Exosomes are a subset of extracellular vesicles (EVs) that have important roles in intercellular communication. They contain and carry bioactive molecules within their membranes which are delivered to target cells. Reproducible isolation and enrichment of these exosomes will aid in evaluation of cellular communication. We present an approach that involved the pre-processing of plasma, combined with ultracentrifugation (UC) and size exclusion chromatography (SEC) to isolate EVs and subsequently enrich exosomes. Four variations of this approach (denoted methods I to IV) were compared. Coupling an ultracentrifugation method with size exclusion chromatography (Method II) provided the best yield by nanoparticle tracking analyses (NTA), the presence of the exosomal markers CD63, Flotillin-1 and TSG-101 (immunoblotting) and showed exosome morphology using transmission electron microscopy (TEM). This method provides an efficient way to enrich the exosomes from blood (plasma), which could be potentially employed for clinical diagnostic assessment and therapeutic intervention.",
            "question": "What is an exosome?",
            "answers": {
                "answer_start": 77,
                "text": "Exosomes are a subset of extracellular vesicles (EVs) that have important roles in intercellular communication. They contain and carry bioactive molecules within their membranes which are delivered to target cells."
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 73,
                "text": "RADAR"
            }
        },
        {
            "context": "Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 1640,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Preparative HPLC separation of underivatized amino acids for isotopic analysis. Single-compound analysis of stable or radio-isotopes has found application in a number of fields ranging from archaeology to forensics. Often, the most difficult part of these analyses is the development of a method for isolating the compounds of interest.Here, we describe three complementary preparative HPLC procedures suitable for separating and isolating single amino acids from bone collagen or hair keratin with minimal isotopic contamination. Using preparative reversed-phase, ion-pair, or mixed-mode chromatography of underivatized amino acids in aqueous mobile phases, single amino acids can be isolated and further analyzed using mass spectrometric techniques.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 469,
                "text": "collagen"
            }
        },
        {
            "context": "α-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 315,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "[Clinical experience in benzodiazepine antagonist]. Flumazenil, a potent benzodiazepine antagonist, is a newly synthetic imidazo-benzodiazepine, which blocks the neurological effects of benzodiazepines. The purpose of this study was to evaluate the effects of this agent in reversal of benzodiazepine overdose and differentiation of comatous patients with drug overdose. Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration. Three cases with different drug history and variant response after flumazenil treatment were also illustrated and discussed. The dosage of flumazenil used in this study ranged from 0.25 mg to 3 mg (average 0.87 +/- 0.74 mg). We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 708,
                "text": "flumazenil"
            }
        },
        {
            "context": "Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease. The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing. Data from preclinical studies and clinical trials suggest that gevokizumab is a potentially effective and well-tolerated treatment for the indicated diseases. At the time of publication, phase II clinical trials were ongoing in patients with T1D, T2D and RA, with the T2D trials assessing key cardiovascular markers. Following promising data from a recent pilot trial, XOMA was also planning a phase I/II trial of gevokizumab for the potential treatment of uveitis in patients with the vasculitic inflammatory disorder Behçet's disease and the autoinflammatory conditions familial cold autoinflammatory syndrome and Muckle-Wells syndrome.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 21,
                "text": "IL-1β"
            }
        },
        {
            "context": "McLeod syndrome resulting from a novel XK mutation. McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1081,
                "text": "XK"
            }
        },
        {
            "context": "TFEB regulates lysosomal proteostasis. Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 839,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model. OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. METHODS: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. RESULTS: Gait deficiency in untreated rats was present 3-7 days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. CONCLUSIONS: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 192,
                "text": "nerve growth factor"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 424,
                "text": "TFIIS"
            }
        },
        {
            "context": "Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 190,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease. Here we define the role of phosphorylation of Ser129 in alpha-synuclein toxicity and inclusion formation using a Drosophila model of Parkinson disease. Mutation of Ser129 to alanine to prevent phosphorylation completely suppresses dopaminergic neuronal loss produced by expression of human alpha-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances alpha-synuclein toxicity. The G protein-coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances alpha-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating alpha-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity.",
            "question": "Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?",
            "answers": {
                "answer_start": 160,
                "text": "serine 129"
            }
        },
        {
            "context": "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease. BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 141,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Increased CXCR4 expression in AsPC1 pancreatic carcinoma cells with RNA interference-mediated knockdown of DNMT1 and DNMT3B. The effect of DNA methylation on CXCR4 expression has been demonstrated in pancreatic cancer and melanoma cells, but little is known about the effect of DNA methyltransferases 1 and 3 (DNMT1 and DNMT3B) on CXCR4 expression. Employing lentiviral vectors, we created stable RNA interference-mediated knockdown of DNMT1 and DNMT3B in AsPC1 pancreatic cancer cells. Using reverse transcription real-time quantitative PCR and flow cytometric analysis, we evaluated the increase in the expression of CXCR4 transcript and protein levels in these cells. Bisulfite sequencing analysis showed that the level of promoter demethylation appeared more effective in cells with knockdown of DNMT1 than in those with DNMT3B knockdown. Furthermore, the combined RNA interference knockdown of both DNMT1 and DNMT3B increased promoter demethylation, leading to a slight increase in CXCR4 expression. However, the demethylating agent 5-Aza-2'-deoxycytidine exhibited the strongest effect on promoter demethylation, which correlated with the highest production of CXCR4 transcript and protein in AsPC1 cells. Our results indicate that DNMT1 plays the main role in maintenance of methylation of CXCR4 promoter, while DNMT3B may function as an accessory DNA methyltransferase to modulate CXCR4 expression in AsPC1 cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1238,
                "text": "DNMT1"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 90,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Several lines of recent evidence support a role for chromatin in splicing regulation. Here, we show that splicing can also contribute to histone modification, which implies bidirectional communication between epigenetic mechanisms and RNA processing. Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with histone H3 Lys36 trimethylation (H3K36me3) relative to intronless genes. In intron-containing genes, H3K36me3 marking is proportional to transcriptional activity, whereas in intronless genes, H3K36me3 is always detected at much lower levels. Furthermore, splicing inhibition impairs recruitment of H3K36 methyltransferase HYPB (also known as Setd2) and reduces H3K36me3, whereas splicing activation has the opposite effect. Moreover, the increase of H3K36me3 correlates with the length of the first intron, consistent with the view that splicing enhances H3 methylation. We propose that splicing is mechanistically coupled to recruitment of HYPB/Setd2 to elongating RNA polymerase II.",
            "question": "What histone trimethylation has been associated to RNA splicing?",
            "answers": {
                "answer_start": 541,
                "text": "H3K36me3"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 614,
                "text": "IL-1β"
            }
        },
        {
            "context": "Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer's disease. Alzheimer's disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI's) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD. Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials. Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI's and NMDA receptor antagonists for the symptomatic treatment of AD.",
            "question": "What does intepirdine target?",
            "answers": {
                "answer_start": 948,
                "text": "5-HT6"
            }
        },
        {
            "context": "Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase. Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm and +138,250/mm) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 65,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "The nucleotide sequence of Saccharomyces cerevisiae chromosome IV. The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome IV has been determined. Apart from chromosome XII, which contains the 1-2 Mb rDNA cluster, chromosome IV is the longest S. cerevisiae chromosome. It was split into three parts, which were sequenced by a consortium from the European Community, the Sanger Centre, and groups from St Louis and Stanford in the United States. The sequence of 1,531,974 base pairs contains 796 predicted or known genes, 318 (39.9%) of which have been previously identified. Of the 478 new genes, 225 (28.3%) are homologous to previously identified genes and 253 (32%) have unknown functions or correspond to spurious open reading frames (ORFs). On average there is one gene approximately every two kilobases. Superimposed on alternating regional variations in G+C composition, there is a large central domain with a lower G+C content that contains all the yeast transposon (Ty) elements and most of the tRNA genes. Chromosome IV shares with chromosomes II, V, XII, XIII and XV some long clustered duplications which partly explain its origin.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 177,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons. The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. We have compared the chromosomal mobilization efficiency and insertion site preference of the two transposons mobilized from the same donor site in mouse embryonic stem (ES) cells under conditions in which there were no selective constraints on the transposons' insertion sites. Compared with Sleeping Beauty, PiggyBac exhibits higher transposition efficiencies, no evidence for local hopping and a significant bias toward reintegration in intragenic regions, which demonstrate its utility for insertional mutagenesis. Although Sleeping Beauty had no detectable genomic bias with respect to insertions in genes or intergenic regions, both Sleeping Beauty and PiggyBac transposons displayed preferential integration into actively transcribed loci.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 521,
                "text": "PiggyBac"
            }
        },
        {
            "context": "McLeod syndrome: life-long neuropsychiatric disorder due to a novel mutation of the XK gene. A 50-year-old man presented with worsening, virtually lifelong, chorea and progressive behavioural disturbance, involving disinhibition and hoarding, over 10 years. Clinical assessment revealed chorea, dysarthria, areflexia, an inappropriately jovial, impulsive manner and neuropsychological evidence of frontosubcortical dysfunction. Investigation results included an elevated creatine kinase, caudate atrophy and hypoperfusion, acanthocytes in the peripheral blood and the McLeod phenotype. DNA studies demonstrated a single-base deletion at position 172 in exon 1 of the XK gene, giving rise to a premature stop codon at position 129 in exon 2.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 667,
                "text": "XK"
            }
        },
        {
            "context": "A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had > 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including > grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 51,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Dermatitis herpetiformis presenting as ataxia in a child. Dermatitis herpetiformis and coeliac disease are gluten-sensitive diseases that share immunopathological mechanisms. Neurological disorders are reported in both diseases, being more frequent in coeliac disease. Dermatitis herpetiformis is rare in paediatric populations and only sporadic cases with neurological dysfunction are reported. Uncertainty exists as to whether early treatment may stop or reverse neurological symptoms. We describe here the case of a child presenting with a rash and ataxia, diagnosed with dermatitis herpetiformis, in whom neurological symptoms and signs regressed after treatment.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 58,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 0,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 733,
                "text": "MethPed"
            }
        },
        {
            "context": "Distinction between upper and lower gastrointestinal perforation: usefulness of the periportal free air sign on computed tomography. PURPOSE: To evaluate the usefulness of the periportal free air (PPFA) sign on computed tomography (CT) to distinguish upper from lower gastrointestinal (GI) tract perforation. MATERIALS AND METHODS: During a 30-month period, we retrospectively analyzed abdominal CT images of 53 consecutive patients with surgically proven GI tract perforation. We divided the patients into two groups, i.e. upper and lower GI tract perforation groups. According to the distribution of free air, we divided the peritoneal cavity into supramesocolic compartment and inframesocolic compartment. We observed the presence or absence of free air in each compartment in each group. When there was free air in the periportal area, it was defined as periportal free air (PPFA) and the sign was positive. To evaluate the usefulness of the PPFA sign, we compared the PPFA sign with the falciform ligament sign and the ligamentum teres sign, both of which are well-known CT signs of pneumoperitoneum. Statistical analyses were performed with univariate and multivariate analyses using SPSS version 11.5 for significant findings among the CT signs. RESULTS: Free air was seen in supramesocolic compartment in 29 of 30 (97%) patients in the upper GI perforation group and in 17 of 23 (74%) in the lower GI perforation group. Free air in inframesocolic compartment did not show significant difference in either group (p=.16). The PPFA sign was seen in 28 of 30 (93%) patients with upper GI tract perforation, but in only 8 of 23 (35%) patients with lower GI tract perforation (p<.0001). The falciform ligament sign was seen in 24 of 30 (80%) patients with upper GI tract perforation and in 10 of 23 (43%) patients with lower GI tract perforation (p=.020). The ligamentum teres sign was seen in 16 of 30 (53%) patients with upper GI tract perforation and in 2 of 23 (8%) patients with lower GI tract perforation (p=.008). Multivariate logistic regression analysis showed that the PPFA sign was the only variable, which adjusted odds ratio of 15.5 (p=.002). CONCLUSION: The PPFA sign is a useful finding which can help to distinguish upper from lower GI tract perforation. When this sign is present, upper GI tract perforation is strongly suggested.",
            "question": "Falciform ligament sign is characteristic to which disease?",
            "answers": {
                "answer_start": 1088,
                "text": "pneumoperitoneum"
            }
        },
        {
            "context": "The CLN3 gene is a novel molecular target for cancer drug discovery. Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons attributable to defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. CLN3 negatively modulates endogenous ceramide levels in NT2 cells and acts upstream of ceramide generation. Because defects in regulation of apoptosis are involved in the development of cancer, we evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. We also observed the effect of the blocking of CLN3 protein expression on cancer cell growth, survival, ceramide production, and apoptosis by using an adenovirus-bearing antisense CLN3 construct. We show that CLN3 mRNA and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse melanoma and breast carcinoma cancer cell lines. We found CLN3 expression is 22-330% higher than in corresponding normal colon control tissue in 8 of 10 solid colon tumors. An adenovirus-expressing antisense CLN3 (Ad-AS-CLN3) blocks CLN3 protein expression in DU-145, BT-20, SW1116, and T98g cancer cell lines as seen by Western blot. Blocking of CLN3 expression using Ad-AS-CLN3 inhibits growth and viability of cancer cells. It also causes elevation in endogenous ceramide production through de novo ceramide synthesis and results in increased apoptosis as shown by propidium iodide and JC-1 staining. This suggests that Ad-AS-CLN3 may be an option for therapy in some cancers. More importantly these results suggest that CLN3 is a novel molecular target for cancer drug discovery.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 1164,
                "text": "lung"
            }
        },
        {
            "context": "A first-in-class NAE inhibitor, MLN4924, blocks lentiviral infection in myeloid cells by disrupting neddylation-dependent Vpx-mediated SAMHD1 degradation. MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells. SAMHD1 is required for MLN4924-mediated SIVmac inhibition. Our findings indicate the potential efficacy of inhibiting neddylation as an antiretroviral strategy and identify the readily available anticancer drug MLN4924 as a candidate agent for that purpose.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 213,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. AIM: Fostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHOD: Three clinical studies were conducted in healthy subjects: (A) A single ascending dose study for R406 with doses ranging from 80-600 mg, (B) a single- and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg twice daily and (C) a study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS: These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension and steady-state was achieved after 3-4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change. CONCLUSION: Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once daily or twice daily oral administration of fostamatinib.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 282,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 668,
                "text": "Nf1"
            }
        },
        {
            "context": "Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.",
            "question": "What do nerve-associated peripheral glial progenitors give rise to?",
            "answers": {
                "answer_start": 18,
                "text": "Parasympathetic neurons"
            }
        },
        {
            "context": "Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes. Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such as IkappaBalpha or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-kappaB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-kappaB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-kappaB-activating pathway.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 1120,
                "text": "H3K4"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1914,
                "text": "IL-1β"
            }
        },
        {
            "context": "Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex. The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 306,
                "text": "Swr1"
            }
        },
        {
            "context": "Transcranial magnetic stimulation for evaluation of motor cortical excitability in restless legs syndrome/Willis-Ekbom disease. There is no consensus about mechanisms underlying restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). Cortical excitability may be abnormal in RLS. Transcranial magnetic stimulation (TMS) can provide insight about cortical excitability. We reviewed studies about measures of excitability to TMS in RLS. Original studies published between January 1999 and January 2015 were searched in PubMed, Scopus, and Web of Science databases. Inclusion criteria were as follows: original studies involving primary RLS in patients from both sexes and ages between 18 and 85 years; TMS protocols clearly described; and they were written in English, in peer-reviewed journals. Fifteen manuscripts were identified. TMS protocols were heterogeneous across studies. Resting motor threshold, active motor threshold, and amplitudes of motor-evoked potentials were typically reported to be normal in RLS. A reduction in short-interval intracortical inhibition (SICI) was the most consistent finding, whereas conflicting results were described in regard to short-interval intracortical facilitation and the contralateral silent period. Decreased SICI can be reversed by treatment with dopaminergic agonists. Plasticity in the motor cortex and sensorimotor integration may be disrupted. TMS may become a useful biomarker of responsiveness to drug treatment in RLS. The field can benefit from increases in homogeneity and sizes of samples, as well as from decrease in methodological variability across studies.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 178,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Netherton syndrome associated with growth hormone deficiency. Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by ichthyosiform scaling, hair abnormalities, and variable atopic features. Mutations in the serine protease inhibitor Kazal type 5 (SPINK5) gene leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency cause NS. Growth retardation is a classic feature of NS, but growth hormone (GH) deficiency with subsequent response to GH therapy is not documented in the literature. It is proposed that a lack of inhibition of proteases due to a deficiency of LEKTI in the pituitary gland leads to the overprocessing of human GH in NS. Herein we report three patients with NS who had growth retardation associated with GH deficiency and responded well to GH therapy.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 343,
                "text": "LEKTI"
            }
        },
        {
            "context": "ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. BACKGROUND & AIMS: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC. RESULTS: ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β inhibits apoptosis emanating from mitochondria. CONCLUSIONS: Thus, ΔNp73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the ΔNp73ß target gene signature can predict the prognosis of patients suffering from HCC.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 359,
                "text": "7"
            }
        },
        {
            "context": "Over-expression of CLN3P, the Batten disease protein, inhibits PANDER-induced apoptosis in neuroblastoma cells: further evidence that CLN3P has anti-apoptotic properties. Juvenile neuronal ceroid-lipofuscinosis (JNCL) or Batten/Spielmeyer-Vogt-Sjogren disease (OMIM #204200) is one of a group of nine clinically related inherited neurodegenerative disorders (CLN1-9). JNCL results from mutations in CLN3 on chromosome 16p12.1. The neuronal loss in Batten disease has been shown to be due to a combination of apoptosis and autophagy suggesting that CLN3P, the defective protein, may have an anti-neuronal death function. PANDER (PANcreatic-DERived factor) is a novel cytokine that was recently cloned from pancreatic islet cells. PANDER is specifically expressed in the pancreatic islets, small intestine, testis, prostate, and neurons of the central nervous system, and has been demonstrated to induce apoptosis. In this study, we over-expressed CLN3P in SH-SY5Y neuroblastoma cells and monitored the effects on PANDER-induced apoptosis. CLN3P significantly increased the survival rate of the SH-SY5Y cells in this system. This study provides additional evidence that the function of CLN3P is related to preventing neuronal apoptosis.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 368,
                "text": "JNCL"
            }
        },
        {
            "context": "TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. The heart responds to injury and chronic pressure overload by pathologic growth and remodeling, which frequently result in heart failure and sudden death. Calcium-dependent signaling pathways promote cardiac growth and associated changes in gene expression in response to stress. The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate cation entry into cells in response to a variety of signals, and in skeletal muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is increased in response to neurostimulation and calcineurin signaling. Here we show that TRPC6 was upregulated in mouse hearts in response to activated calcineurin and pressure overload, as well as in failing human hearts. Two conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of beta-myosin heavy chain, a sensitive marker for pathologic hypertrophy. These findings implicate TRPC6 as a positive regulator of calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory loop that drives pathologic cardiac remodeling.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 410,
                "text": "calcineurin"
            }
        },
        {
            "context": "Effectiveness of Fractionated Plasma Separation and Absorption as a Treatment for Amanita Phalloides Poisoning. BACKGROUND Fractionated plasma separation and absorption (FPSA) is an extracorporeal liver support method that detoxifies accumulated toxins. There are limited data of its use in the treatment of Amanita phalloides intoxication. The objective of this study was to investigate whether FPSA before liver transplantation improves patients' short-term post liver transplantation survival in Amanita phalloides poisoning. MATERIAL AND METHODS The study population consisted of ten patients who had liver transplantation (LT) due to acute liver failure (ALF) caused by Amanita phalloides poisoning. Six patients were treated with FPSA before liver transplantation. All the patients who were started on FPSA were also placed on the liver transplantation list according to emergent liver transplantation criteria. RESULTS Patients treated with FPSA were in a more severe clinical condition presenting in higher mean MELD, total bilirubin, INR and ammonia along with more frequent hypoglycemia and hepatic encephalopathy grade 3/4. FPSA group had longer mean waiting time on the recipient list (3.5 vs. 1.25 days) but inferior thirty-day survival rate (16.5% vs. 100%). CONCLUSIONS When conservative medical modalities are ineffective, the only treatment for Amanita phalloides poisoning is a liver transplant. Although FPSA treated patients had inferior post-LT survival, FPSA was found to prolong the pre surgical waiting time for critically ill patients, consequently giving a chance of life-saving procedure.",
            "question": "Which mushroom is poisonous, Amanita phalloides or Agaricus Bisporus",
            "answers": {
                "answer_start": 499,
                "text": "Amanita phalloides"
            }
        },
        {
            "context": "Identification by in silico and in vitro screenings of small organic molecules acting as reversible inhibitors of kallikreins. Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrome phenotype. The efficacy and mechanism of inhibition of the identified new families of organic compounds were analyzed not only for hK5 but also on other proteases implicated in the cascades (hK7, hK14 and matriptase). These inhibitors are nontoxic on healthy human keratinocytes and are structurally different from traditional serine protease inhibitors validating their potential utility as initial hits to control proteolytic disorders observed in dermatological pathologies such as Netherton syndrome.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 230,
                "text": "LEKTI"
            }
        },
        {
            "context": "Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate. Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 364,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Clinical and Angioarchitectural Risk Factors Associated with Intracranial Hemorrhage in Dural Arteriovenous Fistulas: A Single-Center Retrospective Study. PURPOSE: To investigate which clinical and angioarchitectural features were associated with the occurrence of intracranial hemorrhage in patients with intracranial dural arteriovenous fistulas (DAVFs). MATERIALS AND METHODS: We retrospectively reviewed the clinical and angioarchitectural features of 236 consecutive patients diagnosed with DAVF in our department from April 2009 to November 2013. Two groups of patients, with or without intracranial hemorrhage as clinical presentation at the initial diagnosis, were analysed to identify the differences in clinical and angioarchitectural features in univariate analysis. A multivariate logistic regression model was also developed to assess the independent contribution of the potential risk factors. Associations were considered significant for p<0.05. RESULTS: Fifty-six patients (23.7%) presented with intracranial hemorrhage at the initial diagnosis of DAVF. In univariate analysis, male patients (p = 0.002), patients with medical history of smoking (p<0.001) or alcohol consumption (p = 0.022), and DAVFs located at the tentorium (p = 0.010), frontalbasal (p = 0.007), foramen magnum (p = 0.043) or cerebral convexity (p<0.001) were associated with an increased risk of intracranial hemorrhage. A higher risk of hemorrhagic occurrence was also observed in DAVFs with superficial cortical venous drainage (p<0.001), deep venous drainage (p = 0.003), occluded venous sinus (p<0.032), or higher Borden type (p<0.001). A multivariate logistic regression model showed that intracranial hemorrhage in patients with DAVFs was correlated with higher Borden classification (OR 5.880; 95% CI, 3.370-10.257; p<0.001). CONCLUSION: Venous drainage pattern was the only independent risk factor of intracranial hemorrhage in our patients with intracranial DAVF. The other potential risk factors may be confounding factors in predicting intracranial hemorrhage.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 1722,
                "text": "DAVF"
            }
        },
        {
            "context": "Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (deltaN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not deltaNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 516,
                "text": "7"
            }
        },
        {
            "context": "Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received > 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade > 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade > 3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 93,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "A case of Mowat-Wilson syndrome caused by a truncating mutation within exon 8 of the ZEB2 gene. Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. The cause of MWS is a de novo mutation in the ZEB2 gene. This report describes a Turkish boy who was clinically diagnosed with MWS and had his diagnosis confirmed by molecular analysis of the ZEB2 gene. The investigation identified a heterozygous complex rearrangement in exon 8 of ZEB2, specifically a 48-nucleotide deletion and a 44-nucleotide insertion that caused a frameshift. MWS is a relatively newly identified disorder, and even MWS patients without Hirschsprung disease can be diagnosed easily based on clinical findings alone.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 85,
                "text": "ZEB2"
            }
        },
        {
            "context": "Suvorexant: something new for sleep? Orexin, also called hypocretin, is a neuropeptide that acts on central nervous system receptors to promote arousal. Suvorexant, its receptor antagonist, generates interest as a medication to treat insomnia. Suvorexant helps in decreasing wakefulness by counteracting orexin activity. Its low side effect potential may offer considerable benefit. Compared with other sleep aids, diminished drowsiness and less cognitive dysfunction is an advantage. Now approved for clinical use, an apparent lack of rebound insomnia or drug dependence potential might make suvorexant a good choice pharmacotherapy for patients with insomnia.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 304,
                "text": "orexin"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor. Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 322,
                "text": "telomerase"
            }
        },
        {
            "context": "Diversity and evolution of multiple orc/cdc6-adjacent replication origins in haloarchaea. BACKGROUND: While multiple replication origins have been observed in archaea, considerably less is known about their evolutionary processes. Here, we performed a comparative analysis of the predicted (proved in part) orc/cdc6-associated replication origins in 15 completely sequenced haloarchaeal genomes to investigate the diversity and evolution of replication origins in halophilic Archaea. RESULTS: Multiple orc/cdc6-associated replication origins were predicted in all of the analyzed haloarchaeal genomes following the identification of putative ORBs (origin recognition boxes) that are associated with orc/cdc6 genes. Five of these predicted replication origins in Haloarcula hispanica were experimentally confirmed via autonomous replication activities. Strikingly, several predicted replication origins in H. hispanica and Haloarcula marismortui are located in the distinct regions of their highly homologous chromosomes, suggesting that these replication origins might have been introduced as parts of new genomic content. A comparison of the origin-associated Orc/Cdc6 homologs and the corresponding predicted ORB elements revealed that the replication origins in a given haloarchaeon are quite diverse, while different haloarchaea can share a few conserved origins. Phylogenetic and genomic context analyses suggested that there is an original replication origin (oriC1) that was inherited from the ancestor of archaea, and several other origins were likely evolved and/or translocated within the haloarchaeal species. CONCLUSION: This study provides detailed information about the diversity of multiple orc/cdc6-associated replication origins in haloarchaeal genomes, and provides novel insight into the evolution of multiple replication origins in Archaea.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 108,
                "text": "multiple"
            }
        },
        {
            "context": "Evidence Supporting Idarucizumab for the Reversal of Dabigatran. Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or in those requiring an urgent procedure. In an interim analysis of the first 90 participants, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88%-98% of participants, and there were no safety concerns, with no deaths or serious adverse events being attributable to idarucizumab. Supported by these interim results, idarucizumab has been approved in the United States and the European Union for use when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in patients with life-threatening or uncontrolled bleeding. Clinical use of idarucizumab should follow the same processes as patient enrollment in this study, which is projected to be completed in 2016. The outcomes achieved with this specific reversal agent are likely to be of continued interest to treating physicians.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 137,
                "text": "dabigatran"
            }
        },
        {
            "context": "Restless leg syndrome: is it a real problem? Restless legs syndrome (RLS) is a common condition that is frequently unrecognized, misdiagnosed and poorly managed. It is characterized by uncomfortable sensations deep in the legs developing at rest that compel the person to move; symptoms are worst at night and sleep disturbance is common. RLS occurs in 7%-11% of the population in Western countries, and many such people experience troublesome symptoms. Primary RLS is familial in up to two thirds of patients. RLS may also be secondary to a number of conditions including iron deficiency, pregnancy and end-stage renal failure and, perhaps, neuropathy. Secondary RLS is most common in those presenting for the first time in later life. The pathogenesis of RLS probably involves the interplay of systemic or brain iron deficiency and impaired dopaminergic neurotransmission in the subcortex of the brain. RLS is very responsive to dopaminergic therapies. Rebound of RLS symptoms during the early morning and development of severe symptoms earlier in the day (augmentation) are problematic in those treated for a prolonged period with levodopa. Consequently, dopamine agonists have become first line treatment. Anti-convulsant medications and opioids are helpful in some patients. Correction of underlying problem wherever possible is important in the management of secondary RLS.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 814,
                "text": "iron"
            }
        },
        {
            "context": "Biochemical characterization of major bone-matrix proteins using nanoscale-size bone samples and proteomics methodology. There is growing evidence supporting the need for a broad scale investigation of the proteins and protein modifications in the organic matrix of bone and the use of these measures to predict fragility fractures. However, limitations in sample availability and high heterogeneity of bone tissue cause unique experimental and/or diagnostic problems. We addressed these by an innovative combination of laser capture microscopy with our newly developed liquid chromatography separation methods, followed by gel electrophoresis and mass spectrometry analysis. Our strategy allows in-depth analysis of very limited amounts of bone material, and thus, can be important to medical sciences, biology, forensic, anthropology, and archaeology. The developed strategy permitted unprecedented biochemical analyses of bone-matrix proteins, including collagen modifications, using nearly nanoscale amounts of exceptionally homogenous bone tissue. Dissection of fully mineralized bone-tissue at such degree of homogeneity has not been achieved before. Application of our strategy established that: (1) collagen in older interstitial bone contains higher levels of an advanced glycation end product pentosidine then younger osteonal tissue, an observation contrary to the published data; (2) the levels of two enzymatic crosslinks (pyridinoline and deoxypiridinoline) were higher in osteonal than interstitial tissue and agreed with data reported by others; (3) younger osteonal bone has higher amount of osteopontin and osteocalcin then older interstitial bone and this has not been shown before. Taken together, these data show that the level of fluorescent crosslinks in collagen and the amount of two major noncollagenous bone matrix proteins differ at the level of osteonal and interstitial tissue. We propose that this may have important implications for bone remodeling processes and bone microdamage formation.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 957,
                "text": "collagen"
            }
        },
        {
            "context": "Daratumumab granted breakthrough drug status. Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 586,
                "text": "CD38"
            }
        },
        {
            "context": "mpMoRFsDB: a database of molecular recognition features in membrane proteins. SUMMARY: Molecular recognition features (MoRFs) are small, intrinsically disordered regions in proteins that undergo a disorder-to-order transition on binding to their partners. MoRFs are involved in protein-protein interactions and may function as the initial step in molecular recognition. The aim of this work was to collect, organize and store all membrane proteins that contain MoRFs. Membrane proteins constitute ∼30% of fully sequenced proteomes and are responsible for a wide variety of cellular functions. MoRFs were classified according to their secondary structure, after interacting with their partners. We identified MoRFs in transmembrane and peripheral membrane proteins. The position of transmembrane protein MoRFs was determined in relation to a protein's topology. All information was stored in a publicly available mySQL database with a user-friendly web interface. A Jmol applet is integrated for visualization of the structures. mpMoRFsDB provides valuable information related to disorder-based protein-protein interactions in membrane proteins. AVAILABILITY: http://bioinformatics.biol.uoa.gr/mpMoRFsDB",
            "question": "Which is the database of molecular recognition features in membrane proteins?",
            "answers": {
                "answer_start": 0,
                "text": "mpMoRFsDB"
            }
        },
        {
            "context": "APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination-independent mechanism. The most common transposable genetic element in humans, long interspersed element 1 (L1), constitutes about 20% of the genome. The activity of L1 and related transposons such as Alu elements causes disease and contributes to speciation. Little is known about the cellular mechanisms that control their spread. We show that expression of human APOBEC3B or APOBEC3F decreased the rate of L1 retrotransposition by 5-10-fold. Expression of two related proteins, APOBEC3D or APOBEC3G, had little effect. The mechanism of L1 inhibition did not correlate with an obvious subcellular protein distribution as APOBEC3B appeared predominantly nuclear and APOBEC3F was mostly cytosolic. Two lines of evidence indicated that these APOBEC3 proteins use a deamination-independent mechanism to inhibit L1. First, a catalytically inactive APOBEC3B mutant maintained L1 inhibition activity. Second, cDNA strand-specific C --> T hypermutations were not detected among L1 elements that had replicated in the presence of APOBEC3B or APOBEC3F. In addition, lower levels of retrotransposed L1 DNA accumulated in the presence of APOBEC3B and APOBEC3F. Together, these data combined to suggest a model in which APOBEC3B or APOBEC3F provide a preintegration barrier to L1 retrotransposition. A particularly high level of APOBEC3F protein in human testes and an inverse correlation between L1 activity and APOBEC3 gene number suggest the relevance of this mechanism to mammals.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 727,
                "text": " nuclear"
            }
        },
        {
            "context": "Hematopoietic stem cell quiescence: yet another role for p53. p53, sometimes referred to as the \"guardian of the genome,\" helps regulate cell-cycle arrest, DNA-damage repair, apoptosis, and senescence. Adding to this list, in this issue of Cell Stem Cell, Liu et al. (2009) show that p53 also plays a role in regulating hematopoietic stem cell quiescence.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 62,
                "text": "p53"
            }
        },
        {
            "context": "[Compliance and patience is needed when meeting patients with personality disorder]. Compliance and patience is needed when meeting patients with personality disorder To encounter patients with personality disorders in health care settings is often challenging. Most treatment studies published have included only patients with borderline personality disorder. Of evaluated psychological treatments in borderline personality disorder, dialectical behaviour therapy (DBT) has the strongest research support, followed by mentalization based therapy (MBT). Pharmacological treatment in personality disorders should focus on time-limited crisis intervention and treatment of comorbidity. There are few studies on inpatient care of persons with personality disorder. However, there are some interesting projects on brief self-directed inpatient stays as crisis intervention. There is a consensus to avoid long inpatient stays and coercive measures as far as possible.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 402,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. The intracellular signaling events by which NADPH oxidase-generated reactive oxygen species (ROS) modulate vascular smooth muscle cell (VSMC) function and atherogenesis are yet to be entirely elucidated. We previously demonstrated that NADPH oxidase deficiency decreased atherosclerosis in apoE(-/-) mice and identified adhesion protein CD44 as an important ROS-sensitive gene expressed in VSMC and atherosclerotic lesions. Here, we examined the molecular mechanisms by which NADPH oxidase-generated ROS regulate the expression of CD44 and its principal ligand, hyaluronan (HA), and how CD44-HA interaction affects VSMC proliferation and migration and inflammatory gene expression in apoE(-/-) mice aortas. Thrombin-induced CD44 expression is mediated by transcription factor AP-1 in a NADPH oxidase-dependent manner. NADPH oxidase-mediated ROS generation enhanced thrombin-induced HA synthesis, and hyaluronan synthase 2 expression in VSMC. Hyaluronidase, which generates low molecular weight HA (LMW-HA), is induced in VSMC in a NADPH oxidase-dependent manner and LMW-HA stimulated ROS generation and cell proliferation in wild-type but not p47(phox-/-) VSMC, effects that were enhanced by thrombin pretreatment. Haptotactic VSMC migration toward HA was increased by thrombin in a CD44-dependent manner. HA expression in atherosclerotic lesions and plasma-soluble CD44 and HA levels were higher in apoE(-/-) compared with apoE(-/-)/p47(phox-/-) mice. HA-regulated pro-inflammatory gene expression was higher in apoE(-/-) than apoE(-/-)/p47(phox-/-) mouse aortas. GKT136901, a specific inhibitor of Nox1- and Nox4-containing NADPH oxidase activity, attenuated ROS generation and atherosclerosis and decreased CD44 and HA expression in atherosclerotic lesions. Together, these data suggest that increased CD44 and HA expression and CD44-HA-dependent gene regulation may play a role in atherosclerosis stimulated by NADPH oxidase activation.",
            "question": "Which compound is a specific inhibitor for Nox1 and Nox4?",
            "answers": {
                "answer_start": 1698,
                "text": "GKT136901"
            }
        },
        {
            "context": "Exon skipping restores dystrophin expression, but fails to prevent disease progression in later stage dystrophic dko mice. Antisense therapy with both chemistries of phosphorodiamidate morpholino oligomers (PMOs) and 2'-O-methyl phosphorothioate has demonstrated the capability to induce dystrophin expression in Duchenne muscular dystrophy (DMD) patients in phase II-III clinical trials with benefit in muscle functions. However, potential of the therapy for DMD at different stages of the disease progression is not understood. In this study, we examined the effect of peptide-conjugated PMO (PPMO)-mediated exon skipping on disease progression of utrophin-dystrophin-deficient mice (dko) of four age groups (21-29, 30-39, 40-49 and 50+ days), representing diseases from early stage to advanced stage with severe kyphosis. Biweekly intravenous (i.v.) administration of the PPMO restored the dystrophin expression in nearly 100% skeletal muscle fibers in all age groups. This was associated with the restoration of dystrophin-associated proteins including functional glycosylated dystroglycan and neuronal nitric synthase. However, therapeutic outcomes clearly depended on severity of the disease at the time the treatment started. The PPMO treatment alleviated the disease pathology and significantly prolonged the life span of the mice receiving treatment at younger age with mild phenotype. However, restoration of high levels of dystrophin expression failed to prevent disease progression to the mice receiving treatment when disease was already at advanced stage. The results could be critical for design of clinical trials with antisense therapy to DMD.",
            "question": "In what percentage of skeletal muscle fibers is dystrophin expression restored after PPMO- mediated exon skipping?",
            "answers": {
                "answer_start": 925,
                "text": "100%"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 958,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Chromatin structure characteristics of pre-miRNA genomic sequences. BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs with important roles in regulating gene expression. Recent studies indicate that transcription and cleavage of miRNA are coupled, and that chromatin structure may influence miRNA transcription. However, little is known about the relationship between the chromatin structure and cleavage of pre-miRNA from pri-miRNA. RESULTS: By analysis of genome-wide nucleosome positioning data sets from human and Caenorhabditis elegans (C. elegans), we found an enrichment of positioned nucleosome on pre-miRNA genomic sequences, which is highly correlated with GC content within pre-miRNA. In addition, obvious enrichments of three histone modifications (H2BK5me1, H3K36me3 and H4K20me1) as well as RNA Polymerase II (RNAPII) were observed on pre-miRNA genomic sequences corresponding to the active-promoter miRNAs and expressed miRNAs. CONCLUSION: Our results revealed the chromatin structure characteristics of pre-miRNA genomic sequences, and implied potential mechanisms that can recognize these characteristics, thus improving pre-miRNA cleavage.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 806,
                "text": "RNA Polymerase II"
            }
        },
        {
            "context": "Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. OBJECTIVE: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. METHODS: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. RESULTS: One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. CONCLUSION: The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 217,
                "text": "Calcitonin gene-related peptide"
            }
        },
        {
            "context": "Genetic Determinants of RNA Editing Levels of ADAR Targets in Drosophila melanogaster. RNA editing usually affects only a fraction of expressed transcripts and there is a vast amount of variation in editing levels of ADAR (adenosine deaminase, RNA-specific) targets. Here we explore natural genetic variation affecting editing levels of particular sites in 81 natural strains of Drosophila melanogaster. The analysis of associations between editing levels and single-nucleotide polymorphisms allows us to map putative cis-regulatory regions affecting editing of 16 A-to-I editing sites (cis-RNA editing quantitative trait loci or cis-edQTLs, P < 10(-8)). The observed changes in editing levels are validated by independent molecular technique. All identified regulatory variants are located in close proximity of modulated editing sites. Moreover, colocalized editing sites are often regulated by same loci. Similar to expression and splicing QTL studies, the characterization of edQTLs will greatly expand our understanding of cis-regulatory evolution of gene expression.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 217,
                "text": "ADAR"
            }
        },
        {
            "context": "\"Emplotted Narratives\" and Structured \"Behavioral Observations\" Supporting the Diagnosis of Willis-Ekbom Disease/Restless Legs Syndrome in Children with Neurodevelopmental Conditions. BACKGROUND: Willis-Ekbom disease/restless legs syndrome (WED/RLS) seems to be a frequent cause of intractable chronic insomnia (ICI) but is under-recognized in children/adolescents with neurodevelopmental conditions (NDCs), as many patients do not have the ability to express the underlying \"urge-to-move\". In light of this, we aim to develop a protocol for behavioral observations supporting the diagnosis of WED/RLS. METHODS: We investigated 26 pediatric patients (age 1-16 years, median 8) with NDCs, ICI and evidence of familial WED/RLS employing (1) \"emplotted narratives\" for description of the various \"urge-to-move\" presentations and (2) self-description and \"behavioral observations\" during a \"suggested clinical immobilization test\" (SCIT). RESULTS: Parental narratives reflected typical WED/RLS-related \"urge-to-move\" symptoms during day-, bed-, and nighttime in all patients. Fifteen out of 26 patients could describe the \"urge-to-move\" during the SCIT. Ten out of 26 patients, unable to describe their symptoms due to cognitive disabilities, showed patterns of \"relieving-movements\" upon observation. Sensory processing abnormalities were reported in all patients, with tactile sensitivities (26/26) (including shifted pain threshold) as the most common sensory domain. CONCLUSION: \"Emplotted narratives\" and structured \"behavioral observations\" support recognition of familial WED/RLS associated movement patterns and provide a useful tool for the diagnosis of WED/RLS in children with NDCs in a clinical office setting.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 113,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis in mammals. Mutations at a single N-glycosylation sequon of tyrosinase have been reported to be responsible for oculocutaneous albinism type IA in humans, characterized by inactive tyrosinase and the total absence of pigmentation. To probe the role that each N-glycosylation site plays in the synthesis of biologically active tyrosinase, we analyzed the calnexin mediated folding of tyrosinase N-glycosylation mutants. We have determined that four of the six potential N-glycosylation sites, including that associated with albinism, are occupied. Analysis of the folding pathway and activity of 15 tyrosinase mutants lacking one or more of the occupied N-glycosylation sites shows that glycans at any two N-glycosylation sites are sufficient to interact with calnexin and give partial activity, but a specific pair of sites (Asn(86) and Asn(371)) is required for full activity. The mutants with less than two N-glycosylation sites do not interact with calnexin and show a complete absence of enzyme activity. Copper analysis of selected mutants suggests that the observed partial activity is due to two populations with differential copper content. By correlating the degree of folding with the activity of tyrosinase, we propose a local folding mechanism for tyrosinase that can explain the mechanism of inactivation of tyrosinase N-glycosylation mutants found in certain pigmentation disorders.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 249,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation. Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.",
            "question": "In which condition was protein S100A7 originally identified?",
            "answers": {
                "answer_start": 170,
                "text": "psoriasis"
            }
        },
        {
            "context": "NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. The intracellular signaling events by which NADPH oxidase-generated reactive oxygen species (ROS) modulate vascular smooth muscle cell (VSMC) function and atherogenesis are yet to be entirely elucidated. We previously demonstrated that NADPH oxidase deficiency decreased atherosclerosis in apoE(-/-) mice and identified adhesion protein CD44 as an important ROS-sensitive gene expressed in VSMC and atherosclerotic lesions. Here, we examined the molecular mechanisms by which NADPH oxidase-generated ROS regulate the expression of CD44 and its principal ligand, hyaluronan (HA), and how CD44-HA interaction affects VSMC proliferation and migration and inflammatory gene expression in apoE(-/-) mice aortas. Thrombin-induced CD44 expression is mediated by transcription factor AP-1 in a NADPH oxidase-dependent manner. NADPH oxidase-mediated ROS generation enhanced thrombin-induced HA synthesis, and hyaluronan synthase 2 expression in VSMC. Hyaluronidase, which generates low molecular weight HA (LMW-HA), is induced in VSMC in a NADPH oxidase-dependent manner and LMW-HA stimulated ROS generation and cell proliferation in wild-type but not p47(phox-/-) VSMC, effects that were enhanced by thrombin pretreatment. Haptotactic VSMC migration toward HA was increased by thrombin in a CD44-dependent manner. HA expression in atherosclerotic lesions and plasma-soluble CD44 and HA levels were higher in apoE(-/-) compared with apoE(-/-)/p47(phox-/-) mice. HA-regulated pro-inflammatory gene expression was higher in apoE(-/-) than apoE(-/-)/p47(phox-/-) mouse aortas. GKT136901, a specific inhibitor of Nox1- and Nox4-containing NADPH oxidase activity, attenuated ROS generation and atherosclerosis and decreased CD44 and HA expression in atherosclerotic lesions. Together, these data suggest that increased CD44 and HA expression and CD44-HA-dependent gene regulation may play a role in atherosclerosis stimulated by NADPH oxidase activation.",
            "question": "Which compound is a specific inhibitor for Nox1 and Nox4?",
            "answers": {
                "answer_start": 1698,
                "text": "GKT136901"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 964,
                "text": "thyroid"
            }
        },
        {
            "context": "Acute coronary syndromes: targeting inflammation-what has the VISTA-16 trial taught us? The VISTA-16 trial of varespladib, a secretory phospholipase A2 (sPLA2) inhibitor, in patients with an acute coronary syndrome was terminated prematurely owing to futility and a signal towards harm. Despite these discouraging results, therapies that target inflammation to modify pathways in atherogenesis remain an area of active investigation.",
            "question": "Which enzyme is inhibited by Varespladib?",
            "answers": {
                "answer_start": 125,
                "text": "secretory phospholipase A2"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 173,
                "text": "FSHD"
            }
        },
        {
            "context": "An in vitro and in vivo study of early deficits in associative learning in transgenic mice that over-express a mutant form of human APP associated with Alzheimer's disease. Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3- and 10-month-old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10-month-old APPLd2 mice also presented deficits in paired-pulse facilitation and long-term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimer's disease, and that specific learning tasks could have a relevant diagnostic value.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 313,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization. K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74). Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 microg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an alpha1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 143,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 817,
                "text": "MethPed"
            }
        },
        {
            "context": "PHYLUCE is a software package for the analysis of conserved genomic loci. UNLABELLED: Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales (<5 Ma to > 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. AVAILABILITY AND IMPLEMENTATION: PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth-lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. CONTACT: brant@faircloth-lab.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which software package is available for the analysis of conserved genomic loci?",
            "answers": {
                "answer_start": 0,
                "text": "PHYLUCE"
            }
        },
        {
            "context": "APOBEC3B and AID have similar nuclear import mechanisms. Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 621,
                "text": " nuclear"
            }
        },
        {
            "context": "Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 1120,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease. Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 115,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy. PURPOSE: Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. METHODS: In this randomized, two-sequence crossover study, 28 patients aged < 8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). RESULTS: Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. CONCLUSIONS: Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 328,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8"
            }
        },
        {
            "context": "Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Forty percent of the patients are blood transfusion-dependent. Recent reports show that the ribosomal protein S19 (RPS19) gene is mutated in 25% of all patients with DBA. We constructed oncoretroviral vectors containing the RPS19 gene to develop gene therapy for RPS19-deficient DBA. These vectors were used to introduce the RPS19 gene into CD34(+) bone marrow (BM) cells from 4 patients with DBA with RPS19 gene mutations. Overexpression of the RPS19 transgene increased the number of erythroid colonies by almost 3-fold. High expression levels of the RPS19 transgene improved erythroid colony-forming ability substantially whereas low expression levels had no effect. Overexpression of RPS19 had no detrimental effect on granulocyte-macrophage colony formation. Therefore, these findings suggest that gene therapy for RPS19-deficient patients with DBA using viral vectors that express the RPS19 gene is feasible.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 105,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "OCA1 in different ethnic groups of india is primarily due to founder mutations in the tyrosinase gene. Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 354,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Non-random X chromosome inactivation in mammalian cells. A salient feature of mammalian X dosage compensation is that X-inactivation occurs without regard to the parental origin of either active or inactive X. However, there are variations on the theme of random inactivation, namely paternal X inactivation in marsupials and in placental tissues of some mammals. Whether inactivation is random or paternal seems to depend on the time when this developmental program is initiated. As deletions of the X inactivation center (XIC/Xic) and/or the X inactive specific transcript (XIST/Xist) gene result in failure of cis X-inactivation, mutations in genes from this region might lead to preferential inactivation of one X chromosome or the other. The Xce locus in the murine Xic is considered a prototype for this model. Recent studies suggest that choice involves maintaining the activity of one X, while the other(s) by default is programmed to become inactive. Also, choice resides within the XIC, so that mutations elsewhere, although perhaps able to interfere with cis inactivation, are not likely to affect the X chromosome from only one parent. Mutations affecting the choice of active X will be more difficult to detect in humans than in inbred laboratory mice because of the greater allelic differences between maternal and paternal X chromosomes; some of these differences predispose to growth competition between the mosaic cell populations. I suggest that the skewing of inactivation patterns observed in human females most often occurs after random X inactivation, and is due mainly to cell selection favoring alleles that provide a relative growth advantage.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 576,
                "text": "XIST"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 254,
                "text": "NCX"
            }
        },
        {
            "context": "A cascade of genes related to Waardenburg syndrome. On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 181,
                "text": "MITF"
            }
        },
        {
            "context": "Mortality prediction using serum biomarkers and various clinical risk scales in community-acquired pneumonia. We evaluated the predictive value of serum biomarkers and various clinical risk scales for the 28-day mortality of community-acquired pneumonia (CAP). Serum biomarkers including procalcitonin (PCT) and C-reactive protein (CRP) were evaluated in the emergency department. Scores for the pneumonia severity index (PSI); CURB65 (confusion, urea, respiration, blood pressure; age >65 years); Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) guidelines for severe CAP; Acute Physiology, Chronic Health Evaluation (APACHE) II; Sequential Organ Failure Assessment (SOFA); and quick SOFA (qSOFA) were calculated. Receiver-operating characteristic curves for 28-day mortality were calculated for each predictor using cut-off values, and we applied logistic regression models and area under the curve (AUC) analysis to compare the performance of predictors. Of the 125 enrolled patients, 13 died within 28 days. The AUCs of the PCT and CRP were 0.83 and 0.77, respectively. Using a PCT level >5.6 μg/L as the cut-off, the sensitivity and specificity for mortality were 76.9% and 90.2%, respectively. The three pneumonia severity scales showed an AUC of 0.86 (PSI), 0.87 (IDSA/ATS) and 0.77 (CURB65). The AUCs of the APACHE II, SOFA and qSOFA scores were 0.85, 0.83 and 0.81, respectively. The models combining CRP and/or PCT with PSI or the IDSA/ATS guidelines demonstrated superior performance to those of either PSI or the IDAS/ATS guidelines alone. In conclusion, serum PCT is a reliable single predictor for short-term mortality. Inclusion of CRP and/or PCT could significantly improve the performance of the PSI and IDAS/ATS guidelines.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 396,
                "text": "pneumonia"
            }
        },
        {
            "context": "Periodic limb movement disorder : a clinical and polysomnographic study. Periodic limb movement disorder (PLMD) is one of the commonest neurological disorders and causes significant disability, if left untreated. However, it is rarely diagnosed in clinical practice, probably due to lack of awareness and/or lack of necessary diagnostic facilities. Restless leg syndrome (RLS), aging, pregnancy, uraemia, iron deficiency, polyneuropathy are some of the common causes of secondary PLMD. Clinical presentation, polysomnographic findings and management of six patients of PLMD have been discussed in this report.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 405,
                "text": "iron"
            }
        },
        {
            "context": "A transcription-independent role for TFIIB in gene looping. Recent studies demonstrated the existence of gene loops that juxtapose the promoter and terminator regions of genes with exceptionally long ORFs in yeast. Here we report that looping is not idiosyncratic to long genes but occurs between the distal ends of genes with ORFs as short as 1 kb. Moreover, looping is dependent upon the general transcription factor TFIIB: the E62K (glutamic acid 62 --> lysine) form of TFIIB adversely affects looping at every gene tested, including BLM10, SAC3, GAL10, SEN1, and HEM3. TFIIB crosslinks to both the promoter and terminator regions of the PMA1 and BLM10 genes, and its association with the terminator, but not the promoter, is adversely affected by E62K and by depletion of the Ssu72 component of the CPF 3' end processing complex, and is independent of TBP. We propose a model suggesting that TFIIB binds RNAP II at the terminator, which in turn associates with the promoter scaffold.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 419,
                "text": "TFIIB"
            }
        },
        {
            "context": "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 739,
                "text": "xa"
            }
        },
        {
            "context": "Site-specific deamidation of glutamine: a new marker of bone collagen deterioration. RATIONALE: Non-enzymatic deamidation accumulates in aging tissues in vivo and has been proposed to be potentially useful as a molecular clock. The process continues post mortem, and here we explore the increase in levels of deamidation in archaeological collagen, as measured during Zooarchaeology by Mass Spectrometry (ZooMS) analysis. METHODS: With the high sensitivity of current generation mass spectrometers, ZooMS provides a non-destructive and highly cost-effective method to characterise collagen peptides. Deamidation can be detected by mass spectrometry as a +0.984 Da mass shift; therefore, aside from its original purpose, peptide mass-fingerprinting for bone identification, ZooMS concurrently yields a 'thermal indicator' of the samples. RESULTS: By analysis of conventional ZooMS spectra, we determined the deamidation rate for glutamine residues in 911 bone collagen samples from 50 sites, with ages varying from medieval to Palaeolithic. The degree of deamidation was compared to diagenetic parameters and nearby sequence properties. CONCLUSIONS: The extent of deamidation was found to be influenced more by burial conditions and thermal age than, for example, chronological age, the extent of bioerosion or crystallinity. The method lends itself mostly to screening heterogenic deposits of bone to identify outliers.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 581,
                "text": "collagen"
            }
        },
        {
            "context": "Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease. X-Linked Dystonia-Parkinsonism (XDP or \"Lubag\") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 120,
                "text": "X-Linked Dystonia-Parkinsonism"
            }
        },
        {
            "context": "Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data. INTRODUCTION: To answer the need of a better low-density lipoprotein (LDL) cholesterol control in statin-treated patients at high risk for cardiovascular disease, new injectable lipid-lowering drugs with innovative mechanisms of action are in advanced phase of development or have just been approved. AREAS COVERED: Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation. Mipomersen specifically binds to a segment of the human apolipoprotein B100 messenger RNA, blocking the translation of the gene product. Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. Mipomersen use is mainly associated to hepatosteatosis, increased transaminases (> 3 times the upper limit of normal), mild-to-moderate injection-site reactions and flu-like symptoms. EXPERT OPINION: PCSK9 inhibitors have demonstrated their good safety and tolerability in a large number of subjects with different clinical conditions, including statin-intolerance, enlarging their potential use in a broader range of patients. Further data on long-term mipomersen safety are required.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 492,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. OBJECTIVE: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS: In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: At week 12, ACR20 response rates for patients receiving all tofacitinib dosages > 3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P < 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION: In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage > 3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 318,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene. Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 94,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 155,
                "text": "orbit"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1726,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating enzyme inhibitor, MLN4924, using AlphaScreen. Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct. The inhibited enzyme can no longer transfer Nedd8 downstream to modify and activate the E3 cullin-RING ligases. This results in the stabilization of proteins regulated by the proteasome, leading to cell death. These studies monitored the endogenous cellular changes to NAE∼Nedd8 thioester, the formation of the Nedd8-MLN4924 adduct, and the reduction in the Cul1-Nedd8. Lysates derived from MLN4924-treated HCT116 cells showed that whereas the β-subunit of NAE remained constant, reductions of both NAE∼Nedd8 thioester and Cul1-Nedd8 levels occurred with a concomitant rise of the adduct. Moreover, the formation of the Nedd8-MLN4924 adduct was approximately stoichiometric with the concentration of NAEβ. Higher density 384-well cell-based assays illustrated the kinetics of enzyme inactivation across a wider range of MLN4924 concentrations, showing a rapid loss of NAE∼Nedd8 thioester and Cul1-Nedd8. The reduction of NAE∼Nedd8 thioester precedes the loss of Cul1-Nedd8 at twice the rate. Finally, these results clearly demonstrate the utility of the homogeneous assay for quantitative assessment of these endogenous cellular components in a 384-well plate in response to inhibition of NAE by MLN4924.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 58,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Empiric use of flumazenil in comatose patients: limited applicability of criteria to define low risk. STUDY OBJECTIVE: To develop clinical rules for the safe and effective use of flumazenil in suspected benzodiazepine overdose. METHODS: We assembled a retrospective series of 35 consecutive comatose patients admitted between October 1992 and July 1993 to a toxicologic ICU with the presumptive diagnosis of drug overdose. These patients were divided into two groups. Group A (low-risk) patients had a clinical picture compatible with uncomplicated benzodiazepine intoxication (calm, without abnormalities in pulse or blood pressure, lateralizing signs, hypertonia, hyperreflexia, or myoclonus) in the absence of predefined electrocardiographic or clinical signs of tricyclic antidepressant or other proconvulsant overdose, and absence of an available history of long-term benzodiazepine treatment or an underlying seizure disorder. Group B (\"non-low risk\") comprised all other patients. Efficacy of flumazenil was categorized as complete awakening (with normal level of alertness), partial awakening, or no change in alertness level. The safety of flumazenil was defined on the basis of the absence of seizures or death. RESULTS: In group A (n=4), flumazenil was associated with complete awakening in three patients and partial awakening in one. No seizures were observed. In group B (n=31), flumazenil was associated with complete awakening in 4 patients, partial awakening in 5, and no response in 22. In group B, five seizures occurred. CONCLUSION: Comatose patients with clinical or ECG criteria thought to contraindicate the use of flumazenil have a reasonably high risk of seizures after administration of this drug. Low-risk patients may be able to receive flumazenil safely, but they may be only a small portion of comatose patients with suspected overdose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 179,
                "text": "flumazenil"
            }
        },
        {
            "context": "Can the FAST and ROSIER adult stroke recognition tools be applied to confirmed childhood arterial ischemic stroke? BACKGROUND: Stroke recognition tools have been shown to improve diagnostic accuracy in adults. Development of a similar tool in children is needed to reduce lag time to diagnosis. A critical first step is to determine whether adult stoke scales can be applied in childhood stroke.Our objective was to assess the applicability of adult stroke scales in childhood arterial ischemic stroke (AIS) METHODS: Children aged 1 month to < 18 years with radiologically confirmed acute AIS who presented to a tertiary emergency department (ED) (2003 to 2008) were identified retrospectively. Signs, symptoms, risk factors and initial management were extracted. Two adult stroke recognition tools; ROSIER (Recognition of Stroke in the Emergency Room) and FAST (Face Arm Speech Test) scales were applied retrospectively to all patients to determine test sensitivity. RESULTS: 47 children with AIS were identified. 34 had anterior, 12 had posterior and 1 child had anterior and posterior circulation infarcts. Median age was 9 years and 51% were male. Median time from symptom onset to ED presentation was 21 hours but one third of children presented within 6 hours. The most common presenting stroke symptoms were arm (63%), face (62%), leg weakness (57%), speech disturbance (46%) and headache (46%). The most common signs were arm (61%), face (70%) or leg weakness (57%) and dysarthria (34%). 36 (78%) of children had at least one positive variable on FAST and 38 (81%) had a positive score of > 1 on the ROSIER scale. Positive scores were less likely in children with posterior circulation stroke. CONCLUSION: The presenting features of pediatric stroke appear similar to adult strokes. Two adult stroke recognition tools have fair to good sensitivity in radiologically confirmed childhood AIS but require further development and modification. Specificity of the tools also needs to be determined in a prospective cohort of children with stroke and non-stroke brain attacks.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 30,
                "text": "stroke"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 0,
                "text": "libFLASM"
            }
        },
        {
            "context": "Heterogeneity of genomes: measures and values. Genomic homogeneity is investigated for a broad base of DNA sequences in terms of dinucleotide relative abundance distances (abbreviated delta-distances) and of oligonucleotide compositional extremes. It is shown that delta-distances between different genomic sequences in the same species are low, only about 2 or 3 times the distance found in random DNA, and are generally smaller than the between-species delta-distances. Extremes in short oligonucleotides include underrepresentation of TpA and overrepresentation of GpC in most temperate bacteriophage sequences; underrepresentation of CTAG in most eubacterial genomes; underrepresentation of GATC in most bacteriophage; CpG suppression in vertebrates, in all animal mitochondrial genomes, and in many thermophilic bacterial sequences; and overrepresentation of GpG/CpC in all animal mitochondrial sets and chloroplast genomes. Interpretations center on DNA structures (dinucleotide stacking energies, DNA curvature and superhelicity, nucleosome organization), context-dependent mutational events, methylation effects, and processes of replication and repair.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 184,
                "text": "delta-distance"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 222,
                "text": "xa"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 40,
                "text": "Spinal Muscular Atrophy"
            }
        },
        {
            "context": "Assessment and quantification of telomerase enzyme activity. The enzyme telomerase is activated in 80-90% of all human malignancies and immortal cell lines, where it functions to maintain the integrity of chromosomal-end structures called telomeres. Telomerase enzyme activity can be detected in whole cell lysates by a polymerase chain reaction (PCR)-based method referred to as the telomeric repeat amplification protocol (TRAP). The TRAP assay involves extension of an oligonucleotide through telomerase-mediated enzymatic addition of telomeric DNA repeats and subsequent PCR amplification of the extension products. While the TRAP assay as originally developed utilizes radioactively labelled nucleotides, protocols are provided herein for nonradioactive versions of the TRAP assay, with options for either qualitative assessment of TRAP products by polyacrylamide gel electrophoresis (standard TRAP), or quantitative analysis by real-time PCR (Q-TRAP). The Q-TRAP method poses the additional advantages of exquisite sensitivity, rapidity, and potential for adoption to a high-throughput format.",
            "question": "What is the aim of the TRAP assay?",
            "answers": {
                "answer_start": 250,
                "text": "Telomerase enzyme activity can be detected in whole cell lysates by a polymerase chain reaction (PCR)-based method referred to as the telomeric repeat amplification protocol (TRAP)."
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 436,
                "text": "SLC9A6"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "[Cajal bodies in insect oocytes. I. Identification and immunocytochemical characteristics of Cajal bodies in vitellogenic oocytes of the yellow mealworm beetle]. In vitellogenic oocytes of Tenebrio molitor (inactive stage), numerous fibrogranular nuclear bodies (NBs) are present. Using immunofluorescent microscopy, these NBs were shown to contain pre-mRNA splicing factors (small nuclear [sn] RNPs and SR-protein, SC35) as well as RNA polymerase II. A limited set of NBs also contained coilin, a marker protein for Cajal bodies (CBs). We suggest that in T. molitor oocytes, coilin-containing NBs, which also contain splicing factors and RNA polymerase II, seem to represent CBs. In the species studied, no morphological features of CBs were established as compared with other NBs, which do not contain coilin. Microinjectons in oocytes of myc-tagged coilin mRNA, followed by revealing newly translated protein with antibody specific for this tag, have shown targeting of myc-coilin with CBs. The own and literary data on the morphology and molecular composition of CBs are discussed in terms of searching for criteria for CB identification in cells of different origin, and at active and inactive stages.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 488,
                "text": "coilin"
            }
        },
        {
            "context": "Selexipag for the treatment of pulmonary arterial hypertension. INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.",
            "question": "Selexipag is used for which disease?",
            "answers": {
                "answer_start": 279,
                "text": "pulmonary arterial hypertension"
            }
        },
        {
            "context": "Tyrosine kinase inhibitors in acute and chronic leukemias. INTRODUCTION: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients. AREAS COVERED: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML). EXPERT OPINION: There are now more potent BCR-ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side-effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 210,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 0,
                "text": "Thyroid"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 426,
                "text": "methylKit"
            }
        },
        {
            "context": "Maintenance DNA methyltransferase (Met1) and silencing of CpG-methylated foreign DNA in Volvox carteri. DNA methylation plays an important role in the gene-silencing network of higher eukaryotes. We have analyzed the 21.5-kb maintenance methyltransferase (M-MTase) gene, met1, of the multicellular green alga Volvox carteri. The met1 transcript was detected only during the period when DNA replication and cell division are taking place. It encodes a 238 kDa protein containing eight C-terminal activity domains typical of M-MTases, plus upstream DNA-binding domains including the ProDom domain PD003757, which experimental analyses in animal systems have indicated is required for targeting the enzyme to DNA-replication foci. Several insertions of unknown function make Volvox Met1 the largest known member of the Met1/Dnmt1 family. Here we also show that several endogenous transposon families are CpG-methylated in Volvox, which we think causes them to be inactive. This view is supported by the observation that an in vitro CpG-methylated gene introduced into Volvox was maintained in the methylated and silent state over >100 generations. Thus, we believe that Met1 recognizes and perpetuates the in vitro methylation signal, and that the silencing machinery is then able to transduce such a methylation-only signal into a stable heterochromatic (and silent) state.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 35,
                "text": "Met1"
            }
        },
        {
            "context": "A modified SILCS contraceptive diaphragm for long-term controlled release of the HIV microbicide dapivirine. BACKGROUND: There is considerable interest in developing new multipurpose prevention technologies to address women's reproductive health needs. This study describes an innovative barrier contraceptive device--based on the SILCS diaphragm--that also provides long-term controlled release of the lead candidate anti-HIV microbicide dapivirine. STUDY DESIGN: Diaphragm devices comprising various dapivirine-loaded polymer spring cores overmolded with a nonmedicated silicone elastomer sheath were fabricated by injection molding processes. In vitro release testing, thermal analysis and mechanical characterization were performed on the devices. RESULTS: A diaphragm device containing a polyoxymethylene spring core loaded with 10% w/w dapivirine provided continuous and controlled release of dapivirine over a 6-month period, with a mean in vitro daily release rate of 174 mcg/day. The mechanical properties of the new diaphragm were closely matched to the SILCS diaphragm. CONCLUSIONS: The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. In discontinuous clinical use, release of dapivirine may be readily extended over 1 or more years.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 1235,
                "text": "HIV"
            }
        },
        {
            "context": "Glial involvement in diffuse Lewy body disease. Diffuse Lewy body disease (DLBD) is characterized by the presence of Lewy bodies (LB) in the neurons and neurites of cortical, subcortical, and brain stem structures. Recently, alpha-synuclein (alphaS) has been found to be a central constituent of LB. In DLBD, abnormal accumulation of alphaS has been reported in both neurons and glia, but studies on glial lesions in DLBD have been limited. We examined in detail the constituents and distribution of glial lesions in eight patients with DLBD and report the pathogenesis of the glial lesions. alphaS-positive neuronal cytoplasmic inclusions (NI), neuropil threads (NT), and coiled bodies (CB) showed similar immunostaining profiles. Without pretreatment, NI, NT, and CB were detected by all antibodies against alphaS. The immunostaining profile of star-like astrocytes (SLA) was quite different from those of NI, NT, and CB. A few SLA were stained by an antibody against the non-Abeta component portion of alphaS without pretreatment, but formic acid pretreatment dramatically enhanced SLA immunoreactivity. SLA and CB were found in all eight brains with DLBD. SLA were scarce in the brain stem, but there were hundreds of SLA per visual field at x100 magnification in the temporal cortex of most cases, while CB were found diffusely in both the cerebral cortex and brain stem, similar to NI. This suggests that the pathogenesis of SLA is different from those of NI and CB.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 225,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "[Vascular Ehlers-Danlos syndromes--biochemical and molecular-genetic investigations]. INTRODUCTION: The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterised by joint hypermobility, involvement of skin and tissue fragility. The Villefranche criteria have simplified its diagnosis, which, however, remains difficult in children and young adults with vascular and hypermobile EDS as well as in patients without a positive family history. Diagnosis of vascular EDS is important for clinical follow-up, genetic counseling and prenatal diagnosis. We describe the biochemical and molecular-genetic diagnosis of vascular EDS. MATERIALS AND METHODS: We describe five families with vascular EDS. Analysis of (pro)collagens obtained from cultured fibroblasts was done using SDS-PAGE. The structure and amounts of (pro)collagen I, III and V were determined by autoradioflourography. This was also done in 362 controls or patients without a diagnosis of vascular EDS. Molecular testing was done in Professor Anne de Paepe's laboratory in Belgium by sequencing of COL3A1. RESULTS: (Pro)collagen from all five patients with vascular EDS was abnormal by SDS-PAGE: intracellular retention, reduced secretion and overmodification of the a1 chains of (pro)collagen III. Molecular analysis revealed an abnormality of COL3A1 in all patients. Abnormalities of (pro)collagen III were not observed in patients without a diagnosis of vascular EDS. Among 90 patients with non-vascular EDS, one patient had an abnormality of collagen I. DISCUSSION: Biochemical analysis of (pro)collagen obtained from cultured fibroblasts is a good screening procedure for vascular EDS, but it is of limited value in non-vascular EDS. Molecular testing will disclose an abnormality of COL3A1 in many patients with abnormal (pro)collagen III on SDS-PAGE. The findings make precise genetic counselling and prenatal diagnosis possible in families with vascular EDS.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 173,
                "text": "connective tissue"
            }
        },
        {
            "context": "Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6-month extension study, long-term ( < 8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term ( < 2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for > 2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB.",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 68,
                "text": "tuberculosis"
            }
        },
        {
            "context": "c-Jun-mediated anticancer mechanisms of tylophorine. Tylophorine, a phenanthroindolizidine alkaloid, is the major medicinal constituent of herb Tylophora indica. Tylophorine treatment increased the accumulation of c-Jun protein, a component of activator protein 1 (AP1), in carcinoma cells. An in vitro kinase assay revealed that the resultant c-Jun phosphorylation was primarily mediated via activated c-Jun N-terminal protein kinase (JNK). Moreover, flow cytometry indicated that ectopically overexpressed c-Jun in conjunction with tylophorine significantly increased the number of carcinoma cells that were arrested at the G1 phase. The tylophorine-mediated downregulation of cyclin A2 protein levels is known to be involved in the primary G1 arrest. Chromatin immunoprecipitation and reporter assays revealed that tylophorine enhanced the c-Jun downregulation of the cyclin A2 promoter activity upon increased binding of c-Jun to the deregulation AP1 site and decreased binding to the upregulation activating transcription factor (ATF) site in the cyclin A2 promoter, thereby reducing cyclin A2 expression. Further, biochemical studies using pharmacological inhibitors and RNA silencing approaches demonstrated that tylophorine-mediated elevation of the c-Jun protein level occurs primarily via two discrete prolonged signaling pathways: (i) the NF-κB/PKCδ_(MKK4)_JNK cascade, which phosphorylates c-Jun and increases its stability by slowing its ubiquitination, and (ii) the PI3K_PDK1_PP2A_eEF2 cascade, which sustains eukaryotic elongation factor 2 (eEF2) activity and thus c-Jun protein translation. To the best of our knowledge, this report is the first to demonstrate the involvement of c-Jun in the anticancer activity of tylophorine and the release of c-Jun translation from a global translational blockade via the PI3K_PDK1_eEF2 signaling cascade.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 436,
                "text": "JNK"
            }
        },
        {
            "context": "Transcripts synthesized by RNA polymerase III can be polyadenylated in an AAUAAA-dependent manner. It is well known that nearly all eukaryotic mRNAs contain a 3' poly(A) tail. A polyadenylation signal (AAUAAA) nearby the 3' end of pre-mRNA is required for poly(A) synthesis. The protein complex involved in the pre-mRNA polyadenylation is coupled with RNA polymerase II during the transcription of a gene. According to the commonly accepted view, only RNAs synthesized by RNA polymerase II can be polyadenylated in an AAUAAA-dependent manner. Here we report the polyadenylation of short interspersed elements (SINEs) B2 and VES transcripts generated by RNA polymerase III. HeLa cells were transfected with SINE constructs with or without polyadenylation signals. The analyses of the SINE transcripts showed that only the RNAs with the AAUAAA-signal contained poly(A) tails. Polyadenylated B2 RNA was found to be much more stable in cells than B2 RNA without a poly(A) tail.",
            "question": "Which is the RNA sequence of the canonical polyadenylation signal?",
            "answers": {
                "answer_start": 202,
                "text": "AAUAAA"
            }
        },
        {
            "context": "New mammalian selenocysteine-containing proteins identified with an algorithm that searches for selenocysteine insertion sequence elements. Mammalian selenium-containing proteins identified thus far contain selenium in the form of a selenocysteine residue encoded by UGA. These proteins lack common amino acid sequence motifs, but 3'-untranslated regions of selenoprotein genes contain a common stem-loop structure, selenocysteine insertion sequence (SECIS) element, that is necessary for decoding UGA as selenocysteine rather than a stop signal. We describe here a computer program, SECISearch, that identifies mammalian selenoprotein genes by recognizing SECIS elements on the basis of their primary and secondary structures and free energy requirements. When SECISearch was applied to search human dbEST, two new mammalian selenoproteins, designated SelT and SelR, were identified. We determined their cDNA sequences and expressed them in a monkey cell line as fusion proteins with a green fluorescent protein. Incorporation of selenium into new proteins was confirmed by metabolic labeling with (75)Se, and expression of SelT was additionally documented in immunoblot assays. SelT and SelR did not have homology to previously characterized proteins, but their putative homologs were detected in various organisms. SelR homologs were present in every organism characterized by complete genome sequencing. The data suggest applicability of SECISearch for identification of new selenoprotein genes in nucleotide data bases.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 451,
                "text": "SECIS"
            }
        },
        {
            "context": "Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1708,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Accelerated apoptosis of neutrophils in familial mediterranean Fever. The causative mutations for familial Mediterranean fever (FMF) are located in the MEFV gene, which encodes pyrin. Pyrin modulates the susceptibility to apoptosis via its PYD domain, but how the mutated versions of pyrin affect apoptotic processes are poorly understood. Spontaneous and induced rates of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering apoptosis compared to control (6.27 ± 2.14 vs. 1.69 ± 0.18%). This elevated ratio was retained after 24 h incubation of neutrophils in the growth medium (32.4 ± 7.41 vs. 7.65 ± 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response to the inducing agents, the neutrophils from FMF patients also displayed significantly elevated apoptotic rates compared to control. The elevated rates, however, can be largely explained by the higher basal ratio of apoptotic cells in the former group. Monitoring of several proteins involved in apoptosis has not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive infiltration of neutrophils in the acute period of the disease.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 152,
                "text": "MEFV gene"
            }
        },
        {
            "context": "Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. RATIONALE: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 392,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Cognition-induced modulation of serotonin in the orbitofrontal cortex: a controlled cross-over PET study of a delayed match-to-sample task using the 5-HT2a receptor antagonist [18F]altanserin. Behavioral and cellular studies indicate that serotonin interacting with the 5-HT2a receptor (5-HT2aR) is involved in cognitive processes supporting working memory (WM). However, 5-HT receptor neuroimaging studies directly relating WM-induced neuronal activations to concomitant changes in the availability of 5-HT receptors as a functional measure for serotonin release are lacking. This controlled cross-over PET study aimed to identify brain regions with WM-induced changes in the binding potential (BP(nd)) of the 5-HT2aR antagonist [(18)F]altanserin. Ten young males underwent a delayed match-to-sample task using photographs of faces and a control task. The BP(nd)s for both conditions were calculated by applying Ichise's noninvasive plot. Statistics were performed with the SPM toolbox statistical nonparametric mapping (SnPM3) particularly suited for analyzing whole-brain PET data in an exploratory way. A higher BP(nd) for [(18)F]altanserin during WM versus control was found in the orbitofrontal cortex (OFC) pointing towards an increased [(18)F]altanserin/5-HT2aR interaction in OFC while BP(nd) decreases during WM were not found. Furthermore, no BP(nd) changes in regions known from functional neuroimaging studies to be more specifically involved in WM were identified. These findings may suggest that the increased [(18)F]altanserin BP(nd) under WM challenge and hence the increased availability of 5-HT2aR reflects a decrease in local OFC serotonin. As the OFC plays a prominent role in decision-making and supports cognitive processes related to the central executive functions of WM it might be modulated by the serotoninergic system via the 5-HT2aR in order to support and optimize basic cognitive functions.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 711,
                "text": "5-HT2a"
            }
        },
        {
            "context": "The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 142,
                "text": "NCX"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 424,
                "text": "CD38"
            }
        },
        {
            "context": "Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 321,
                "text": "SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein)"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 0,
                "text": "webSDA"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 289,
                "text": "BRG1"
            }
        },
        {
            "context": "SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 164,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Use of dialectical behavior therapy in borderline personality disorder: a view from residency. OBJECTIVE: The authors describe the use of dialectical behavior therapy (DBT) in treating borderline personality disorder during psychiatry residency, and assess the status of DBT education within psychiatry residencies in the United States. METHOD: The authors present a patient with borderline personality disorder treated by a resident using DBT, along with perspectives from the resident's supervisors. Additionally, self-report surveys inquiring about the attitudes and experiences of residency directors and PGY-4 residents regarding DBT were sent to program directors with available e-mail addresses on FREIDA online. RESULTS: The DBT method employed by the resident had to be modified to fit the constraints of a residency program. The patient in therapy had a tumultuous course, ultimately resulting in the discontinuation of treatment. Survey results suggested an underemphasis on the education and use of DBT during residency, though the strength of this conclusion is limited by the small proportion of surveys returned. CONCLUSIONS: Achieving the efficacy of DBT-based treatment of borderline personality disorder reported in the literature in the setting of a residency program is challenging. Greater exposure to DBT during residency may increase residents' skills in using the technique and the likelihood that they will use it after residency.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 185,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease. BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 530,
                "text": "AD"
            }
        },
        {
            "context": "A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. Lipoprotein glomerulopathy (LPG) is a rare glomerulopathy caused by lipoprotein thrombi. In almost all cases of LPG, several apolipoprotein (apo) E mutations were reported. Here, we present a case of LPG caused by a novel mutation that we named ApoE2 Kurashiki, which substitutes arginine with proline at apoE codon 158. ApoE2 polymorphism is well known for its relationship to type III hyperlipoproteinemia, and the common apoE2 isoform is encoded by the R158C allele. ApoE2 Kurashiki substitutes at the same codon and cannot be distinguished from common apoE2 by stan-dard apoE genotyping or phenotyping.",
            "question": "Which ApoE isoform is associated with hyperlipoproteinemia?",
            "answers": {
                "answer_start": 511,
                "text": "apoE2 isoform"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 896,
                "text": "miR-7"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. BACKGROUND: Monoclonal antibodies (MoAbs) are increasingly integrated in the standard of care. The notion that therapeutic MoAbs can interfere with clinical laboratory tests is an emerging concern that requires immediate recognition and the development of appropriate solutions. Here, we describe that treatment of multiple myeloma patients with daratumumab, a novel anti-CD38 MoAb, resulted in false-positive indirect antiglobulin tests (IATs) for all patients for 2 to 6 months after infusion. This precluded the correct identification of irregular blood group antibodies for patients requiring blood transfusion. STUDY DESIGN AND METHODS: The IAT was performed using three- and 11-donor-cell panels. Interference of daratumumab and three other anti-CD38 MoAbs was studied using fresh-frozen plasma spiked with different MoAb concentrations. Additionally it was tested whether two potentially neutralizing agents, anti-idiotype antibody and recombinant soluble CD38 (sCD38) extracellular domain, were able to inhibit the interference. RESULTS: The CD38 MoAbs caused agglutination in the IAT in a dose-dependent manner. Addition of an excess of anti-idiotype antibodies or sCD38 protein to the test abrogated CD38 MoAb interference and successfully restored irregular antibody screening and identification. DISCUSSION: CD38 MoAb therapy causes false-positive results in the IAT. The reliability of the test could be restored by adding a neutralizing agent against the CD38 MoAb to the patient's plasma. This study emphasizes that during drug development, targeted therapeutics should be investigated for potential interference with laboratory tests. Clinical laboratories should be informed when patients receive MoAb treatments and matched laboratory tests to prevent interference should be employed.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 476,
                "text": "CD38"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 555,
                "text": "RADAR"
            }
        },
        {
            "context": "Drug candidates in clinical trials for Alzheimer's disease. Alzheimer's disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. The lowered concentrations of acetylcholine (ACh) in AD result in a progressive and significant loss of cognitive and behavioral function. Current AD medications, memantine and acetylcholinesterase inhibitors (AChEIs) alleviate some of these symptoms by enhancing cholinergic signaling, but they are not curative. Since 2003, no new drugs have been approved for the treatment of AD. This article focuses on the current research in clinical trials targeting the neuropathological findings of AD including acetylcholine response, glutamate transmission, Aβ clearance, tau protein deposits, and neuroinflammation. These investigations include acetylcholinesterase inhibitors, agonists and antagonists of neurotransmitter receptors, β-secretase (BACE) or γ-secretase inhibitors, vaccines or antibodies targeting Aβ clearance or tau protein, as well as anti-inflammation compounds. Ongoing Phase III clinical trials via passive immunotherapy against Aβ peptides (crenezumab, gantenerumab, and aducanumab) seem to be promising. Using small molecules blocking 5-HT serotonin receptor (intepirdine), inhibiting BACE activity (E2609, AZD3293, and verubecestat), or reducing tau aggregation (TRx0237) are also currently in Phase III clinical trials. We here systemically review the findings from recent clinical trials to provide a comprehensive review of novel therapeutic compounds in the treatment and prevention of AD.",
            "question": "In what phase of clinical trials is crenezumab? (November 2017)",
            "answers": {
                "answer_start": 1492,
                "text": "Phase III"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyr"
            }
        },
        {
            "context": "Blockage of RNA polymerase II at a cyclobutane pyrimidine dimer and 6-4 photoproduct. The blockage of transcription elongation by RNA polymerase II (pol II) at a DNA damage site on the transcribed strand triggers a transcription-coupled DNA repair (TCR), which rapidly removes DNA damage on the transcribed strand of the expressed gene and allows the resumption of transcription. To analyze the effect of UV-induced DNA damage on transcription elongation, an in vitro transcription elongation system using pol II and oligo(dC)-tailed templates containing a cyclobutane pyrimidine dimer (CPD) or 6-4 photoproduct (6-4PP) at a specific site was employed. The results showed that pol II incorporated nucleotides opposite the CPD and 6-4PP and then stalled. Pol II formed a stable ternary complex consisting of pol II, the DNA damage template, and the nascent transcript. Furthermore, atomic force microscopy imaging revealed that pol II stalled at the damaged region. These findings may provide the basis for analysis of the initiation step of TCR.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 291,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 26,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Red hair--a desirable mutation? Red hair is one of the most striking variants of human hair coloration and has historically been of profound social importance. Red hair in man is due to certain loss of function mutations of one of the peptide products of the pro-opiomelanocortin (POMC) gene, the melanocortin-1 receptor (MC1R, MIM 155555). Such functional mutations enable the melanocyte to produce red-yellow pheomelanin in preference to the default, black-brown eumelanin. This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 524,
                "text": "MC1R"
            }
        },
        {
            "context": "Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 1335,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 39,
                "text": "CD38"
            }
        },
        {
            "context": "Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with \"other type I fibrillinopathy.\" In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete \"clinical\" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 223,
                "text": "FBN1"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 784,
                "text": "traseR"
            }
        },
        {
            "context": "The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies. Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 569,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "MR and CT imaging in the Dyke-Davidoff-Masson syndrome. Report of three cases and contribution to pathogenesis and differential diagnosis. Cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome is a condition characterized by seizures, facial asymmetry, contralateral hemiplegia or hemiparesis, and mental retardation. These findings are due to cerebral injury that may occur early in life or in utero. The radiological features are unilateral loss of cerebral volume and associated compensatory bone alterations in the calvarium, like thickening, hyperpneumatization of the paranasal sinuses and mastoid cells and elevation of the petrous ridge. The authors describe three cases. Classical findings of the syndrome are present in variable degrees according to the extent of the brain injury. Pathogenesis is commented.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 139,
                "text": "Cerebral hemiatrophy"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 405,
                "text": "Xa"
            }
        },
        {
            "context": "Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 924,
                "text": "CD38"
            }
        },
        {
            "context": "H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast. BACKGROUND: The packaging of DNA into chromatin regulates transcription from initiation through 3' end processing. One aspect of transcription in which chromatin plays a poorly understood role is the co-transcriptional splicing of pre-mRNA. RESULTS: Here we provide evidence that H2B monoubiquitylation (H2BK123ub1) marks introns in Saccharomyces cerevisiae. A genome-wide map of H2BK123ub1 in this organism reveals that this modification is enriched in coding regions and that its levels peak at the transcribed regions of two characteristic subgroups of genes. First, long genes are more likely to have higher levels of H2BK123ub1, correlating with the postulated role of this modification in preventing cryptic transcription initiation in ORFs. Second, genes that are highly transcribed also have high levels of H2BK123ub1, including the ribosomal protein genes, which comprise the majority of intron-containing genes in yeast. H2BK123ub1 is also a feature of introns in the yeast genome, and the disruption of this modification alters the intragenic distribution of H3 trimethylation on lysine 36 (H3K36me3), which functionally correlates with alternative RNA splicing in humans. In addition, the deletion of genes encoding the U2 snRNP subunits, Lea1 or Msl1, in combination with an htb-K123R mutation, leads to synthetic lethality. CONCLUSION: These data suggest that H2BK123ub1 facilitates cross talk between chromatin and pre-mRNA splicing by modulating the distribution of intronic and exonic histone modifications.",
            "question": "What histone trimethylation has been associated to RNA splicing?",
            "answers": {
                "answer_start": 1206,
                "text": "H3K36me3"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 840,
                "text": "TYR"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 249,
                "text": "NCX"
            }
        },
        {
            "context": "Red hair is the null phenotype of MC1R. The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible for production of the darker eumelanin pigment and the tanning response. The MC1R gene has many polymorphisms, some of which have been linked to variation in pigmentation phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and p.D294 H alleles have been strongly associated with red hair, fair skin and increased skin cancer risk. These red hair colour (RHC) variants are relatively well described and are thought to result in altered receptor function, while still retaining varying levels of signaling ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W and p.D294 H alleles were able to partially rescue this phenotype, leading to the question of what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null alleles in human populations, they have only been found in the heterozygous state until now. We report here the first case of a homozygous MC1R null individual, phenotypic analysis indicates that red hair and fair skin is found in the absence of MC1R function.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 69,
                "text": "MC1R"
            }
        },
        {
            "context": "Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection. The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. Methods: The chelator p-SCN-Bn-DFO was conjugated to AMG102, radiolabeling with Zr was performed in high radiochemical yields and purity (>99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Results: Tumor uptake of Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 ± 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 ± 1.3 %ID/g and a control of nonspecific human IgG Zr-DFO-IgG in U87MG tumors was 11.5 ± 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. Conclusion: The new immuno-PET imaging agent Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes.",
            "question": "What is inhibited by a drug rilotumumab?",
            "answers": {
                "answer_start": 130,
                "text": "hepatocyte growth factor"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome. Dyke Davidoff Masson syndrome (DDMS) is characterized by seizures, facial asymmetry, contralateral hemiplegia and mental retardation. The characteristic radiologic features are cerebral hemiatrophy with homolateral hypertrophy of the skull and sinuses. We report a case of DDMS in an 18-month-old girl who presented with right sided focal seizures, hemiparesis of the same side, and delayed milestones.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 208,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 656,
                "text": "SERCA2"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1441,
                "text": "XK"
            }
        },
        {
            "context": "Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up. Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 289,
                "text": "IgG4"
            }
        },
        {
            "context": "Dermatitis herpetiformis: jejunal findings and skin response to gluten free diet. Fifty seven children with dermatitis herpetiformis, 18 from Finland and 39 from Hungary, were studied. Diagnostic criteria included the finding of granular IgA deposits in the skin of all patients. The mean age at onset of the rash was 7 X 2 years and favoured sites were the elbows, knees, and buttocks. Symptoms suggesting small intestinal disease were rare but in 35 (61%) of the children subtotal villous atrophy and in 16 (28%) partial villous atrophy were found on jejunal biopsy. Eighteen children underwent a second biopsy after a mean of 21 months on a gluten free diet; villous height was found to be increased and the intraepithelial lymphocyte count decreased in all these patients. Gluten challenge caused a reversal in the two children who underwent a third biopsy. The effect of the gluten free diet on the rash was examined in Finnish children by observing the daily requirements of dapsone, a drug used to control the rash at the beginning of the diet. Eight (67%) of the 12 children were able to stop taking dapsone after a mean of 11 months on the diet and all three patients treated with diet alone became asymptomatic after three to 6 months on the diet. These results confirm that most children with dermatitis herpetiformis have jejunal villous atrophy, though they rarely have gastrointestinal symptoms. The central role of gluten in childhood dermatitis herpetiformis is evidenced by the fact that a gluten free diet helps the damaged jejunal mucosa to recover and controls the rash even in those children who do not have an abnormal jejunal biopsy.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 1450,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity. Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.",
            "question": "Which type of cells is affected in Amyotrophic Lateral Sclerosis?",
            "answers": {
                "answer_start": 410,
                "text": "motor neurons"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1139,
                "text": "CO2"
            }
        },
        {
            "context": "JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations, yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells, and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 1021,
                "text": "interleukin-6"
            }
        },
        {
            "context": "A case of orbital metastasis as disease progression of anaplastic lymphoma kinase-positive lung cancer treated with crizotinib. Orbital metastasis of lung cancer is rare. It often causes visual disorder. To date, there are only a few case reports. Crizotinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that leads to responses in most patients with ALK-positive non-small-cell lung cancer. Visual disorder is one of the popular adverse events of crizotinib, but the symptom almost decreases over time. We report a case of orbital metastasis as the disease progression of ALK-positive lung cancer treated with crizotinib. It should be kept in mind that orbital metastasis can be the disease progression of lung adenocarcinoma with ALK translocation treated with crizotinib. When physicians encounter a patient receiving crizotinib with visual disorder, we must distinguish between adverse events and orbital metastasis.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 403,
                "text": "cancer"
            }
        },
        {
            "context": "Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Dementia with Lewy bodies (DLB) is characterized by the widespread presence of Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is expressed as two main isoforms (112 and 140), but little is known about their differential expression in the brain. We compared alpha-synuclein 112 and alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB patients, eight Alzheimer disease (AD) patients, and six control subjects. Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were determined by real-time polymerase chain reaction with competimer technology using a LightCycler System. Whereas total alpha-synuclein levels were just marginally elevated in DLB in comparison with the other groups, alpha-synuclein 112 was seen to be markedly increased in DLB compared with AD cases and controls. In contrast, alpha-synuclein 140 levels were significantly diminished in both neurodegenerative disorders in comparison with controls. These results show differential overexpression of alpha-synuclein 112 in DLB, a finding that could be of importance in DLB pathogenesis.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 193,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Mechanisms of backtrack recovery by RNA polymerases I and II. During DNA transcription, RNA polymerases often adopt inactive backtracked states. Recovery from backtracks can occur by 1D diffusion or cleavage of backtracked RNA, but how polymerases make this choice is unknown. Here, we use single-molecule optical tweezers experiments and stochastic theory to show that the choice of a backtrack recovery mechanism is determined by a kinetic competition between 1D diffusion and RNA cleavage. Notably, RNA polymerase I (Pol I) and Pol II recover from shallow backtracks by 1D diffusion, use RNA cleavage to recover from intermediary depths, and are unable to recover from extensive backtracks. Furthermore, Pol I and Pol II use distinct mechanisms to avoid nonrecoverable backtracking. Pol I is protected by its subunit A12.2, which decreases the rate of 1D diffusion and enables transcript cleavage up to 20 nt. In contrast, Pol II is fully protected through association with the cleavage stimulatory factor TFIIS, which enables rapid recovery from any depth by RNA cleavage. Taken together, we identify distinct backtrack recovery strategies of Pol I and Pol II, shedding light on the evolution of cellular functions of these key enzymes.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 1009,
                "text": "TFIIS"
            }
        },
        {
            "context": "Functional analysis of splicing mutations in exon 7 of NF1 gene. BACKGROUND: Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing. METHODS: In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X), c.945G>A/c.946C>A (Q315Q/L316M), c.1005T>C (N335N)] identified in exon 7 of three different NF1 patients. RESULTS: Our results detected the presence of three exonic splicing enhancers (ESEs) and one putative exonic splicing silencer (ESS) element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1DeltaE7). Both the wild type and the mutated constructs shared NF1DeltaE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1DeltaE7, while in the presence of N335N variant, the NF1DeltaE7 expression is abolished. CONCLUSION: In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 195,
                "text": "NF1"
            }
        },
        {
            "context": "Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Allelic expression differences contribute to phenotypic variation. In X chromosome inactivation (XCI), unfavorable XCI ratios promote X-linked disease penetrance in females. During XCI, one X is randomly silenced by Xist. X chromosome choice is determined by asymmetric expression of Tsix whose antisense action represses Xist. Here, we discover a cis element in the mouse X-inactivation center that regulates Tsix. Xite harbors intergenic transcription start sites and DNaseI hypersensitive sites with allelic differences. At the onset of XCI, deleting Xite downregulates Tsix in cis and skews XCI ratios, suggesting that Xite promotes Tsix persistence on the active X. Truncating Xite RNA is inconsequential, indicating that Xite action does not require intact transcripts. We propose that allele-specific Xite action promotes Tsix asymmetry and generates X chromosome inequality. Therefore, Xite is a candidate for the Xce, the classical modifier of XCI ratios.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 312,
                "text": "Xist"
            }
        },
        {
            "context": "Selective JAK1 inhibitor and selective Tyk2 inhibitor patents. INTRODUCTION: The JAK family comprises of the four non-receptor tyrosine kinases JAK1, JAK2, JAK3 and Tyk2, which play key, but differing, roles in cytokine receptor signal transduction. A non-selective JAK inhibitor, ruxolitinib, has recently been approved to treat myelofibrosis whereas tofacitinib is poised for approval to treat rheumatoid arthritis. Selective inhibition of JAK3, JAK1 or Tyk2 provides the opportunity to achieve clinical efficacy in the treatment of inflammatory diseases while reducing the risk of dose-limiting effects attributable to JAK2 inhibition. AREAS COVERED: This review considers the small number of published patent filings that claim either selective JAK1 or selective Tyk2 inhibitors. These are considered in the context of the considerably larger number of disclosures and patent filings claiming selective JAK2 or JAK3 inhibitors. EXPERT OPINION: The recent disclosure of the clinical efficacy of a selective JAK1 inhibitor (GLPG-0634) in rheumatoid arthritis and detailed disclosure of the some potent and highly selective JAK1 inhibitors provide a clear stimulus for further activity in this area. The availability of a selective Tyk2 inhibitor will provide the opportunity for better understanding of the physiological role of this kinase. Recent patent applications indicate that Tyk2 selectivity is achievable and Tyk2 inhibitors have potential in the treatment of multiple sclerosis.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 352,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Expression of TAP73 and DeltaNP73 in malignant gliomas. The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. We studied differential expression of these forms in normal brain as well as glial tumors, by semiquantitative RT-PCR. The expression of p73 was low or undetectable in normal brain tissues. Most of the tumors and non-tumor brain tissues also lacked significant expression of p73 in patients with low-grade astrocytomas. In contrast, most high-grade glial tumors displayed strong up-regulation of TAp73, whereas only a few displayed DeltaNp73 expression. These aberrations may reflect the inactivation of retinoblastoma pathway in these tumors which result in the activation of E2F transcription factors, since TAp73 is a known target of E2F1 gene. The study of TAp73 expression in brain tumors may serve as a means to evaluate the retinoblastoma pathway-dependent tumor progression.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 165,
                "text": "7"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8"
            }
        },
        {
            "context": "Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. OBJECTIVES: Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. DESIGN: Prospective analysis. PATIENTS: 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses. SETTING: All analyses were performed in a large German laboratory specialised in genetic diagnostics. RESULTS: 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. CONCLUSIONS: On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1616,
                "text": "MITF"
            }
        },
        {
            "context": "Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder for which the exact pathophysiology remains unclear. Brain iron insufficiency and altered dopaminergic function appear to play important roles in the etiology of the disorder. This concept is based partly on extensive research studies using cerebrospinal fluid (CSF), autopsy material, and brain imaging indicating reduced regional brain iron and on the clinical efficacy of dopamine receptor agonists for alleviating RLS symptoms. Finding causal relations, linking low brain iron to altered dopaminergic function in RLS, has required however the use of animal models. These models have provided insights into how alterations in brain iron homeostasis and dopaminergic system may be involved in RLS. The results of animal models of RLS and biochemical, postmortem, and imaging studies in patients with the disease suggest that disruptions in brain iron trafficking lead to disturbances in striatal dopamine neurotransmission for at least some patients with RLS. This review examines the data supporting an iron deficiency-dopamine metabolic theory of RLS by relating the results from animal model investigations of the influence of brain iron deficiency on dopaminergic systems to data from clinical studies in patients with RLS.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 107,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Red hair--a desirable mutation? Red hair is one of the most striking variants of human hair coloration and has historically been of profound social importance. Red hair in man is due to certain loss of function mutations of one of the peptide products of the pro-opiomelanocortin (POMC) gene, the melanocortin-1 receptor (MC1R, MIM 155555). Such functional mutations enable the melanocyte to produce red-yellow pheomelanin in preference to the default, black-brown eumelanin. This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 586,
                "text": "MC1R"
            }
        },
        {
            "context": "A protein complex containing the conserved Swi2/Snf2-related ATPase Swr1p deposits histone variant H2A.Z into euchromatin. The conserved histone variant H2A.Z functions in euchromatin to antagonize the spread of heterochromatin. The mechanism by which histone H2A is replaced by H2A.Z in the nucleosome is unknown. We identified a complex containing 13 different polypeptides associated with a soluble pool of H2A.Z in Saccharomyces cerevisiae. This complex was designated SWR1-Com in reference to the Swr1p subunit, a Swi2/Snf2-paralog. Swr1p and six other subunits were found only in SWR1-Com, whereas six other subunits were also found in the NuA4 histone acetyltransferase and/or the Ino80 chromatin remodeling complex. H2A.Z and SWR1 were essential for viability of cells lacking the EAF1 component of NuA4, pointing to a close functional connection between these two complexes. Strikingly, chromatin immunoprecipitation analysis of cells lacking Swr1p, the presumed ATPase of the complex, revealed a profound defect in the deposition of H2A.Z at euchromatic regions that flank the silent mating type cassette HMR and at 12 other chromosomal sites tested. Consistent with a specialized role for Swr1p in H2A.Z deposition, the majority of the genome-wide transcriptional defects seen in swr1Delta cells were also found in htz1Delta cells. These studies revealed a novel role for a member of the ATP-dependent chromatin remodeling enzyme family in determining the region-specific histone subunit composition of chromatin in vivo and controlling the epigenetic state of chromatin. Metazoan orthologs of Swr1p (Drosophila Domino; human SRCAP and p400) may have analogous functions.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 473,
                "text": "SWR1"
            }
        },
        {
            "context": "Musashi1 as a potential therapeutic target and diagnostic marker for lung cancer. Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in spheroid cultures of tumor cells and in the CD133+ cell population. Downregulation of Msi1 by lentivirus-mediated expression of an Msi1 shRNA reduced spheroid colony proliferation. Growth inhibition was associated with reduced nuclear localization of β-catenin and inhibition of the processing of intracellular Notch. In primary lung cancer, Msi1 protein expression was elevated in 86% of 202 tissue microarray specimens, and Msi1 mRNA was increased in 80% of 118 bronchoscopic biopsies, including metastatic disease, but was rarely detected in adjacent normal lung tissue and in non-malignant diseased tissue. Msi1 was expressed in a diffuse pattern in most tumor subtypes, except in squamous cell carcinomas, where it appeared in a focal pattern in 50% of specimens. Thus, Msi1 is a sensitive and specific diagnostic marker for all lung cancer subtypes.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 558,
                "text": "squamous cell carcinoma"
            }
        },
        {
            "context": "Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. OBJECTIVES: This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. BACKGROUND: Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. RESULTS: Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 560,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "[Atypical paraneoplastic myasthenic syndrome: Lambert-Eaton syndrome or myasthenia?]. We report a case of paraneoplastic myasthenic syndrome with clinical features suggesting Lambert Eaton syndrome but without the electromyographic elements required for diagnosis. Anti-calcium channel antibodies were also lacking. The electromyogram evidenced a block and the Tensilon test was positive. The efficacy of anticholinesterases argued in favor of myasthenia but anti-acetylcholine receptor antibodies were negative. The block was more of a mixed nature, involving both presynaptic transmission as in Lambert Eaton syndrome and post-synaptic transmission as in paraneoplastic myasthenia. The primary tumor was identified as a small-cell neuroendocrine lung carcinoma on mediastinal biopsies obtained directly on CT-scan guided puncture of a mediastinal node. Thoracotomy was thus avoided. The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer. A mixed paraneoplastic neuro-muscle junction disorder with aspects of each can be exceptionally observed.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 1064,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "Identification of Leishmania species causing cutaneous leishmaniasis using Random Amplified Polymorphic DNA (RAPD-PCR) in Kharve, Iran. BACKGROUND: Leishmaniasis, especially cutaneous leishmaniasis, is considered an important health problem in many parts of Iran including Kharve, Khorasan Razavi province. Cutaneous leishmaniasis is caused by various species of Leishmania, each having a different secondary host. Thus, identifying the parasites' specie is of paramount importance for containment strategy planning. The morphological differentiation of Leishmania species is not possible, rendering the molecular methods as the sole means to this purpose. Therefore, to identify the causative agent of cutaneous leishmaniasis in Kharve, Random Amplified Polymorphic DNA-PCR (RAPD-PCR) was used. METHODS: The disease was first confirmed by direct smears. Samples were gathered from 22 patients with established cutaneous leishmaniasis. The samples were immediately cultured in NNN medium, followed by sub-culture in RPMI-1640. Afterwards, DNA was extracted and amplified using RAPD-PCR. Electrophoresis patterns from each isolate were compared with reference strains of Leishmania major (L. major) and Leishmania tropica (L. tropica). RESULTS: The results of this study indicated that the parasite causing cutaneous leishmaniasis in Kharve is L. tropica. CONCLUSION: It seems that L. tropica is the only causative agent of cutaneous leishmaniasis in Kharve, and RAPD-PCR is a suitable tool for Leishmania characterization in epidemiological studies.",
            "question": "What causes leishmaniasis?",
            "answers": {
                "answer_start": 18,
                "text": "Leishmania species"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 408,
                "text": "7"
            }
        },
        {
            "context": "Characterization of cancer stem cells in chronic myeloid leukaemia. CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-kappaB (nuclear factor kappaB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 277,
                "text": "bcr-abl"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 831,
                "text": "CisMapper"
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1037,
                "text": "PD-L1"
            }
        },
        {
            "context": "Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled repair. BACKGROUND: In eukaryotic cells, there are two sub-pathways of nucleotide excision repair (NER), the global genome (gg) NER and the transcription-coupled repair (TCR). TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA. This strand-specific repair in a suitable restriction fragment is usually determined by alkaline gel electrophoresis followed by Southern blotting transfer and hybridization with an indirect end-labeled single-stranded probe. Here we describe a new method of TCR assay based on strand-specific-PCR (SS-PCR). Using this method, we have investigated the role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related protein kinases (PIKK) family, in the TCR pathway of UV-induced DNA damage. RESULTS: Although depletion of DNA-PKcs sensitized HeLa cells to UV radiation, it did not affect the ggNER efficiency of UV-induced cyclobutane pyrimidine dimers (CPD) damage. We postulated that DNA-PKcs may involve in the TCR process. To test this hypothesis, we have firstly developed a novel method of TCR assay based on the strand-specific PCR technology with a set of smart primers, which allows the strand-specific amplification of a restricted gene fragment of UV radiation-damaged genomic DNA in mammalian cells. Using this new method, we confirmed that siRNA-mediated downregulation of Cockayne syndrome B resulted in a deficiency of TCR of the UV-damaged dihydrofolate reductase (DHFR) gene. In addition, DMSO-induced silencing of the c-myc gene led to a decreased TCR efficiency of UV radiation-damaged c-myc gene in HL60 cells. On the basis of the above methodology verification, we found that the depletion of DNA-PKcs mediated by siRNA significantly decreased the TCR capacity of repairing the UV-induced CPDs damage in DHFR gene in HeLa cells, indicating that DNA-PKcs may also be involved in the TCR pathway of DNA damage repair. By means of immunoprecipitation and MALDI-TOF-Mass spectrometric analysis, we have revealed the interaction of DNA-PKcs and cyclin T2, which is a subunit of the human transcription elongation factor (P-TEFb). While the P-TEFb complex can phosphorylate the serine 2 of the carboxyl-terminal domain (CTD) of RNA polymerase II and promote transcription elongation. CONCLUSION: A new method of TCR assay was developed based the strand-specific-PCR (SS-PCR). Our data suggest that DNA-PKcs plays a role in the TCR pathway of UV-damaged DNA. One possible mechanistic hypothesis is that DNA-PKcs may function through associating with CyclinT2/CDK9 (P-TEFb) to modulate the activity of RNA Pol II, which has already been identified as a key molecule recognizing and initializing TCR.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 363,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "\"These boots were made for walking\": the isotopic analysis of a C(4) Roman inhumation from Gravesend, Kent, UK. As part of the road widening scheme between London and Dover, Oxford Archaeology South uncovered a large boundary ditch of Iron Age origin that contained Iron Age and Roman inhumations, adjacent to which was a small mid-late Roman cemetery, interpreted as a rural cemetery for Romano-British farmers. Grave goods in the cemetery were restricted to a few individuals with hobnailed boots. Bulk bone collagen isotopic analysis of 11 skeletons of Iron Age and Roman date gave a typical C(3) terrestrial signal (average δ(13) C = -19.8‰, δ(15) N = 9.3‰), but also revealed one (SK12671) with a diet which included a substantial C(4) component (δ(13) C = -15.2‰, δ(15) N = 11.2‰). This is only the second such diet reported in Roman Britain. Subsequent δ(18) O(c) and (87) Sr/(86) Sr measurements on the dental enamel in this individual were, however, consistent with a \"local\" origin, indicating that either C(4) protein was consumed in Late Roman Britain, or that he came from somewhere else, but where conditions gave rise to similar isotopic values. If we accept the latter, then it indicates that using oxygen and strontium isotopes alone to identify \"incomers\" may be problematic. The provision of hobnailed boots for the dead appears to have had a strong symbolic element in Late Roman Britain. We suggest that in this case the boots may be significant, in that he was being equipped for the long march home.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 510,
                "text": "collagen"
            }
        },
        {
            "context": "Ecallantide is a novel treatment for attacks of hereditary angioedema due to C1 inhibitor deficiency. Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor protein is a rare disease, characterized by paroxysms of edema formation in the subcutis and in the submucosa. Edema can cause obstruction of the upper airway, which may lead to suffocation. Prompt elimination of edema is necessary to save patients from this life-threatening condition. Essentially, these edematous attacks are related to the activation of the kinin-kallikrein system and the consequent release of bradykinin. Ecallantide (known as DX-88 previously), a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. This is the only agent approved recently by the FDA for all localizations of edematous HAE attacks. Its advantages include no risk of viral contamination, high selectivity, very rapid onset of action, good tolerability, and straightforward subcutaneous administration. Owing to the risk of anaphylaxis, ecallantide should be administered by a health care professional. A postmarketing survey to improve risk-assessment and risk-minimization has been launched. The results of these studies may lead to the approval of ecallantide for self-administration.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 607,
                "text": "Ecallantide"
            }
        },
        {
            "context": "The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review. INTRODUCTION: Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. AREAS COVERED: SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1443,
                "text": "Xa"
            }
        },
        {
            "context": "Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 190,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Mechanism-based neddylation inhibitor. Brownell et al. (2010) elucidate the mechanism of action of MLN4924, a NEDD8-activating enzyme inhibitor. MLN4924 requires the activity of the enzyme to generate a NEDD8-adenylate analog that potently and selectively shuts down this posttranslational modification system.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 110,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Investigational anticoagulants for hematological conditions: a new generation of therapies. INTRODUCTION: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options. AREAS COVERED: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV. EXPERT OPINION: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 637,
                "text": "xa"
            }
        },
        {
            "context": "Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 924,
                "text": "CD38"
            }
        },
        {
            "context": "Microsporidia infection of the cornea--a unique and challenging disease. Microsporidia are a diverse group of obligate, intracellular, eukaryotic, spore-forming parasites. Traditionally, these were considered as protozoans but recently have been reclassified as fungi. Microsporidia behave as opportunistic pathogens causing systemic infections. In the eye, Microsporidia cause keratoconjunctivitis, corneal stromal keratitis, scleritis, and endophthalmitis. This review shares our experiences with anterior segment infections caused by this pathogen. Keratoconjunctivitis is a common form of ocular infection caused by the parasite. Although early reports described it as occurring only in immunosuppressed individuals, it can also occur in immunocompetent individuals. The disease shows a seasonal pattern with a peak incidence during the rainy season. Although several drugs have been considered, our experience suggests that keratoconjunctivitis is a self-limiting disease. In contrast to keratoconjunctivitis, stromal keratitis is an ill-defined disease. We collected 30 cases and analyzed the various aspects of this disease. Stromal keratitis is characterized by a slowly progressive course. The corneal picture resembles herpes simplex virus stromal keratitis or fungal keratitis cases, and is characterized by deep stromal infiltrates with overlying and surrounding stromal edema and keratic precipitates. The diagnosis of Microsporidia infection is confirmed by a microscopic examination of smears from patients with ulcerative keratitis or by a histopathological examination of corneal tissues. Definitive genus identification requires the examination of specimens by electron microscopy or by molecular methods. In the absence of a definitive medical treatment, nearly all patients require surgical treatment. The confusion regarding Microsporidia is not only limited to their classification but also extends to various aspects of the corneal disease caused by them.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 262,
                "text": "fungi"
            }
        },
        {
            "context": "Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation. Monocarboxylate transporter 8 (MCT8 or SLC16A2) is important for the neuronal uptake of triiodothyronine (T3) in its function as a specific and active transporter of thyroid hormones across the cell membrane, thus being essential for human brain development. We report on a German male with Allan-Herndon-Dudley syndrome presenting with severe intellectual and motor disability, paroxysmal dyskinesia combined with truncal muscular hypotonia, and peripheral muscular hypertonia at his current age of 9 years. Additionally, the patient has a lesion in the left putamen region revealed by magnetic resonance imaging and elevated serum T3 levels. The male appeared to have a hemizygous mutation (R271H) in the MCT8 gene that was sequenced directly from genomic DNA and occurred de novo in the maternal germline, as both his mother and his sister were not carriers of the mutation. Ruling out a common polymorphism, 50 normal individuals of the same ethnic background did not harbour the mutation. The identified MCT8 gene mutation (R271H) is very likely to be the genetic cause for neuronal hypothyroidism despite elevated serum T3 levels.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 1246,
                "text": "thyroid"
            }
        },
        {
            "context": "Giant axonal neuropathy diagnosed on skin biopsy. Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 506,
                "text": "GAN gene"
            }
        },
        {
            "context": "Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1009,
                "text": "PD-L1"
            }
        },
        {
            "context": "Tolerance to oats in dermatitis herpetiformis. OBJECTIVES: Recent studies on coeliac disease have shown that oats can be included in a gluten-free diet without adverse effects on the small bowel. The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats. PATIENTS/METHODS: Eleven patients with dermatitis herpetiformis in remission on a gluten-free diet were challenged daily with 50 g oats for six months. Clinical symptoms were recorded, serum samples taken, and skin and small bowel biopsies performed before and after the oat challenge. A control group comprised of 11 patients with dermatitis herpetiformis on a conventional gluten-free diet was also studied. RESULTS: Eight patients challenged with oats remained asymptomatic, two developed a transient rash, and one withdrew because of the appearance of a more persistent but mild rash. Three of the 11 controls also developed a transient rash. IgA endomysial antibodies remained negative in all patients. The small bowel villous architecture, the densities of intraepithelial CD3 and alpha/beta and gamma/delta T cell receptor positive lymphocytes and crypt epithelial cell DR expression remained unaltered during the oat challenge. CONCLUSIONS: The results confirm the absence of oat toxicity on the gluten sensitive small bowel mucosa and suggest that the rash in patients with dermatitis herpetiformis is not activated by eating oats.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 425,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Structural and functional variations in human apolipoprotein E3 and E4. There are three major apolipoprotein E (apoE) isoforms. Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 is a dual risk factor to atherosclerosis and Alzheimer disease. We have expressed full-length and N- and C-terminal truncated apoE3 and apoE4 tailored to eliminate helix and domain interactions to unveil structural and functional disturbances. The N-terminal truncated apoE4-(72-299) and C-terminal truncated apoE4-(1-231) showed more complicated or aggregated species than those of the corresponding apoE3 counterparts. This isoformic structural variation did not exist in the presence of dihexanoylphosphatidylcholine. The C-terminal truncated apoE-(1-191) and apoE-(1-231) proteins greatly lost lipid binding ability as illustrated by the dimyristoylphosphatidylcholine turbidity clearance. The low density lipoprotein (LDL) receptor binding ability, determined by a competition binding assay of 3H-LDL to the LDL receptor of HepG2 cells, showed that apoE4 proteins with N-terminal (apoE4-(72-299)), C-terminal (apoE4-(1-231)), or complete C-terminal truncation (apoE4-(1-191)) maintained greater receptor binding abilities than their apoE3 counterparts. The cholesterol-lowering abilities of apoE3-(72-299) and apoE3-(1-231) in apoE-deficient mice were decreased significantly. The structural preference of apoE4 to remain functional in solution may explain the enhanced opportunity of apoE4 isoform to display its pathophysiologic functions in atherosclerosis and Alzheimer disease.",
            "question": "Which ApoE isoform is associated with atherosclerosis and Alzheimer's disease?",
            "answers": {
                "answer_start": 1487,
                "text": "apoE4 isoform"
            }
        },
        {
            "context": "Disease-causing mutations in the cystic fibrosis transmembrane conductance regulator determine the functional responses of alveolar macrophages. Alveolar macrophages (AMs) play a major role in host defense against microbial infections in the lung. To perform this function, these cells must ingest and destroy pathogens, generally in phagosomes, as well as secrete a number of products that signal other immune cells to respond. Recently, we demonstrated that murine alveolar macrophages employ the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel as a determinant in lysosomal acidification (Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., and Nelson, D. J. (2006) Nat. Cell Biol. 8, 933-944). Lysosomes and phagosomes in murine cftr(-/-) AMs failed to acidify, and the cells were deficient in bacterial killing compared with wild type controls. Cystic fibrosis is caused by mutations in CFTR and is characterized by chronic lung infections. The information about relationships between the CFTR genotype and the disease phenotype is scarce both on the organismal and cellular level. The most common disease-causing mutation, DeltaF508, is found in 70% of patients with cystic fibrosis. The mutant protein fails to fold properly and is targeted for proteosomal degradation. G551D, the second most common mutation, causes loss of function of the protein at the plasma membrane. In this study, we have investigated the impact of CFTR DeltaF508 and G551D on a set of core intracellular functions, including organellar acidification, granule secretion, and microbicidal activity in the AM. Utilizing primary AMs from wild type, cftr(-/-), as well as mutant mice, we show a tight correlation between CFTR genotype and levels of lysosomal acidification, bacterial killing, and agonist-induced secretory responses, all of which would be expected to contribute to a significant impact on microbial clearance in the lung.",
            "question": "Which is the most common CFTR mutation in Caucasians?",
            "answers": {
                "answer_start": 1235,
                "text": "DeltaF508"
            }
        },
        {
            "context": "The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women's health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer. The search for the 'ideal' SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained. In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 33,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1028,
                "text": "NCX"
            }
        },
        {
            "context": "Anesthetic approach to the Dyke-Davidoff-Masson syndrome--a case report. The so-called Dyke-Davidoff-Masson syndrome (DDMS) is a rare disorder of cerebral hemiatrophy. The clinical presentation may consist of facial asymmetry, contralateral atrophy (including the trunk, and the extremities) and hemiparesis, speech difficulties, mental retardation, and epilepsy. Because it involves multiple systems, especially problem of the airway, occult myopathy, and seizure disorder, anesthesia for such a patient is a challenge to any anesthesiologist. However, there are no clinical reports which concern the anesthetic management of such patients in the literature. We herein report a 5-year-old girl, a sufferer of DDMS, scheduled for burr trephination. The successful anesthetic management is brought forward with highlights of inference from the experience.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 146,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Intravenous immunoglobulin treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Intravenous immunoglobulin (IVIG) is an established treatment of immune-mediated demyelinating neuropathy. Since IVIG possesses multiple immunomodulatory and anti-inflammatory properties, IVIG therapy may represent a way of interfering with the disease process in multiple sclerosis (MS). In the MS animal model experimental autoimmune encephalomyelitis (EAE), infusions of IVIG significantly reduced disease symptoms as well as the underlying CNS pathology. IVIG was only effective in EAE when administered in a prophylactic treatment protocol, since IVIG infusions during the established phase of EAE did not alter the disease course or the degree of inflammation found in the central nervous system. IVIG also has the potential to act through myelin repair mechanisms as evidenced by work done in the Theilers murine encephalomyelitis virus model of demyelination. Together these observations have led to certain expectations for IVIG as a treatment for MS, and have resulted in various clinical trials. Several controlled trials report beneficial effects of IVIG on relapse rate, new MRI lesions, and disease progression in relapsing-remitting MS, while a remyelinating effect of IVIG has not been documented. IVIG is, therefore, presently regarded as a second-line therapy of MS.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 436,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2. In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro and p.His1045Arg, identified in the highly conserved C-zinc-finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects or HSCR. In vitro studies showed that all the three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of the zebrafish morphant technology, we performed rescue experiments using wild-type (WT) and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed. Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2 mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 443,
                "text": "ZEB2"
            }
        },
        {
            "context": "In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first 'outside to in' signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of interleukin 17 (IL-17) and interferon γ production and proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA animal model using SCID mice implanted with synovium and cartilage from patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice and also reduced synovial inflammation and invasion into the implanted cartilage. A phase 2 double-blind study using tofacitinib was carried out in Japanese patients with active RA and inadequate response to methotrexate (MTX). A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo twice daily and the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12, a primary end point, was significant for all tofacitinib treatment groups. Thus, an orally available tofacitinib in combination with MTX was efficacious and had a manageable safety profile. Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation to optimise the treatment of RA.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1757,
                "text": "Tofacitinib"
            }
        },
        {
            "context": "Casein kinase II phosphorylates the eukaryote-specific C-terminal domain of topoisomerase II in vivo. The decatenation activity of DNA topoisomerase II is essential for viability as eukaryotic cells traverse mitosis. Phosphorylation has been shown to stimulate topoisomerase II activity in vitro. Here we show that topoisomerase II is a phosphoprotein in yeast and that the level of incorporated phosphate is significantly higher at mitosis than in G1. Comparison of tryptic phosphopeptide maps reveals that the major phosphorylation sites in vivo are targets for casein kinase II. Incorporation of phosphate into topoisomerase II is nearly undetectable at the non-permissive temperature in a conditional casein kinase II mutant. The sites modified by casein kinase II are located in the extreme C-terminal domain of topoisomerase II. This domain is absent in prokaryotic and highly divergent among eukaryotic type II topoisomerases, and may serve to regulate functions of topoisomerase II that are unique to eukaryotic cells.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 135,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "[STI571 (Glivec)--a new drug for the treatment of chronic myeloid leukemia]. Chronic myeloid leukaemia (CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase. In the chronic phase of the disease, normal peripheral blood values are achieved within the first month of treatment in the large majority of patients and in many patients also a cytogenic response within the following months. The results in the advanced phase are far less favourable, which is explained by the development of resistance owing to reactivation of the BCR-ABL signal transduction. Side effects are primarily nausea, vomiting, various rashes, oedema, most often in the periorbital region, and musculoskeletal symptoms, including muscle cramps. Perspectives for treatment with STI571 are described, as are combinations with alpha-interferon and other cytostatics with a synergistic profile.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 244,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "The properties of a tRNA-specific adenosine deaminase from Drosophila melanogaster support an evolutionary link between pre-mRNA editing and tRNA modification. Pre-mRNA editing involving the conversion of adenosine to inosine is mediated by adenosine deaminases that act on RNA (ADAR1 and ADAR2). ADARs contain multiple double-stranded RNA(dsRNA)-binding domains in addition to an adenosine deaminase domain. An adenosine deaminase acting on tRNAs, scTad1p (also known as scADAT1), cloned from Saccharomyces cerevisiae has a deaminase domain related to the ADARs but lacks dsRNA-binding domains. We have identified a gene homologous to scADAT1 in the region of Drosophila melanogaster Adh chromosome II. Recombinant Drosophila ADAT1 (dADAT1) has been expressed in the yeast Pichia pastoris and purified. The enzyme has no activity on dsRNA substrates but is a tRNA deaminase with specificity for adenosine 37 of insect alanine tRNA. dADAT1 shows greater similarity to vertebrate ADARs than to yeast Tad1p, supporting the hypothesis of a common evolutionary origin for ADARs and ADATs. dAdat1 transcripts are maternally supplied in the egg. Zygotic expression is widespread initially and later concentrates in the central nervous system.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 979,
                "text": "ADAR"
            }
        },
        {
            "context": "Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome. The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 549,
                "text": "FBN1"
            }
        },
        {
            "context": "Evidence for a complex of transcription factor IIB with poly(A) polymerase and cleavage factor 1 subunits required for gene looping. Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB). We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner (El Kaderi, B., Medler, S., Raghunayakula, S., and Ansari, A. (2009) J. Biol. Chem. 284, 25015-25025). The presence of TFIIB at the 3' end of a gene required its interaction with cleavage factor 1 (CF1) 3' end processing complex subunit Rna15. Here, employing affinity chromatography and glycerol gradient centrifugation, we show that TFIIB associates with poly(A) polymerase and the entire CF1 complex in yeast cells. The factors required for general transcription such as TATA-binding protein, RNA polymerase II, and TFIIH are not a component of the TFIIB complex. This holo-TFIIB complex was resistant to MNase digestion. The complex was observed only in the looping-competent strains, but not in the looping-defective sua7-1 strain. The requirement of Rna15 in gene looping has been demonstrated earlier. Here we provide evidence that poly(A) polymerase (Pap1) as well as CF1 subunits Rna14 and Pcf11 are also required for loop formation of MET16 and INO1 genes. Accordingly, cross-linking of TFIIB to the 3' end of genes was abolished in the mutants of Pap1, Rna14, and Pcf11. We further show that in sua7-1 cells, where holo-TFIIB complex is not formed, the kinetics of activated transcription is altered. These results suggest that a complex of TFIIB, CF1 subunits, and Pap1 exists in yeast cells. Furthermore, TFIIB interaction with the CF1 complex and Pap1 is crucial for gene looping and transcriptional regulation.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 284,
                "text": "TFIIB"
            }
        },
        {
            "context": "Analysis of mutations of neurofibromatosis type 1 gene and N-ras gene in acute myelogenous leukemia. Neurofibromatosis type 1 (NF1) gene is a tumor suppressor gene, and the NF1 gene product, neurofibromin, can downregulate the N-ras gene. Because the N-ras gene is often mutated in acute myelogenous leukemia (AML), we wondered if the NF1 gene might be mutated in those AML samples not having N-ras mutations. We investigated the mutational status of the N-ras gene and the FLR exon of codons 1371-1423 of the open reading frame of the full-length NF1 cDNA, which has a strong homology with the mammalian ras GTPase-activating protein (GAP), especially for a stretch of three consecutive amino acids (F, L, R), by single-strand conformation polymorphism analysis and direct sequencing in samples from patients with AML. Of 48 AML patients, 10 (21%) had point (missense) mutations of the N-ras gene involving codons 12, 13 and 61. However, mutations in the FLR exon of the NF1 gene were not detected in any of the AML samples. We also examined the difference of clinical response to induction therapy between AML patients with and without N-ras mutation. A significantly lower rate of complete remission was noted in individuals with N-ras gene mutations. These results suggest that mutation of the NF1 gene, at least in the FLR exon, is very rare in AML and the NF1 gene probably is not a functional complement of the N-ras gene mutation. The presence of N-ras gene mutation may be associated with a lower clinical response to antileukemic therapy.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 127,
                "text": "NF1"
            }
        },
        {
            "context": "C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin. We identified 2 cases with C9ORF72 repeat expansions. Both harbored phosphorylated TDP-43 and DPR inclusions. We show that DPR inclusions can incorporate or occur independently of ubiquilin. We also identified 1 case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 1194,
                "text": "ALS"
            }
        },
        {
            "context": "RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China. BACKGROUND: Genetic screening for germline mutations in the RET proto-oncogene has been extensively exploited worldwide to optimize the diagnostic and clinical management of multiple endocrine neoplasia type 2 (MEN2) patients and their relatives. However, a distinct lag period exists not only in the recognition but also in the medical treatment of patients with MEN2. Here we present a comprehensive genetic and clinical analysis of MEN2 among Chinese families followed from 1975 to 2011. Our series comprises 36 index cases and 134 relatives from 11 independent families. METHODS: Genetic diagnosis was performed in all participants by direct sequencing all relevant RET exons. Thyroidectomy was performed in 50 patients with varying cervical neck dissection procedures. Patients with pheochromocytoma (PHEO) underwent specific surgery. Demographic, clinical profiles, mutation types, tumor histopathologic features, and follow-up records were systematically analyzed. RESULTS: The RET mutations p.C634Y (n=34), p.C634R (n=6), p.C618S (n=13), p.V292M/R67H/R982C (n=7), p.L790F (n=2), and p.C634Y/V292M/R67H/R982C (n=1) were confirmed in 31 index cases and then identified in 32 at-risk relatives (mutation carriers), with MEN2A as the most common clinical subtype. The overall penetrance of PHEO in patients with MEN2A was 46.7%. A total of 50 patients underwent thyroidectomy, and there was a significant lowering of their mean age at thyroidectomy and the tumor diameter of the mutation carriers that were detected and operated on compared with the index cases (age at first surgery: 29.3 vs. 39.3 years, p<0.05; maximum size: 1.1 vs. 3.3 cm, p<0.001). There was also a decrease in the TNM staging and the proportion of patients who underwent inappropriate initial thyroid surgery (pN1: 31.6% vs. 100%, p<0.001; inappropriate surgery: 0% vs. 29%). Meanwhile, disease-free survival (DFS) increased (DFS: 100% vs. 58.1%, p<0.05). Both medullary thyroid carcinoma-specific (n=1) and PHEO-specific (n=5) deaths were reported during the study period. CONCLUSIONS: Our results further substantiate that gene scanning of all relevant RET exons is a powerful tool in the management of MEN2 patients, especially in asymptomatic carriers, and has led to earlier diagnosis and more complete initial treatment of patients with MEN2 in China.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 2277,
                "text": "RET"
            }
        },
        {
            "context": "Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. Activation of the non-phagocytic superoxide-producing NADPH oxidase Nox1, complexed with p22(phox) at the membrane, requires its regulatory soluble proteins Noxo1 and Noxa1. However, the role of the small GTPase Rac remained to be clarified. Here we show that Rac directly participates in Nox1 activation via interacting with Noxa1. Electropermeabilized HeLa cells, ectopically expressing Nox1, Noxo1, and Noxa1, produce superoxide in a GTP-dependent manner, which is abrogated by expression of a mutant Noxa1(R103E), defective in Rac binding. Superoxide production in Nox1-expressing HeLa and Caco-2 cells is decreased by depletion or sequestration of Rac; on the other hand, it is enhanced by expression of the constitutively active Rac1(Q61L), but not by that of a mutant Rac1 with the A27K substitution, deficient in binding to Noxa1. We also demonstrate that Nox1 activation requires membrane recruitment of Noxa1, which is normally mediated via Noxa1 binding to Noxo1, a protein tethered to the Nox1 partner p22(phox): the Noxa1-Noxo1 and Noxo1-p22(phox) interactions are both essential for Nox1 activity. Rac likely facilitates the membrane localization of Noxa1: although Noxa1(W436R), defective in Noxo1 binding, neither associates with the membrane nor activates Nox1, the effects of the W436R substitution are restored by expression of Rac1(Q61L). The Rac-Noxa1 interaction also serves at a step different from the Noxa1 localization, because the binding-defective Noxa1(R103E), albeit targeted to the membrane, does not support superoxide production by Nox1. Furthermore, a mutant Noxa1 carrying the substitution of Ala for Val-205 in the activation domain, which is expected to undergo a conformational change upon Rac binding, fully localizes to the membrane but fails to activate Nox1.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 173,
                "text": "Nox1"
            }
        },
        {
            "context": "Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. BACKGROUND: Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. METHODS: Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. RESULTS: NSD1 gene mutations were detected in 26 (72%) Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations (6 frameshift, 8 nonsense, 2 spice site, and 7 missense). Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. CONCLUSIONS: Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 12,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome. A 14-month-old male child presented with recurrent generalized seizures, spastic hemiplegia, microcephaly and had developmental delay in motor and speech domains. CT of the brain revealed characteristic features diagnostic of infantile type of cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 275,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Acute first onset of Ehlers-Danlos syndrome type 4 with spontaneous rupture of posterior tibial artery pseudoaneurysm. Ehlers-Danlos syndrome type 4, the vascular type, is a rare, life-threatening inherited disorder of the connective tissue. Affected patients are at risk of arterial, bowel and uterine rupture during pregnancy. Generally, this syndrome remains undiagnosed until a sudden, acute presentation with organ rupture, and results in premature death, even if the patients survive the first and second major complications. An early diagnosis with genetic assays can help to plan the best treatment, which is often challenging due to the frailty of the arterial tissue. We report on a 28-year-old lady who presented with spontaneous rupture of a pseudoaneurysm of the posterior tibial artery.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 223,
                "text": "connective tissue"
            }
        },
        {
            "context": "Microbial lysate upregulates host oxytocin. Neuropeptide hormone oxytocin has roles in social bonding, energy metabolism, and wound healing contributing to good physical, mental and social health. It was previously shown that feeding of a human commensal microbe Lactobacillus reuteri (L. reuteri) is sufficient to up-regulate endogenous oxytocin levels and improve wound healing capacity in mice. Here we show that oral L. reuteri-induced skin wound repair benefits extend to human subjects. Further, dietary supplementation with a sterile lysate of this microbe alone is sufficient to boost systemic oxytocin levels and improve wound repair capacity. Oxytocin-producing cells were found to be increased in the caudal paraventricular nucleus [PVN] of the hypothalamus after feeding of a sterile lysed preparation of L. reuteri, coincident with lowered blood levels of stress hormone corticosterone and more rapid epidermal closure, in mouse models. We conclude that microbe viability is not essential for regulating host oxytocin levels. The results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals.",
            "question": "Which is the \"bonding hormone\"?",
            "answers": {
                "answer_start": 65,
                "text": "oxytocin"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 488,
                "text": "xa"
            }
        },
        {
            "context": "Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristics of the BD GeneOhm MRSA assay, the Xpert MRSA assay, and broth-enriched culture in an area with a low prevalence of MRSA infections. Universal surveillance upon patient admission is important in reducing the transmission of methicillin-resistant Staphylococcus aureus (MRSA) and associated disease in hospitals. High costs for the health care system in conjunction with MRSA have promoted the development of rapid screening methods to detect MRSA carriers. This study compared two real-time PCR methods, the BD GeneOhm MRSA assay (BDGO) and the Xpert MRSA assay, with broth-enriched culture to define their performance characteristics and rapidity in an area with low MRSA prevalence. In total, 414 swabs from the nose and 389 swabs from the groin from 425 patients were tested. Of those 425 patients, 378 had swabs from both the nose and groin in parallel. Two hundred thirty-one and 194 patients were randomly assigned to the BDGO group and the Xpert MRSA group, respectively. In general, sensitivity, specificity, and negative predictive value (NPV) were high for the BDGO (100%, 98.5%, and 100%, respectively) and the Xpert MRSA (100%, 98.2%, and 100%, respectively), irrespective of whether or not nasal and inguinal specimens were considered alone or combined. In contrast, the positive predictive value (PPV) was lower: before the resolution of discrepant results, the PPVs for nasal and inguinal specimens alone and combined were 87.5%, 86.7%, and 82.4% for the BDGO and 91.7%, 66.7%, and 92.9% for the Xpert MRSA, respectively. After the resolution of discrepant results, PPVs were 93.8%, 93.3% and 94.1% for the BDGO and 91.7%, 88.9% and 92.9% for the Xpert MRSA, respectively. With the BDGO, 4 of 16 carriers were each identified by nasal or inguinal swabs alone, whereas in the Xpert MRSA group, 4 of 13 carriers were exclusively identified by nasal swabs and 2 of 13 were identified by inguinal swabs alone. Both PCR methods showed no significant difference in the number of discrepant results (odds ratio, 0.70 [P = 0.789]), but specimens from wounds and other body sites (axilla, vagina, and throat) produced discrepancies more often than nasal and groin specimens (odds ratios, 4.724 [P = 0.058] and 12.163 [P < 0.001], respectively). The facts that no false-negative PCR results were detected and increased PPVs were found after the resolution of discrepant results point to PCR as the actual gold standard. Since both sensitivity and NPV were exceptionally high for PCR, backup cultures may, therefore, be unnecessary in an area with low prevalence and with a preemptive isolation strategy but may still be useful for PCR-positive specimens because of the lower PPV for both methods and the possibility of susceptibility testing. The median time for analysis, including extraction, hands-on time, and actual PCR was 2 h 20 min for the Xpert MRSA versus 5 h 40 min for the BDGO. Concerning reporting time, including administration and specimen collection, the Xpert MRSA was faster than the BDGO (7 h 50 min versus 17 h).",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 148,
                "text": "MRSA"
            }
        },
        {
            "context": "Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies. Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 309,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 14,
                "text": "FBN1"
            }
        },
        {
            "context": "S100A4 interacts with p53 in the nucleus and promotes p53 degradation. S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.",
            "question": "Where in the cell does the proteins S100A4 and p53 interact ?",
            "answers": {
                "answer_start": 731,
                "text": "nucleus"
            }
        },
        {
            "context": "Histone variant H2A.Z regulates centromere silencing and chromosome segregation in fission yeast. The incorporation of histone variant H2A.Z into nucleosomes plays essential roles in regulating chromatin structure and gene expression. A multisubunit complex containing chromatin remodeling protein Swr1 is responsible for the deposition of H2A.Z in budding yeast and mammals. Here, we show that the JmjC domain protein Msc1 is a novel component of the fission yeast Swr1 complex and is required for Swr1-mediated incorporation of H2A.Z into nucleosomes at gene promoters. Loss of Msc1, Swr1, or H2A.Z results in loss of silencing at centromeres and defective chromosome segregation, although centromeric levels of CENP-A, a centromere-specific histone H3 variant that is required for setting up the chromatin structure at centromeres, remain unchanged. Intriguingly, H2A.Z is required for the expression of another centromere protein, CENP-C, and overexpression of CENP-C rescues centromere silencing defects associated with H2A.Z loss. These results demonstrate the importance of H2A.Z and CENP-C in maintaining a silenced chromatin state at centromeres.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 466,
                "text": "Swr1"
            }
        },
        {
            "context": "Should the annular tendon of the eye be named 'annulus of Zinn' or 'of Valsalva'? The annular tendon is commonly named 'annulus of Zinn', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755). This structure, however, had been previously discovered not by Zinn, but by Antonio Maria Valsalva (1666-1723) some decades before the publication of Zinn, in his Dissertatio anatomica prima and Dissertatio anatomica altera (First and Second Anatomical Dissertations), inside Valsalva's Opera omnia published in 1740. We advance that this structure could be re-named such as 'annulus of Valsalva-Zinn' because Valsalva, even making a mistake in its functional interpretation, first described this anatomical structure. Likewise, Valsalva, with his discovery, advanced a revolutionary idea for that time on the usefulness of anatomy for clinic and pathology.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 318,
                "text": "Eye"
            }
        },
        {
            "context": "Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well-ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 318,
                "text": "H3K4"
            }
        },
        {
            "context": "A disrupted homologue of the human CLN3 or juvenile neuronal ceroid lipofuscinosis gene in Saccharomyces cerevisiae: a model to study Batten disease. 1. In order to investigate the biological function of the human CLN3 gene that is defective in Batten disease, we created a yeast strain by PCR-targeted disruption of the yeast gene (YHC3), which is a homologue of the human CLN3 gene. 2. The phenotypic characterization revealed that the yhc3 delta mutants are more sensitive to combined heat and alkaline stress than the wild-type strains as determined by inhibition of cell proliferation. 3. This suggests that the yhc3 delta mutant is a good model to investigate the biological function of human CLN3 gene in mammalian cells and to understand the pathophysiology of juvenile Batten disease.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 245,
                "text": "Batten disease"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 419,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans. Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner. In this paper we provide further insight into frataxin control of C. elegans longevity by showing that a substantial reduction of frataxin protein expression is required to extend lifespan, affect sensory neurons functionality, remodel lipid metabolism and trigger autophagy. We find that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. In sum, we demonstrate a causal connection between induction of autophagy and lifespan extension following reduced frataxin expression, thus providing the rationale for investigating autophagy in the pathogenesis and treatment of Friedreich's ataxia and possibly other human mitochondria-associated disorders.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 524,
                "text": "frataxin"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 152,
                "text": "xa"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 0,
                "text": "webSDA"
            }
        },
        {
            "context": "Adult neuronal ceroid lipofuscinosis with clinical findings consistent with a butterfly glioma. Case report. The authors report a case of neuronal ceroid lipofuscinosis (Kufs' disease) confirmed by stereotactically obtained brain biopsy findings and initially diagnosed as a butterfly glioma. The presenting symptoms in the 64-year-old patient were mental alterations with progressive dementia, followed by muscular atrophy and myoclonia with distal preponderance. The mild initial disturbances of coordination increased, and the patient developed a markedly ataxic gait. Computerized tomography (CT) scanning and magnetic resonance imaging revealed generalized cerebral atrophy and a bifrontal space-occupying lesion involving the callosum. The original \"clearcut\" diagnosis of glioblastoma multiforme, based on CT scans, was unexpectedly disproved by examination of stereotactically obtained brain biopsy specimens, which revealed a neuronal ceroid lipofuscinosis (Kufs' disease). To the authors' knowledge, this is the first report of a case presenting with both diffuse brain atrophy and localized accumulation of neuronal lipofuscin, mimicking a mass lesion on radiological studies.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 779,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "Treatment of Phthiriasis Palpebrarum and Crab Louse: Petrolatum Jelly and 1% Permethrin Shampoo. Phthiriasis palpebrarum is an uncommon cause of blepharoconjunctivitis in which Pthirus pubis infest the eyelashes. We report a case of unilateral phthiriasis palpebrarum with crab louse. A 45-year-old man presented with conjunctival hyperaemia and moderate itching associated with irritation, and crusty excretions of the eyelashes in the left eye. Careful slit-lamp examination revealed many lice and nits in left eye and mild conjunctival hyperaemia. No abnormality was found in the right eye. On dermatologic examination, only one louse was found at the pubic area. The patient was treated effectively with petrolatum jelly (Vaseline) and 1% permethrin shampoo (Kwellada 1% shampoo). At the end of the first week no louse or nit was present on eyelashes and pubic area.",
            "question": "What is the cause of Phthiriasis Palpebrarum?",
            "answers": {
                "answer_start": 177,
                "text": "Pthirus pubis"
            }
        },
        {
            "context": "Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use).",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 598,
                "text": "naloxone"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1184,
                "text": "xa"
            }
        },
        {
            "context": "Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 908,
                "text": "NGF"
            }
        },
        {
            "context": "Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies. Cortical dysplasias comprise a variable spectrum of clinical, neuroradiological and histopathological findings. We report about a cohort of 25 pediatric patients (mean age 8.1+/-4.8 years) with severe drug-resistant early onset focal epilepsies (mean duration 2.1+/-0.4 years), mental/psychomotor retardation, and multilobar epileptogenesis. Compared to age-matched biopsy controls, microscopical inspection of neurosurgically resected specimens revealed dysplastic neurons with/without balloon cells in only 7 patients. According to Palmini's classification system, these lesions were categorized as focal cortical dysplasia (FCD) type II. All other patients presented with rather subtle but statistically significant neuroanatomical abnormalities. We identified increased numbers of ectopic neurons in white matter and cortical gliosis. However, most intriguing was our finding of a microcolumnar arrangement of cortical neurons in layer III. These microcolumns can be statistically defined as vertical lining of more than eight neurons (two times standard deviation of cell countings obtained from controls). In addition, neuronal perikarya were significantly smaller in epilepsy patients. Although histological abnormalities occurring during postnatal maturation of the brain challenge any neuropathological classification in this group of young patients, we propose that these findings are classified according to FCD type I. Our observations support a concept compatible with regional loss of high-order brain organization.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 692,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Mowat-Wilson syndrome: deafness in the first Egyptian case who was conceived by intracytoplasmic sperm injection. Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects. The prevalence of Mowat-Wilson syndrome is currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed, particularly in patients without Hirschsprung disease. We report here the first Egyptian case of Mowat-Wilson syndrome who was conceived by intracytoplasmic sperm injection. The patient manifested bilateral sensorineural hearing loss--a new feature not previously reported in cases of Mowat-Wilson syndrome. This report describes the first Egyptian patient of Mowat-Wilson syndrome who was conceived after intracytoplasmic sperm injection, and provides a new evidence for the inclusion of deafness among the congenital defects of the syndrome.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 248,
                "text": "ZEB2"
            }
        },
        {
            "context": "Idarucizumab as Antidote to Intracerebral Hemorrhage under Treatment with Dabigatran. BACKGROUND AND PURPOSE: Non-vitamin K anticoagulants (NOAC) such as dabigatran have become important therapeutic options for the prevention of stroke. Until recently, there were only nonspecific agents to reverse their anticoagulant effects in a case of emergency. Idarucizumab, an antibody fragment targeting dabigatran, is the first specific antidote for a NOAC to be approved, but real-world experience is limited. METHODS: We report two cases of patients on dabigatran with acute intracerebral hemorrhage who received idarucizumab. RESULTS: In both cases, idarucizumab promptly reversed the anticoagulant effect of dabigatran and there was no hematoma expansion in follow-up imaging. CONCLUSIONS: In addition to clinical and preclinical studies, our cases add to the experience regarding the safety and efficacy of idarucizumab. They show that idarucizumab may be an important safety option for patients on dabigatran in emergency situations.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 396,
                "text": "dabigatran"
            }
        },
        {
            "context": "Branched chain amino acid suppresses hepatocellular cancer stem cells through the activation of mammalian target of rapamycin. Differentiation of cancer stem cells (CSCs) into cancer cells causes increased sensitivity to chemotherapeutic agents. Although inhibition of mammalian target of rapamycin (mTOR) leads to CSC survival, the effect of branched chain amino acids (BCAAs), an mTOR complex 1 (mTORC1) activator remains unknown. In this study, we examined the effects of BCAA on hepatocellular carcinoma (HCC) cells expressing a hepatic CSC marker, EpCAM. We examined the effects of BCAA and/or 5-fluorouracil (FU) on expression of EpCAM and other CSC-related markers, as well as cell proliferation in HCC cells and in a xenograft mouse model. We also characterized CSC-related and mTOR signal-related molecule expression and tumorigenicity in HCC cells with knockdown of Rictor or Raptor, or overexpression of constitutively active rheb (caRheb). mTOR signal-related molecule expression was also examined in BCAA-treated HCC cells. In-vitro BCAA reduced the frequency of EpCAM-positive cells and improved sensitivity to the anti-proliferative effect of 5-FU. Combined 5-FU and BCAA provided better antitumor efficacy than 5-FU alone in the xenograft model. Stimulation with high doses of BCAA activated mTORC1. Knockdown and overexpression experiments revealed that inhibition of mTOR complex 2 (mTORC2) or activation of mTORC1 led to decreased EpCAM expression and little or no tumorigenicity. BCAA may enhance the sensitivity to chemotherapy by reducing the population of cscs via the mTOR pathway. This result suggests the utility of BCAA in liver cancer therapy.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 269,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "About three cases of ulceroglandular tularemia, is this the re-emergence of Francisella tularensis in Belgium? Tularemia is a zoonosis caused by Francisella tularensis that can be transmitted by several ways to human being and cause different clinical manifestations. We report three clinical cases of tularemia with ulceroglandular presentation in young males acquired during outdoor activities in Southern Belgium. Confirmation of the diagnosis was established by serology. Only three cases of tularemia have been reported in Belgium between 1950 and 2012 by the National Reference Laboratory CODA-CERVA (Ref Lab CODA-CERVA) but re-emergence of tularemia is established in several European countries and F. tularensis is also well known to be present in animal reservoirs and vectors in Belgium. The diagnosis of tularemia has to be considered in case of suggestive clinical presentation associated with epidemiological risk factors.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 145,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "The perplexing complexity of cardiac arrhythmias: beyond electrical remodeling. Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 233,
                "text": "af"
            }
        },
        {
            "context": "A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. INTRODUCTION: Previously, autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT [1]) was mapped to chromosome 1q42-43 with identification of pathogenic mutations in RYR2. Autosomal recessive CPVT (2) was mapped to chromosome 1p13-21, leading to the identification of mutations in CASQ2. In this study, we aimed to elucidate clinical phenotypes of a new variant of CPVT (3) in an inbred Arab family and also delineate the chromosomal location of the gene causing CPVT (3). METHODS AND RESULTS: In a highly inbred family, clinical symptoms of CPVT appeared early in childhood (7-12 years) and in three of the four cases, the first appearance of symptoms turned into a fatal outcome. Parents of the affected children were first-degree cousins and without any symptoms. Segregation analysis suggested an autosomal recessive inheritance. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 25-Mb interval on chromosome 7p14-p22. A maximal multipoint LOD score of 3.17 was obtained at marker D7S493. Sequencing of putative candidate genes, SP4, NPY, FKBP9, FKBP14, PDE1C, and TBX20, in and around this locus, did not reveal any mutation. CONCLUSIONS: We have identified a novel highly malignant autosomal recessive form of CPVT and mapped this disorder to a 25-Mb interval on chromosome 7p14-p22.",
            "question": "What is the inheritance pattern of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) caused by RYR2 mutations?",
            "answers": {
                "answer_start": 144,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "[Imatinib therapy for patients with chronic myelogenous leukemia]. Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 465,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 587,
                "text": "stroke"
            }
        },
        {
            "context": "Fresh approaches stem MRSA tide. The theory of positive deviance holds that in any group, some people are more effective than others even when they have the same resources at hand. The object is to identify those people, see what they're doing differently and share it with the larger group. The Plexus Institute and the Robert Wood Johnson Foundation recently collaborated on a six-hospital positive-deviance study that reduced methicillin-resistant Staphylococcus aureus (MRSA) infection rates by 70 percent. What these hospitals learned may help others cut their MRSA rates.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 474,
                "text": "MRSA"
            }
        },
        {
            "context": "In vivo analysis of Cajal body movement, separation, and joining in live human cells. Cajal bodies (also known as coiled bodies) are subnuclear organelles that contain specific nuclear antigens, including splicing small nuclear ribonucleoproteins (snRNPs) and a subset of nucleolar proteins. Cajal bodies are localized in the nucleoplasm and are often found at the nucleolar periphery. We have constructed a stable HeLa cell line, HeLa(GFP-coilin), that expresses the Cajal body marker protein, p80 coilin, fused to the green fluorescent protein (GFP-coilin). The localization pattern and biochemical properties of the GFP-coilin fusion protein are identical to the endogenous p80 coilin. Time-lapse recordings on 63 nuclei of HeLa(GFP-coilin) cells showed that all Cajal bodies move within the nucleoplasm. Movements included translocations through the nucleoplasm, joining of bodies to form larger structures, and separation of smaller bodies from larger Cajal bodies. Also, we observed Cajal bodies moving to and from nucleoli. The data suggest that there may be at least two classes of Cajal bodies that differ in their size, antigen composition, and dynamic behavior. The smaller size class shows more frequent and faster rates of movement, up to 0.9 microm/min. The GFP-coilin protein is dynamically associated with Cajal bodies as shown by changes in their fluorescence intensity over time. This study reveals an unexpectedly high level of movement and interactions of nuclear bodies in human cells and suggests that these movements may be driven, at least in part, by regulated mechanisms.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 440,
                "text": "coilin"
            }
        },
        {
            "context": "Recurrence of the D409H mutation in Spanish Gaucher disease patients: description of a new homozygous patient and haplotype analysis. Gaucher disease results, in most patients, from mutations in the gene encoding glucocerebrosidase. Mutation D409H is the third most frequent in Spanish patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the neurological forms of the disease. Recently, homozygosity for the D409H mutation has been associated with a particular phenotype, including specific cardiovascular symptoms. Here we report a second Spanish patient bearing the D409H/D409H genotype with a very early manifestation of the disease. The patient started enzyme replacement therapy at 3 months of age. A common origin for the Spanish D409H alleles was ruled out by haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 213,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BACKGROUND: X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. RESULTS: We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. CONCLUSIONS: Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 161,
                "text": "X"
            }
        },
        {
            "context": "Management of cutaneous erythrasma. Corynebacterium minutissimum is the bacteria that leads to cutaneous eruptions of erythrasma and is the most common cause of interdigital foot infections. It is found mostly in occluded intertriginous areas such as the axillae, inframammary areas, interspaces of the toes, intergluteal and crural folds, and is more common in individuals with diabetes mellitus than other clinical patients. This organism can be isolated from a cutaneous site along with a concurrent dermatophyte or Candida albicans infection. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis and intertrigo, and methods for differentiating include Wood's light examination and bacterial and mycological cultures. Erythromycin 250mg four times daily for 14 days is the treatment of choice and other antibacterials include tetracycline and chloramphenicol; however, the use of chloramphenicol is limited by bone marrow suppression potentially leading to neutropenia, agranulocytosis and aplastic anaemia. Further studies are needed but clarithromycin may be an additional drug for use in the future. Where there is therapeutic failure or intertriginous involvement, topical solutions such as clindamycin, Whitfield's ointment, sodium fusidate ointment and antibacterial soaps may be required for both treatment and prophylaxis. Limited studies on the efficacy of these medications exist, however, systemic erythromycin demonstrates cure rates as high as 100%. Compared with tetracyclines, systemic erythromycin has greater efficacy in patients with involvement of the axillae and groin, and similar efficacy for interdigital infections. Whitfield's ointment has equal efficacy to systemic erythromycin in the axillae and groin, but shows greater efficacy in the interdigital areas and is comparable with 2% sodium fusidate ointment for treatment of all areas. Adverse drug effects and potential drug interactions need to be considered. No cost-effectiveness data are available but there are limited data on cost-related treatment issues. A guideline is proposed for the detection, evaluation, treatment and prophylaxis of this cutaneous eruption.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 36,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "Lipopolysaccharide (LPS) induces the apoptosis and inhibits osteoblast differentiation through JNK pathway in MC3T3-E1 cells. Bone degradation is a serious complication of chronic inflammatory diseases such as septic arthritis, osteomyelitis, and infected orthopedic implant failure. Up to date, effective therapeutic treatments for bacteria-caused bone destruction are limited. In our previous study, we found that LPS promoted osteoclast differentiation and activity through activation of mitogen-activated protein kinases (MAPKs) pathway such as c-Jun N-terminal kinases (JNK) and extracellular signal regulated kinase (ERK1/2). The current study was to evaluate the mechanism of LPS on the apoptosis and osteoblast differentiation in MC3T3-E1 cells. MC3T3-E1 osteoblasts were non-treated, treated with LPS. After treatment, the cell viability, the activity of alkaline phosphatase (ALP) and caspase-3 were measured. The expressions of osteoblast-specific genes and Bax, Bcl-2, and caspase-3 were determined by real-time quantitative polymerase chain reaction (qPCR). Protein levels of Bax, Bcl-2, caspase-3, and phosphorylation of MAPKs were measured using Western blotting assays. The MAPK signaling pathway was blocked by pretreatment with JNK inhibitor SP600125. LPS treatment induced a significant decrease in cell metabolism, viability, and ALP activity in MC3T3-E1 cells. LPS also significantly decreased mRNA expressions of osteoblast-related genes in MC3T3-E1 cells. On the other hand, LPS significantly upregulated mRNA expressions and protein levels of Bax and caspase-3 as well as activation of caspase-3, whereas decreased Bcl-2 expression in MC3T3-E1 cells. Furthermore, LPS significantly promoted MAPK pathway including the phosphorylation of JNK and the phosphorylation of ERK1/2; moreover, pretreatment with JNK inhibitor not only attenuated both of phosphorylation-JNK and ERK1/2 enhanced by LPS in MC3T3-E1 cells, but also reversed the downregulated expressions of osteoblast-specific genes including ALP and BSP induced by LPS. In conclusion, LPS could induce osteoblast apoptosis and inhibit osteoblast differentiation via activation of JNK pathway.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 575,
                "text": "JNK"
            }
        },
        {
            "context": "Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs disease. Two affected HEXA alleles were found in an Israeli Druze Tay-Sachs child born to first-cousin parents. His paternal allele contained two adjacent changes in exon 5: delta496C, which resulted in a frameshift and premature termination codon 96 nucleotides downstream, and 498C-->G, a silent mutation. The maternal allele had a 835T-->C transition in exon 8 (S279P). Phosphoimaging quantitation of the parents' RNAs showed that the steady-state levels of mRNAs of the mutant exons 5 and 8 were 5% and 50%, respectively, of normal levels. The exon 5 mutated allele with the premature translation termination resulted in severe deficiency of Hex A. Transient expression of the exon 8 mutated alpha-chain cDNA in COS-1 cells resulted in deficiency of enzymatic activity. The child exhibited a late-infantile-type disease.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 12,
                "text": "HEXA"
            }
        },
        {
            "context": "subSeq: determining appropriate sequencing depth through efficient read subsampling. MOTIVATION: Next-generation sequencing experiments, such as RNA-Seq, play an increasingly important role in biological research. One complication is that the power and accuracy of such experiments depend substantially on the number of reads sequenced, so it is important and challenging to determine the optimal read depth for an experiment or to verify whether one has adequate depth in an existing experiment. RESULTS: By randomly sampling lower depths from a sequencing experiment and determining where the saturation of power and accuracy occurs, one can determine what the most useful depth should be for future experiments, and furthermore, confirm whether an existing experiment had sufficient depth to justify its conclusions. We introduce the subSeq R package, which uses a novel efficient approach to perform this subsampling and to calculate informative metrics at each depth. AVAILABILITY AND IMPLEMENTATION: The subSeq R package is available at http://github.com/StoreyLab/subSeq/.",
            "question": "Which method for subsampling of NGS reads requires only gene counts?",
            "answers": {
                "answer_start": 837,
                "text": "subSeq"
            }
        },
        {
            "context": "Active surveillance of sudden cardiac death in young athletes by periodic Internet searches. The authors hypothesized that prospective, systematic Internet searches could identify occurrences of sudden cardiac death (SCD) in athletes and would be useful for establishing a system of active surveillance. Weekly advanced Google searches of the Internet were conducted for cases of SCD in young athletes during a 12-month period (2007-2008). Athletes ages 11-30 years who collapsed during a game, practice, or within an hour of exercise were included in the study. Individuals with known histories of cardiac issues and events occurring outside the United States were excluded. Verification of SCD was by autopsy reports and death certificates from county coroner offices and vital record agencies. Initially, 71 events were identified. Verification for the cause of death by coroner reports was possible in 45 cases, 43 (96 %) of which were confirmed to be SCDs. A total of 69 individuals 11-30 years of age (mean 17 ± 5 years) died suddenly of cardiovascular causes while participating in 15 different organized sports and a variety of nonorganized physical activities. The most common cause of death was hypertrophic cardiomyopathy (30 %), followed by coronary artery anomalies (9 %), and myocarditis (9 %). The incidence of athlete SCD, the types of sports involved, and the cardiac causes of death in our study were comparable with those of previous reports. Readily available Internet searches have the potential to be a powerful tool for identifying occurrences of athlete SCD. An active surveillance system using Google searches followed by coroner report verification can provide important epidemiologic and clinical information.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 1205,
                "text": "hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "[Botulinum toxin: from poison to drug. A historical review]. Botulinumtoxin (BTX) is a neurotoxin produced from Clostridium botulinum under anaerobic conditions and is responsible for botulism, a notifiable, bacterial form of food poisoning. The first case of botulism is believed to have occurred in 1735. An epidemic in Southern Germany in 1793 claimed the death of over the half of those patients who had become ill through eating uncooked blood sausages. The term \"pharmakon\" is Greek and implicates that a drug originates from poison (potion, remedy). Theophrastus Bombast von Hohenheim known as Paracelsus (1493/94-1541) first described this duality with his dictum \"alle ding sind gift und nichts on gift; alein die dosis macht das ein ding kein gift ist\" (only the dose makes a remedy poisonous). In Baden-Württemberg in 1817, the poet and physician Dr. Justinus Christian Kerner described the symptoms of botulism, so that at this time botulism was also called Kerner disease. Until the turn of the century the reason for poisoning was not known. Van Ermengem succeeded in isolating the anaerobic bacterium causing botulism, but the specific mechanism of BTX was only established after the second World War. In the late seventies the ophthalmologist Dr. Alan Scott used BTX the first time in the treatment of strabismus. The drug was then used in the treatment of several muscle spasticities such as, for example, torticollis or hemifacial spasm. Only recently BTX has been successfully used for focal hyperhidrosis. We review the history of botulinum toxin from its discovery in the nineteenth century and the research into its effect in the middle of the 20th century up to its clinical use at the present time.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 112,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "BRCA1 affects global DNA methylation through regulation of DNMT1. Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCA1-associated breast cancer formation.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 265,
                "text": "DNMT1"
            }
        },
        {
            "context": "The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies. Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 569,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. PURPOSE: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. RESULTS: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. CONCLUSION: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.",
            "question": "What is targeted by Palbociclib?",
            "answers": {
                "answer_start": 368,
                "text": "epidermal growth factor receptor"
            }
        },
        {
            "context": "The proteome of the calcified layer organic matrix of turkey (Meleagris gallopavo) eggshell. BACKGROUND: Chicken eggshell mineralization is a prominent model for biomineralization not only because of its importance for avian reproduction but also because of the commercial interest associated with eggshell quality. An analysis and comparison of the protein constituents of eggshells of several species would contribute to a better understanding of the shell mineralization process. The recent publication of the turkey genome sequence now provides a basis for the in-depth analysis of the turkey eggshell proteome. RESULTS: Proteomic analysis of turkey acid-soluble and acid-insoluble organic eggshell matrix yielded 697 identified proteins/protein groups. However, intensity-based absolute quantification (iBAQ) results indicated that the 47 most abundant identified proteins already constituted 95% of the total turkey eggshell matrix proteome. Forty-four of these proteins were also identified in chicken eggshell matrix previously. Despite these similarities there were important and unexpected differences. While ovocleidin-116 and ovocalyxin-36 were major proteins constituting approximately 37% of the identified proteome, other members of the group of so-called eggshell-specific proteins were not identified. Thus ovocalyxin-21 and ovocalyxin-32 were missing among matrix proteins. Conversely, major turkey eggshell proteins were not detected in chicken, such as the bone protein periostin, the mammalian counterpart of which is involved in many aspects of bone metabolism and which represented 10-11% of the total identified proteome. CONCLUSIONS: Even members of the same avian family show important differences in eggshell matrix composition and more studies on the proteome and the transcriptome level will be necessary to identify a common toolkit of eggshell mineralization and to work out species differences among functional eggshell protein sets and their role in eggshell production.",
            "question": "What does iBAQ stand for in proteomic analysis?",
            "answers": {
                "answer_start": 767,
                "text": "intensity-based absolute quantification"
            }
        },
        {
            "context": "The dopamine transporter is decreased in the striatum of subjects with restless legs syndrome. STUDY OBJECTIVES: Prior studies, all using SPECT techniques, failed to find any differences for dopamine transporter (DAT) in restless legs syndrome (RLS) subjects. The distinct pharmacokinetic properties associated with SPECT-determined DAT along with rapid biodynamic changes in DAT may, however, have missed membrane-bound DAT differences. The current studies assessed real-time DAT binding potentials (BP) in striatum of RLS patients using (11)C-methylphenidate and PET techniques. DESIGN: RLS medications were stopped at least 11 days prior to the PET study. Clinical severity of RLS was also assessed. PET scans were performed at 2 different times of day (starting at 08:30 and 19:30) in separate groups of subjects. The primary outcome measure was total striatal DAT BP. PARTICIPANTS: Thirty-six patients with primary RLS and 34 age- and gender-matched controls. RESULTS: RLS subjects had significantly lower DAT binding in the striatum compared to controls on both the Day and the Night scans. DAT was decreased in putamen and caudate but not the ventral striatum of RLS subjects. There were no diurnal differences in DAT for the total group or for control and RLS separately. DAT BP did not correlate with any clinical measures of RLS. CONCLUSION: The current study found a significant decrease in DAT BP in two independent studies. These results when viewed along with prior RLS SPECT and autopsy studies of DAT, and cell culture studies with iron deficiency and DAT, suggest that membrane-bound striatal DAT, but not total cellular DAT, may be decreased in RLS.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1548,
                "text": "iron"
            }
        },
        {
            "context": "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways. The transition between a unicellular yeast form to multicellular filaments is crucial for budding yeast foraging and the pathogenesis of many fungal pathogens such as Candida albicans. Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation. Overexpression of either ECM22 or UPC2 leads to increased filamentation, whereas cells lacking both ECM22 and UPC2 do not exhibit filamentous growth. Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes. These genes all play a positive role in filamentous growth, and their expression is upregulated during filamentation in an Ecm22/Upc2-dependent manner. Furthermore, ergosterol content increases during filamentous growth. UPC2 expression also increases during filamentation and is inhibited by the transcription factors Sut1 and Sut2. The expression of SUT1 and SUT2 in turn is under negative control of the transcription factor Ste12. We suggest that during filamentation Ste12 becomes activated and reduces SUT1/SUT2 expression levels. This would result in increased UPC2 levels and as a consequence to transcriptional activation of FHN1, NPR1, PRR2 and sterol biosynthesis genes. Higher ergosterol levels in combination with the proteins Fhn1, Npr1 and Prr2 would then mediate the transition to filamentous growth.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 399,
                "text": "Ecm22"
            }
        },
        {
            "context": "MR of craniocerebral hemiatrophy. The magnetic resonance (MR) findings of three patients with cerebral hemiatrophy, the so-called Dyke-Davidoff-Masson syndrome, which is characterized by variable degrees of unilateral loss of cerebral volume and compensatory changes of the calvarium are presented. The condition was due to middle cerebral artery stroke in all patients. The pathologic alterations of cerebral tissue and the brainstem were reflected in detail on the MR studies. MR findings in addition to the primary vascular insult included prominence of the cortical sulci and perimesencephalic cistern in one subject with acquired infarction, but an absence of such generalized sulcal prominence in two cases of congenital infantile paralysis. Otherwise the secondary ipsilateral pathologic observations were quite similar in the patients with congenital and acquired ischemic disease and encompassed a unilaterally small cerebral hemisphere together with ipsilateral diploic calvarial expansion, elevation of the petrous bone and orbital roof, and hypoplasia/atrophy of the cerebral peduncle. Although computed tomography (CT) and MR are complimentary, it is felt that MR represents the imaging procedure of choice with respect to the assessment of the etiology and extent of cerebral parenchymal involvement in patients presenting with a clinical combination of congenital or early onset of seizures, hemiparesis/plegia, and/or craniofacial asymmetry.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 94,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 630,
                "text": "MC1R"
            }
        },
        {
            "context": "Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis. SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING protein required for the activity of Cullin-RING ligase (CRL). Our recent study showed that Sag total knockout caused embryonic lethality at E11.5-12.5 days with associated defects in vasculogenesis. Whether Sag is required for de novo vasculogenesis in embryos and angiogenesis in tumors is totally unknown. Here, we report that Sag endothelial deletion also causes embryonic lethality at E15.5 with poor vasculogenesis. Sag deletion in primary endothelial cells (ECs) or knockdown in MS-1 ECs inhibits migration, proliferation and tube formation, with p27 accumulation being responsible for the suppression of migration and proliferation. Furthermore, Sag deletion significantly inhibits angiogenesis in an in vivo Matrigel plug assay, and tumor angiogenesis and tumorigenesis in a B16F10 melanoma model. Finally, MLN4924, an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE) that inhibits CRL, suppresses in vitro migration, proliferation and tube formation, as well as in vivo angiogenesis and tumorigenesis. Taken together, our study, using both genetic and pharmaceutical approaches, demonstrates that Sag is essential for embryonic vasculogenesis and tumor angiogenesis, and provides the proof-of-concept evidence that targeting Sag E3 ubiquitin ligase may have clinical value for anti-angiogenesis therapy of human cancer.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 1061,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Vimentin intermediate filaments as a template for silica nanotube preparation. Organic compounds are used as templates to regulate the morphology of inorganic nanostructures. In the present study, we used intermediate filaments (IFs), the major cytoskeleton component of most eukaryotic cells, as a template for hollow silica nanotube preparation. Sol-gel polymerization of tetraethoxysilane proceeded preferentially on the surface of IFs assembled from vimentin protein in vitro, resulting in silica-coated fibres. After removing IFs by calcination, electron microscopy revealed hollow silica nanotubes several micrometers long, with outer diameters of 35-55 nm and an average inner diameter of 10 nm (comparable to that of IFs). Furthermore, the silica nanotubes exhibited a gnarled surface structure with an 18-26 nm repeating pattern (comparable to the 21-nm beading pattern along IFs). Thus, the characteristic morphology of IFs were well replicated into hollow silica nanotubes, suggesting that IFs maybe useful as an organic template.",
            "question": "What is the average diameter of intermediate filaments?",
            "answers": {
                "answer_start": 696,
                "text": "10 nm"
            }
        },
        {
            "context": "Antinociceptive mechanism of L-DOPA. The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 203,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene. Sotos syndrome is a well-known overgrowth syndrome caused by haploinsufficiency of NSD1 gene located at 5q35. There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). We investigated detailed craniofacial, dental, and oral findings in five patients with deletion type, and three patients with mutation type Sotos syndrome. All eight patients had a high palate, excessive tooth wear, crowding, and all but one patient had hypodontia and deep bite. Hypodontia was exclusively observed in the second premolars, and there were no differences between the deletion and mutation types in the number of missing teeth. Another feature frequently seen in common with both types was maxillary recession. Findings seen more frequently and more pronounced in deletion-type than in mutation-type included mandibular recession, scissors or posterior cross bite, and small dental arch with labioclination of the maxillary central incisors. It is noteworthy that although either scissors bite or cross bite was present in all of the deletion-type patients, neither of these was observed in mutation-type patients. Other features seen in a few patients include enamel hypoplasia (two deletion patients), and ectopic tooth eruption (one deletion and one mutation patients). Our study suggests that Sotos syndrome patients should be observed closely for possible dental and oral complications especially for malocculusion in the deletion-type patients.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 415,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 29,
                "text": "MC1R"
            }
        },
        {
            "context": "The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments. The prevention and treatment of cognitive impairment in the elderly has assumed increasing importance in an aging population. This article presents a qualitative review of recent research on experimental interventions for the prevention and treatment of mild cognitive impairment and Alzheimer's disease in elderly subjects. Interventions addressed range from lifestyle measures to pharmacological treatments. Epidemiological studies suggest that dietary measures, physical exercise, and mental activity may reduce the risk of cognitive impairment and Alzheimer's disease in elderly subjects. Statins may protect against incident dementia, and lithium may convey similar benefits to bipolar patients. Ginkgo appears ineffective as a primary preventive measure. Donepezil but not Vitamin E may benefit persons with mild cognitive impairment. Experimental treatments potentially useful for Alzheimer's disease include dimebon, PBT2 and etanercept; the safety and efficacy of the Alzheimer's vaccine remains to be proven, and growth hormone secretagogue and tarenflurbil are likely ineffective. Herbal treatments merit study in elderly subjects with cognitive syndromes.",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 1011,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 453,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Rheb and Rags come together at the lysosome to activate mTORC1. mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.",
            "question": "Which type of GTPases is required for amino acid-dependent activation of mTORC1?",
            "answers": {
                "answer_start": 430,
                "text": "heterodimeric Rag GTPases"
            }
        },
        {
            "context": "New insights into pri-miRNA processing and accumulation in plants. MicroRNAs (miRNAs) regulate many biological processes such as development, metabolism, and others. They are processed from their primary transcripts called primary miRNA transcripts (pri-miRNAs) by the processor complex containing the RNAse III enzyme, DICER-LIKE1 (DCL1), in plants. Consequently, miRNA biogenesis is controlled through altering pri-miRNA accumulation and processing, which is crucial for plant development and adaptation to environmental changes. Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins. Here, we summarize recent progresses related to pri-miRNA transcription, stability, and processing in plants.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 582,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Marfan syndrome patient experiences as ascertained through postings on social media sites. Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents [Population Reference Bureau, 2013]. Some adolescent patients with MS may use social media to express their experiences and emotions, but little is known about what patients choose to share online. To investigate social media content related to Marfan syndrome we used search terms \"Marfan syndrome\" and \"Marfans\" on six different social media sites. The top five recent and popular posts for each site were collected and coded weekly for five weeks. Posts were excluded if they were reshared content or not in English. A codebook was developed using an iterative process to categorize posts and comments. Out of 300 posts collected 147 posts (49.0%) were included for evaluation. Categories of displayed content included personal pictures, memes and pictures featuring symptoms of MS (41.5%) and personal MS experiences (27.1% of posts). One quarter of the posts specifically mentioned a positive experience or how thankful the profile owner was for their life. A unique category of posts (13.7%) referenced Austin Carlile, a celebrity singer with MS, as a role model. Physicians and healthcare providers may consider using social media to understand common MS concerns and to place future health education materials.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 117,
                "text": "connective tissue"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 542,
                "text": "Genomiser"
            }
        },
        {
            "context": "Macromolecular crowding in the Escherichia coli periplasm maintains alpha-synuclein disorder. The natively disordered protein alpha-synuclein is the primary component of Lewy bodies, the cellular hallmark of Parkinson's disease. Most studies of this protein are performed in dilute solution, but its biologically relevant role is performed in the crowded environment inside cells. We addressed the effects of macromolecular crowding on alpha-synuclein by combining NMR data acquired in living Escherichia coli with in vitro NMR data. The crowded environment in the E.coli periplasm prevents a conformational change that is detected at 35 degrees C in dilute solution. This change is associated with an increase in hydrodynamic radius and the formation of secondary structure in the N-terminal 100 amino acid residues. By preventing this temperature-induced conformational change, crowding in the E.coli periplasm stabilizes the disordered monomer. We obtain the same stabilization in vitro upon crowding alpha-synuclein with 300 g/l of bovine serum albumin, indicating that crowding alone is sufficient to stabilize the disordered, monomeric protein. Two disease-associated variants (A30P and A53T) behave in the same way in both dilute solution and in the E.coli periplasm. These data reveal the importance of approaching the effects of macromolecular crowding on a case-by-case basis. Additionally, our work shows that discrete structured protein conformations may not be achieved by alpha-synuclein inside cells, implicating the commonly overlooked aspect of macromolecular crowding as a possible factor in the etiology of Parkinson's disease.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 126,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "[Antagonism of the effects of benzodiazepines using flumazenil (Ro 15-1788)]. Flumazenil (Ro 15-1788) proved to be a very efficacious competitive antagonist of benzodiazepines that reliably counteracts their pharmacological actions within 1-2 min as could be demonstrated in clinical and EEG studies. In general, a total dose of 0.3-0.8 mg will be sufficient in clinical practice, avoiding side effects like nausea, tremor, sweating, or transient anxiety that could be observed when higher dosages were administered. Its therapeutic range is very high as could be demonstrated in experimental animal in which up to 8.000-fold the clinical dose was administered. The total volume of distribution (Vdes) amounts to nearly 1.000 ml/kg BW and the total clearance exceeds 1.200 ml/min, resulting in a biological half-life of less than 60 min. According to the benzodiazepine dosage and the rapid plasma concentration decline of flumazenil, in some cases a resedation could be observed. Hence, a careful observation of the antagonised patient on the ward is mandatory for 1.5-2 h, even if at first sight the antagonization seemed successful and the patient fully awake and cooperative. In anaesthesia, indications to administer flumazenil are adverse drug reactions and prolonged recovery after adequate benzodiazepine dosage. In intensive care medicine, the antagonist may be used in the treatment of benzodiazepine overdose as well as in the differential diagnosis of a coma of unknown origin. Additionally, the antagonist may be administered to interrupt benzodiazepine sedation e.g. for neurological examination.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 78,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Nasal MRSA colonization: impact on surgical site infection following spine surgery. BACKGROUND: Prior studies published in the cardiothoracic, orthopedic and gastrointestinal surgery have identified the importance of nasal (methicillin-resistant Staphylococcus aureus) MRSA screening and subsequent decolonization to reduce MRSA surgical site infection (SSI). This is the first study to date correlating nasal MRSA colonization with postoperative spinal MRSA SSI. OBJECTIVE: To assess the significance of nasal MRSA colonization in the setting of MRSA SSI. METHODS: A retrospective electronic chart review of patients from year 2011 to June 2013 was conducted for patients with both nasal MRSA colonization within 30 days prior to spinal surgery. Patients who tested positive for MRSA were put on contact isolation protocol. None of these patients received topical antibiotics for decolonization of nasal MRSA. RESULTS: A total of 519 patients were identified; 384 negative (74%), 110 MSSA-positive (21.2%), and 25 (4.8%) MRSA-positive. Culture positive surgical site infection (SSI) was identified in 27 (5.2%) cases and was higher in MRSA-positive group than in MRSA-negative and MSSA-positive groups (12% vs. 5.73% vs. 1.82%; p=0.01). The MRSA SSI rate was 0.96% (n=5). MRSA SSI developed in 8% of the MRSA-positive group as compared to only in 0.61% of MRSA-negative group, with a calculated odds ratio of 14.23 (p=0.02). In the presence of SSI, nasal MRSA colonization was associated with MRSA-positive wound culture (66.67 vs. 12.5%; p<0.0001). CONCLUSION: Preoperative nasal MRSA colonization is associated with postoperative spinal MRSA SSI. Preoperative screening and subsequent decolonization using topical antibiotics may help in decreasing the incidence of MRSA SSI after spine surgery. Nasal MRSA+ patients undergoing spinal surgery should be informed regarding their increased risk of developing surgical site infection.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 269,
                "text": "MRSA"
            }
        },
        {
            "context": "Peroxiredoxin 2 inhibits granulosa cell apoptosis during follicle atresia through the NFKB pathway in mice. Peroxiredoxin 2 (PRDX2) has been known to act as an antioxidant enzyme whose main function is H(2)O(2) reduction in cells. We aimed to study the expression patterns of PRDX2 in mouse ovaries and explore the function of this protein in apoptosis of granulosa cells (GCs). We found that the expression of the PRDX2 protein in atretic follicle GCs was markedly higher than in healthy follicle GCs. In vitro, the transfection of siRNA targeting the Prdx2 gene inhibited the proliferation and induced the apoptosis of primary cultured GCs. Furthermore, suppression of PRDX2 resulted in the augmentation of endogenous H(2)O(2), and the ability to eliminate the exogenous H(2)O(2) was attenuated. The expression of PRDX2 and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB), whose activity was inhibited by binding to IKB, increased in GCs treated with various concentrations of H(2)O(2) for 30 min. However, no significant change in cytoplasmic IKB expression was observed. At 2 h after treatment with H(2)O(2), nuclear NFKB expression level was reduced, cytoplasmic IKB expression was increased, and PRDX2 expression was unchanged. Silencing of the Prdx2 gene caused early changes in NFKB and IKB expression in the primary cultured GCs compared to that in control cells. Taken together, these data suggest that PRDX2 plays an important role in inhibiting apoptosis in GCs and that PRDX2 actions may be related to the expression of NFKB and IKB.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 160,
                "text": "antioxidant"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 902,
                "text": "53BP1"
            }
        },
        {
            "context": "Aberrant functional network recruitment of posterior parietal cortex in Turner syndrome. Turner syndrome is a genetic disorder caused by the complete or partial absence of an X chromosome in affected women. Individuals with TS show characteristic difficulties with executive functions, visual-spatial and mathematical cognition, with relatively intact verbal skills, and congruent abnormalities in structural development of the posterior parietal cortex (PPC). The functionally heterogeneous PPC has recently been investigated using connectivity-based clustering methods, which sub-divide a given region into clusters of voxels showing similar structural or functional connectivity to other brain regions. In the present study, we extended this method to compare connectivity-based clustering between groups and investigate whether functional networks differentially recruit the PPC in TS. To this end, we parcellated the PPC into sub-regions based on temporal correlations with other regions of the brain. fMRI data were collected from 15 girls with TS and 14 typically developing (TD) girls, aged 7-14, while they performed a visual-spatial task. Temporal correlations between voxels in the PPC and a set of seed regions were calculated, and the PPC divided into clusters of voxels showing similar connectivity. It was found that in general the PPC parcellates similarly in TS and TD girls, but that regions in bilateral inferior parietal lobules, and posterior right superior parietal lobule, were reliably recruited by different networks in TS relative to TD participants. These regions showed weaker correlation in TS with a set of regions involved in visual processing. These results suggest that abnormal development of visuospatial functional networks in TS may relate to the well documented cognitive difficulties in this disorder.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 175,
                "text": "X"
            }
        },
        {
            "context": "A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade > 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed > 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 215,
                "text": "interleukin-6"
            }
        },
        {
            "context": "(18)F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 73,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Control of muscle ryanodine receptor calcium release channels by proteins in the sarcoplasmic reticulum lumen. 1. Many biological processes that are governed by intracellular calcium signals rely on intracellular stores, which provide a reliable, controlled release of calcium into the cytoplasm. Calcium release through the ryanodine receptor (RyR), the main ion channel in the sarcoplasmic reticulum (the calcium store in muscle) is the key determinant of muscle force. 2. Calsequestrin, the main calcium buffer in the sarcoplasmic reticulum, provides a pool of calcium for release through the RyR and acts as a luminal calcium sensor for the channel via its interactions with triadin and junctin. Until recently, how calsequestrin communicated the store Ca(2+) load to the RyR remained unknown. 3. Calsequestrin 1 (skeletal calsequestrin) has been shown to both inhibit and activate the skeletal RyR1, dependent on whether it's bound to the RyR1 directly or indirectly via anchoring proteins. 4. The phosphorylation status of calsequestrin 1 is deemed important: it influences the Ca(2+) binding capacity of calsequestrin, the way in which calsequestrin 1 regulates the RyR1 and how calsequestrin 1 interacts with the key anchoring protein junctin. 5. In skeletal muscle, junctin plays a more critical role than triadin in the mechanism that controls Ca(2+) release from the sarcoplasmic reticulum. 6. The close relationship between altered expression and dysfunction of calsequestrin in several skeletal and cardiac disorders highlights the critical role that calsequestrin plays in maintaining Ca(2+) homeostasis and regulation of muscle contraction.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 475,
                "text": "Calsequestrin"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 251,
                "text": "Xa"
            }
        },
        {
            "context": "Synergistic loss of prostate cancer cell viability by coinhibition of HDAC and PARP. UNLABELLED: Tumors with BRCA germline mutations are defective in repairing DNA double-strand breaks (DSB) through homologous recombination (HR) pathways, making them sensitive to PARP inhibitors (PARPi). However, BRCA germline mutations are rare in prostate cancer limiting the ability to therapeutically target these pathways. This study investigates whether histone deacetylase (HDAC) inhibitors (HDACi), reported to modulate DSB repair pathways in sporadic cancers, can downregulate DSB repair pathways and sensitize prostate cancer cells to PARPi. Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not. Similarly, clonogenicity was significantly decreased after cotreatment. Flow cytometric cell-cycle analysis and Annexin-V staining revealed significant apoptosis upon treatment with SAHA+olaparib. This coincided with increased DNA damage observed by immunofluorescence microscopy analysis of γH2AX foci, a marker of DSBs. In addition, immunoblot analysis showed a significant and persistent increase in nuclear γH2AX levels. Both SAHA and olaparib downregulated the expression of HR-related proteins, BRCA1 and RAD51, whereas SAHA + olaparib had an additive effect on RAD51. Silencing RAD51 sensitized prostate cancer cells to SAHA and olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated HR-related protein expression and concomitantly increased DNA damage, resulting in prostate cancer cell death. IMPLICATIONS: These findings provide a strong rationale for supporting the use of combined HDAC and PARP inhibition in treating advanced prostate cancer.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 741,
                "text": "PARP"
            }
        },
        {
            "context": "A novel family with an unusual early-onset generalized dystonia. We report on an Italian family in which three brothers and their maternal grandfather had a generalized early-onset dystonia with mild parkinsonian signs. Genetic testing excluded the rapid-onset dystonia-parkinsonism locus (DYT12; OMIM*128235), autosomal recessive Parkin locus (PARK2; OMIM *602544), and DYT1 dystonia. Three affected siblings were found to share an identical haplotype at the X-linked dystonia-parkinsonism locus (XDP; Lubag; OMIM*314250). This haplotype differed from the haplotype observed in Filipino patients, ruling out the hypothesis of a common underlying mutation. In addition, direct sequencing analysis of the putative disease causing changes observed in Filipino patients were not found in the Italian patients. The condition we describe could be a newly recognized dystonia syndrome with parkinsonism.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 460,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "A variant of the Southern German clone of methicillin-resistant Staphylococcus aureus is predominant in Croatia. The aim of the present study was to investigate the antibiotic susceptibility patterns and molecular epidemiology of clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered in 24 hospitals in 20 cities in Croatia from October to December 2004. A total of 1815 consecutive S. aureus isolates were recovered, 248 of which were MRSA. The MRSA isolates were analysed using spa typing, multilocus sequence typing and SCCmec typing. Furthermore, the presence of Panton-Valentine leukocidin (PVL) genes was determined as a genetic marker for community-associated MRSA. The MRSA prevalence was 14%. Ninety-six per cent of the MRSA isolates were resistant to ciprofloxacin, 95% to clindamycin and azithromycin, 94% to gentamicin, and 93% to erythromycin. The majority of the MRSA isolates (78%) was associated with the ST111-MRSA-I clone. In addition, various other endemic MRSA clones were observed, such as the ST247-MRSA-I (4%), the ST45-MRSA-IV (2%), the ST5-MRSA-I (2%), the ST239-MRSA-III (2%), the ST5-MRSA-II (1%), the ST8-MRSA-IV (1%) and the ST5-MRSA-IV (<1%) clones. Furthermore, we observed one PVL-negative ST80-MRSA-IV isolate. Four PVL-positive MRSA isolates were found, associated with ST8-MRSA-IV, ST80-MRSA-IV and ST80-MRSA-I. The ST111-MRSA-I clone was predominant in Croatia. Future surveillance studies of MRSA are important to elucidate whether changes in the clonal distribution of MRSA will occur, and if the minor endemic MRSA clones observed in the present study will replace the ST111-MRSA-I clone on a large scale.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 284,
                "text": "MRSA"
            }
        },
        {
            "context": "European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 359,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 253,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1069,
                "text": "XK"
            }
        },
        {
            "context": "A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. RATIONALE: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans. OBJECTIVES: To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400-1,000 mug of beclomethasone or equivalent). METHODS: Multicenter, randomized, double-blind, placebo-controlled study. MEASUREMENTS AND MAIN RESULTS: Morning peak expiratory flow, forced expiratory volume in 1 second, daily beta(2)-agonist use, symptom scores, exacerbation rates, and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood, P < 0.001 for both doses; sputum, P = 0.006 for 250 mg and P = 0.004 for 750 mg). There were no statistically significant changes in any of the clinical end points measured. There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group (P = 0.065). CONCLUSIONS: Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 499,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Dinutuximab for the treatment of pediatric patients with high-risk neuroblastoma. Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-year survival rate for HR-NB remains below 40%, with the majority of patients suffering relapse from chemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease and clinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid disialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a, human-mouse chimeric ch14.18 and 3F8. Anti-GD2 MoAb induces cellular cytoxicity against NB and is most effective when effector cells like natural killer cells, granulocytes and macrophages are amplified by cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18 (Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMA approved dinutuximab (Unituxin(R)) in 2015 for the treatment of patients with HR-NB who achieved at least a partial response after multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 67,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Preservation of Specific Protein Signaling States Using Heat Based Stabilizor System. The ability to adequately measure the phosphorylation state of a protein has major biological as well as clinical relevance. Due to its variable nature, reversible protein phosphorylations are sensitive to changes in the tissue environment. Stabilizor T1 is a system for rapid inactivation of enzymatic activity in biological samples. Enzyme inactivation is accomplished using thermal denaturation in a rapid, homogeneous, and reproducible fashion without the need of added chemical inhibitors. Using pCREB(Ser133) as a model system, the applicability of the Stabilizor system to preserve a rapidly lost phosphorylation is shown.",
            "question": "Which aminoacid position in the human CREB protein is phosphorylated?",
            "answers": {
                "answer_start": 593,
                "text": "Ser133"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 1032,
                "text": "miR-7"
            }
        },
        {
            "context": "Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols. Friedreich's ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron-sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1-ISD11-ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 198,
                "text": "frataxin"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 535,
                "text": "CD38"
            }
        },
        {
            "context": "Clinical assessment of bortezomib for multiple myeloma in comparison with thalidomide. PURPOSE: We studied the efficacy and safety of bortezomib (BOR) for treatment of multiple myeloma in comparison with thalidomide (THAL) by reference to adverse events, and searched for laboratory markers that could be used for prognostication of patients. METHODS: Biochemical data of patients receiving BOR and THAL for treatment of multiple myeloma at the Japanese Red Cross Narita Hospital were investigated retrospectively, after obtaining Institutional Review Board approval. Judgment of curative effects complied with the effects criteria of the International Myeloma Working Group (IMWG). RESULTS: BOR showed a higher rate of effectiveness than THAL for refractory multiple myeloma, and its effects were rapid. BOR treatment prolonged the survival time of THAL-resistant patients. The efficacy of BOR was unrelated to patient age, the number of previous therapeutic regimens, or the disease period. After medication with BOR, patients in whom it had been effective tended to show an increase of the serum alkaline phosphatase (ALP) level. Thrombocytopenia (86.2%) and leucopenia (69.0%) were observed at high frequencies, but no previously unreported adverse events or fatalities were associated with BOR therapy. CONCLUSION: It is suggested that BOR has therapeutic efficacy for multiple myeloma as a first-line medical treatment and/or for patients with THAL resistance, and can improve prognosis and survival. Since serum ALP elevation was observed in many patients for whom BOR was effective, this may be a predictor of BOR efficacy.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 1374,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Coilin, more than a molecular marker of the cajal (coiled) body. The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 655,
                "text": "coilin"
            }
        },
        {
            "context": "Delayed cell cycle progression from SEPW1 depletion is p53- and p21-dependent in MCF-7 breast cancer cells. Selenium (Se) is an essential redox-active trace element with close connections to cancer. Most of Se's biological functions have been attributed to the antioxidant properties of Se-containing proteins. However, the relative contribution of selenoproteins and small Se compounds in cancer protection is still a matter of debate. The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the \"guardian of the genome\". In response to genomic stresses, p53 causes cell cycle arrest to allow time for genomic damage to be repaired before cell division or induces apoptosis to eliminate irreparably damaged cells. Selenoprotein W (SEPW1) is a highly conserved small thioredoxin-like protein required for cell cycle progression. The present work shows that SEPW1 facilitates the G1 to S-phase transition by down-regulating expression of the cyclin-dependent kinase inhibitor p21. SEPW1 controls p21 by modulating levels of the p53 transcription factor, and this is associated with changes in phosphorylation of Ser-33 in p53. More work is needed to identify the mechanism by which SEPW1 regulates phosphorylation of Ser-33 and the kinase or phosphatase enzymes involved.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 458,
                "text": "p53"
            }
        },
        {
            "context": "In vivo regulation of precursor cells in the subventricular zone of adult rat brain by thyroid hormone and retinoids. The mature central nervous system contains precursor cells in the subventricular zone of the lateral ventricle. In this study we examined the possibility to affect fate of precursor cells through exogenous manipulations. The results indicate that administration of thyroid hormone and retinoic acid increases the expression of Ki67, a nuclear antigen associated with cell proliferation, and of nestin, a marker protein for precursor cells in the subventricular zone of adult male rats. Moreover, retinoic acid increases polysialated-neural cell adhesion molecules (PSA-NCAM)-immunoreactivity. These data suggest that nuclear receptor ligands are potential candidates for fate determination of precursor cells in the subventricular zone also in the adult brain.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 512,
                "text": "nestin"
            }
        },
        {
            "context": "Determination of cis/trans phase of variations in the MC1R gene with allele-specific PCR and single base extension. The MC1R gene encodes a protein with key regulatory functions in the melanin synthesis. A multiplex PCR and a multiplex single base extension protocol were established for genotyping six exonic MC1R variations highly penetrant for red hair (R), four exonic MC1R variations weakly penetrant for red hair (r), two frameshift variations highly penetrant for red hair (R) and three variations in the promoter region. We genotyped 600 individuals from Denmark using either CE or MALDI-TOF MS as the detection platform. A total of 62 individuals were genotyped R/R and among the 62 individuals, 57 had red hair and five had blond hair colour. Two different R alleles may be located in cis (RR/-) position or trans (R/R) position, and the phenotype associated with RR/- and R/R may be different. Two allele-specific PCRs were established with primers targeting the -G445A variation in the MC1R promoter and the allele-specific PCR products were used in the multiplex single base extension assay. In all 62 individuals, the MC1R variants were situated in trans position. Another 18 individuals with red hair colour were either genotyped R/- or R/r, suggesting that other genes influence hair colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 373,
                "text": "MC1R"
            }
        },
        {
            "context": "Early fetal gender determination using real-time PCR analysis of cell-free fetal DNA during 6th-10th weeks of gestation. Nowadays, new advances in the use of cell free fetal DNA (cffDNA) in maternal plasma of pregnant women has provided the possibility of applying cffDNA in prenatal diagnosis as a non-invasive method. In contrary to the risks of invasive methods that affect both mother and fetus, applying cffDNA is proven to be highly effective with lower risk. One of the applications of prenatal diagnosis is fetal gender determination, which is important in fetuses at risk of sex-linked genetic diseases. In such cases by obtaining the basic information of the gender, necessary time management can be taken in therapeutic to significantly reduce the necessity of applying the invasive methods. Therefore in this study, the probability of detecting sequences on the human Y-chromosome in pregnant women has been evaluated to identify the gender of fetuses. Peripheral blood samples were obtained from 80 pregnant women with gestational age between 6th to 10th weeks and the fetal DNA was extracted from the plasma. Identification of SRY, DYS14 &amp; DAZ sequences, which are not presentin the maternal genome, was performed using Real-Time PCR. All the obtained results were compared with the actual gender of the newborns to calculate the test accuracy. Considerable 97.3% sensitivity and 97.3% specificity were obtained in fetal gender determination which is significant in the first trimester of pregnancy. Only in one case, false positive result was obtained. Using non-invasive method of cffDNAs in the shortest time possible, as well as avoiding invasive tests for early determination of fetal gender, provides the opportunity of deciding and employing early treatment for fetuses at risk of genetic diseases.",
            "question": "How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?",
            "answers": {
                "answer_start": 1488,
                "text": "first trimester of pregnancy"
            }
        },
        {
            "context": "A monoclonal antibody based capture ELISA for botulinum neurotoxin serotype B: toxin detection in food. Botulism is a serious foodborne neuroparalytic disease, caused by botulinum neurotoxin (BoNT), produced by the anaerobic bacterium Clostridium botulinum. Seven toxin serotypes (A-H) have been described. The majority of human cases of botulism are caused by serotypes A and B followed by E and F. We report here a group of serotype B specific monoclonal antibodies (mAbs) capable of binding toxin under physiological conditions. Thus, they serve as capture antibodies for a sandwich (capture) ELISA. The antibodies were generated using recombinant peptide fragments corresponding to the receptor-binding domain of the toxin heavy chain as immunogen. Their binding properties suggest that they bind a complex epitope with dissociation constants (KD's) for individual antibodies ranging from 10 to 48 × 10-11 M. Assay performance for all possible combinations of capture-detector antibody pairs was evaluated and the antibody pair resulting in the lowest level of detection (L.O.D.), ~20 pg/mL was determined. Toxin was detected in spiked dairy samples with good recoveries at concentrations as low as 0.5 pg/mL and in ground beef samples at levels as low as 2 ng/g. Thus, the sandwich ELISA described here uses mAb for both the capture and detector antibodies (binding different epitopes on the toxin molecule) and readily detects toxin in those food samples tested.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 235,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package is used for the detection of chromosomal abnormalities from microarray data?",
            "answers": {
                "answer_start": 252,
                "text": "CAFE"
            }
        },
        {
            "context": "The relevance of Simpson Grade I and II resection in modern neurosurgical treatment of World Health Organization Grade I meningiomas. OBJECT: In 1957, Simpson published a seminal paper defining the risk factors for recurrence following surgical treatment of intracranial meningiomas. Given that Simpson's study was published more than 50 years ago, preceding image guidance technology and MR imaging, the authors reviewed their own experience with surgical treatment of Grade I meningiomas to determine if Simpson's grading scale is still relevant to modern neurosurgical practice. METHODS: From this cohort, the authors evaluated all patients undergoing craniotomy for resection of a histologically proven WHO Grade I meningioma as their initial therapy. Clinical information was retrospectively reconstructed using patient medical records and radiological data. Recurrence analysis was performed using the Kaplan-Meier method. RESULTS: The 5-year recurrence/progression-free survival for all patients receiving a Simpson Grade I, II, III, or IV resection was 95, 85, 88, and 81%, respectively (p = not significant, log-rank test). Kaplan-Meier analysis revealed no significant difference in recurrence-free survival between patients receiving a Simpson Grade I, II, III, or IV resection. Analysis limited to meningiomas arising from the skull base (excluding the cavernous sinus) similarly found no significant benefit to Simpson Grade I or II resection, and the survival curves were nearly superimposed. CONCLUSIONS: In this study of a cohort of patients undergoing surgery for WHO Grade I meningiomas, the authors demonstrate that the benefit of more aggressive attempts to resect the tumor with dura and underlying bone was negligible compared with simply removing the entire tumor, or even leaving small amounts of tumor attached to critical structures. The authors believe that these data reflect an evolution in the nature of meningioma surgery over the past 2 decades, and bring into question the relevance of using Simpson's grading system as the sole predictor of recurrence.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 121,
                "text": "meningioma"
            }
        },
        {
            "context": "Hemophagocytic syndrome. This case report is about an elderly man who presented with a long-standing history of high-grade fever and weight loss. He initially had only hepatosplenomegaly, but then developed jaundice. He also had pancytopenia and raised liver enzymes. His septic screen was negative, but he had a positive Monospot test and immunoglobulin G for Epstein-Barr virus. The liver biopsy showed sinusoidal phagocytosis and the subsequent bone marrow aspiration and biopsy showed significant hemophagocytosis, hence Hemophagocytic syndrome was diagnosed. The fever was refractory to antibiotic and anti-tuberculosis therapy, but it responded only partially to steroids. Full response was only noticed following anti-viral treatment in the form of intravenous Ganciclovir. The patient's general condition, liver enzymes, bilirubin, hematological parameters and even the weight returned back to their normal range 2 weeks after Ganciclovir therapy. Cessation of this drug resulted in relapse of his symptoms and oral antivirals did not help. Splenectomy, steroid pulse therapy and immunosuppressive treatment were only partially helpful. Reintroduction of Ganciclovir did help for a short period. We conclude that our patient had virus-associated hemophagocytic syndrome most likely related to Epstein-Barr virus infection, which was then confirmed by the splenic biopsy, and that Ganciclovir can be of great help in eradicating the virus and treating the disease, provided that it is given for a long enough period.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 361,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome. The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 348,
                "text": "MITF"
            }
        },
        {
            "context": "In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 119,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 858,
                "text": "ADAR"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8 times"
            }
        },
        {
            "context": "Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. BACKGROUND: Sulfonylureas (SUs) are commonly used in the treatment of type 2 diabetes (T2DM), usually as second-line treatment after the failure of metformin. However, SUs are associated with poor durability, hypoglycemia and weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of T2DM. In Phase II/III trials, empagliflozin reduced hyperglycemia, body weight and blood pressure, with a low incidence of hypoglycemia. The aim of this Phase III study is to compare the effects of empagliflozin and the SU glimepiride as second-line therapy in patients with T2DM inadequately controlled with metformin immediate release (IR) and diet/exercise. METHOD: After a 2-week placebo run-in, patients were randomized to receive empagliflozin 25 mg once daily (qd) or glimepiride 1-4 mg qd double-blind for 2 years, in addition to metformin IR. Patients who participate in the initial 2-year randomization period will be eligible for a 2-year double-blind extension. The primary endpoint is change from baseline in HbA1c. Secondary endpoints are change from baseline in body weight, the incidence of confirmed hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory endpoints include markers of insulin secretion, body composition and responder analyses. Safety endpoints include the incidence of adverse events (AEs) (including macro- and microvascular adverse events) and changes from baseline in clinical laboratory parameters. RESULTS: Between August 2010 and June 2011, 1549 patients were randomized and 1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m², systolic blood pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg. DISCUSSION: This is the largest study to compare the efficacy and safety of an SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on metformin to date. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate effects on beta-cell function, cardiovascular risk factors and markers of renal function/damage. The results will help to inform the choice of second-line treatment in patients with T2DM who have failed on metformin. TRIAL REGISTRATION: Clinicaltrials.gov NCT01167881.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 183,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Mitral valve disease in Marfan syndrome and related disorders. Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys-Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 115,
                "text": "connective tissue"
            }
        },
        {
            "context": "Monitoring twenty-six chronic myeloid leukemia patients by BCR-ABL mRNA level in bone marrow:a single hospital experience. Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 171,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue. Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by defective function of the lysosomal membrane glycoprotein CLN3. The activity of the lysosomal acid phosphatase (LAP/ACP2) was found to be significantly increased in the cerebellum and brain stem of Cln3-targeted mice during the early stages of postnatal life. Histochemical localization studies revealed an increased LAP/ACP2 staining intensity in neurons of the cerebral cortex of 48-week-old Cln3-targeted mice as compared with controls. Additionally, the expression of another lysosomal membrane protein LAMP-2 was increased in all brain areas. Knockdown of CLN3 expression in HeLa cells by RNA interference also resulted in increased LAP/ACP2 and LAMP-2 expression. Finally in fibroblasts of two juvenile neuronal ceroid lipofuscinosis patients elevated levels of LAP/ACP2 were found. Both activation of gene transcription and increased protein half-life appear to contribute to increased LAP/ACP2 protein expression in CLN3-deficient cells. The data suggest that lysosomal dysfunction and accumulation of storage material require increased biogenesis of LAP/ACP2 and LAMP-2 positive membranes which makes LAP/ACP2 suitable as biomarker of Batten disease.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 140,
                "text": "Batten disease"
            }
        },
        {
            "context": "Chasing the ubiquitous RET proto-oncogene in South African MEN2 families--implications for the surgeon. UNLABELLED: The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B). METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel. RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery. CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 2346,
                "text": "RET"
            }
        },
        {
            "context": "In silico predicted robustness of viroids RNA secondary structures. I. The effect of single mutations. Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Despite this genomic simplicity, they are able of inducing devastating symptoms in susceptible plants. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as branched structures. The shape of these RNA structures is perhaps one of the most characteristic properties of viroids and sometimes is considered their only phenotype. Here we use RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. After characterizing the statistical properties of the distribution of mutational effects on structure stability and the wideness of neutral neighborhood for each viroid species, we show an evolutionary trend toward increased structural robustness during viroid radiation, giving support to the adaptive value of robustness. Differences in robustness among the 2 viroid families can be explained by the larger fragility of branched structures compared with the rodlike ones. We also show that genomic redundancy can contribute to the robustness of these simple RNA genomes.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 103,
                "text": "Viroids"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 472,
                "text": "xa"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyrosinase"
            }
        },
        {
            "context": "[Lambert-Eaton syndrome. Apropos of 2 cases]. Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer. It seems to be an autoimmune disease responsible for a deficit of acetylcholine ejection in the motor end plate. On the occasion of two recent cases, we review the clinical, physiopathological and diagnostic aspects of this paraneoplastic syndrome.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 166,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "Genetic analysis of chemosensory traits in human twins. We explored genetic influences on the perception of taste and smell stimuli. Adult twins rated the chemosensory aspects of water, sucrose, sodium chloride, citric acid, ethanol, quinine hydrochloride, phenylthiocarbamide (PTC), potassium chloride, calcium chloride, cinnamon, androstenone, Galaxolide™, cilantro, and basil. For most traits, individual differences were stable over time and some traits were heritable (h(2) from 0.41 to 0.71). Subjects were genotyped for 44 single nucleotide polymorphisms within and near genes related to taste and smell. The results of these association analyses confirmed previous genotype-phenotype results for PTC, quinine, and androstenone. New associations were detected for ratings of basil and a bitter taste receptor gene, TAS2R60, and between cilantro and variants in three genes (TRPA1, GNAT3, and TAS2R50). The flavor of ethanol was related to variation within an olfactory receptor gene (OR7D4) and a gene encoding a subunit of the epithelial sodium channel (SCNN1D). Our study demonstrates that person-to-person differences in the taste and smell perception of simple foods and drinks are partially accounted for by genetic variation within chemosensory pathways.",
            "question": "Which olfactory gene senses androsterone?",
            "answers": {
                "answer_start": 991,
                "text": "OR7D4"
            }
        },
        {
            "context": "Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend. Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 595,
                "text": "phospholamban"
            }
        },
        {
            "context": "A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 295,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab-A Case Report. INTRODUCTION: Idarucizumab is a reversal agent for dabigatran etexilate. By reversing the anticoagulating effect of dabigatran etexilate with idarucizumab (Praxbind), patients presenting with an acute ischemic stroke can now be eligible for thrombolysis. PATIENT: We describe our experience with idarucizumab in a 71-year-old male patient pretreated with dabigatran etexilate. The patient arrived with a hemiparesis, central facial palsy, and dysarthria. METHOD: Dabigatran etexilate was antagonized with idarucizumab, approximately 2.5 hours after the patient's last dose. Immediately after the infusion of idarucizumab, the patient received thrombolytic therapy. RESULTS: The hemiparesis and the central facial palsy were fully remitted 3 days after the onset of symptoms, and the dysarthria was remitted 2 days afterwards. DISCUSSION: Non-vitamin K oral anticoagulants (NOACs) are widely used for the prevention of embolic stroke in patients with atrial fibrillation. Dabigatran etexilate is an oral thrombin inhibitor that can be reversed by idarucizumab. Idarucizumab, a monoclonal antibody fragment, directly binds dabigatran etexilate and neutralizes its activity. CONCLUSION: Reversal of dabigatran etexilate using idarucizumab was safe and successful with no recombinant tissue plasminogen activator interactions.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1087,
                "text": "Dabigatran"
            }
        },
        {
            "context": "Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength. Site-directed mutagenesis shows that the proton leak function of NHE6 is required for neuronal arborization. We find that TrkB receptor colocalizes to NHE6-associated endosomes. TrkB protein and phosphorylation are reduced in NHE6 mutant neurons in response to BDNF signaling. Finally, exogenous BDNF rescues defects in neuronal arborization. We propose that NHE6 mutation leads to circuit defects that are in part due to impoverished neuronal arborization that may be treatable by enhanced TrkB signaling.",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 0,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study. BACKGROUND AND OBJECTIVES: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS: Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses > 2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS: Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01955720.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 286,
                "text": "dabigatran"
            }
        },
        {
            "context": "Detection of long repeat expansions from PCR-free whole-genome sequence data. Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.",
            "question": "Which algorithm is used for detection of long repeat expansions?",
            "answers": {
                "answer_start": 1444,
                "text": "ExpansionHunter"
            }
        },
        {
            "context": "DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. Methylation at the 5-position of DNA cytosine on the vertebrate genomes is accomplished by the combined catalytic actions of three DNA methyltransferases (DNMTs), the de novo enzymes DNMT3A and DNMT3B and the maintenance enzyme DNMT1. Although several metabolic routes have been suggested for demethylation of the vertebrate DNA, whether active DNA demethylase(s) exist has remained elusive. Surprisingly, we have found that the mammalian DNMTs, and likely the vertebrates DNMTs in general, can also act as Ca(2+) ion- and redox state-dependent active DNA demethylases. This finding suggests new directions for reinvestigation of the structures and functions of these DNMTs, in particular their roles in Ca(2+) ion-dependent biological processes, including the genome-wide/local DNA demethylation during early embryogenesis, cell differentiation, neuronal activity-regulated gene expression, and carcinogenesis.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 315,
                "text": "DNMT1"
            }
        },
        {
            "context": "The radiology of pulmonary cryptococcosis in a tertiary medical center. Pulmonary cryptococcal infections occur in both immunocompetent and immunocompromised individuals, with a reported increased incidence of diffuse pulmonary disease in acquired immune deficiency syndrome (AIDS) patients. The authors observed no differences in the radiographic appearances of pulmonary cryptococcal disease between human immunodeficiency virus (HIV) patients and other immunocompromised individuals. Chest computed tomography (CT) contributes to a more comprehensive understanding of pulmonary cryptococcal infections.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 432,
                "text": "HIV"
            }
        },
        {
            "context": "Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. Patients with Tietz syndrome have congenital profound deafness and generalised hypopigmentation, inherited in a fully penetrant autosomal dominant fashion. The pigmentary features and complete penetrance make this syndrome distinct among syndromes with pigmentary anomalies and deafness, which characteristically have patchy depigmentation and variable penetrance. Only one family has been reported with the exact features described in the original report of this syndrome. This family was reascertained and a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome. Mutations in other regions of this gene have been found to produce Waardenburg syndrome type 2 (WS2), which also includes pigmentary changes and hearing loss, but in contrast to Tietz syndrome, depigmentation is patchy and hearing loss is variable in WS2.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 65,
                "text": "MITF"
            }
        },
        {
            "context": "p73 plays a role in erythroid differentiation through GATA1 induction. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. Although TAp73alpha and -beta proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, DeltaNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or DeltaN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73alpha. Furthermore, TAp73alpha induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and DeltaNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 77,
                "text": "7"
            }
        },
        {
            "context": "An Algorithmic Approach to Management of Venous Thromboembolism. Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Factors such as the presence of transient risk factors for VTE, risk of bleeding, and location of deep vein thrombosis (DVT) determine the duration of anticoagulation. Extended anticoagulation is offered to patients with unprovoked pulmonary embolism (PE) or proximal DVT and a low risk of bleeding. Anticoagulation for 3 months is advised in patients with provoked DVT or PE, high risk of bleeding, and isolated distal or upper extremity DVT. In patients with unprovoked PE or proximal DVT and a low risk of bleeding, who want to stop anticoagulation after 3 months, further risk stratification is necessary. Clinical scoring system, and thrombophilia testing otherwise not routinely performed, may be considered to measure risk of annual recurrence in such cases. Short-term anticoagulation may be considered in subsegmental PE and superficial vein thrombosis, particularly if patients are at low risk of bleeding and have persistent risk factors for recurrent VTE. In cases of catheter-associated thrombosis, the catheter need not be removed routinely, and the patient may be anticoagulated for 3 months or longer if the catheter is maintained in patients with cancer. Extensive screening for occult cancer in cases of unprovoked VTE is not beneficial. New oral anticoagulants such as apixaban, rivaroxaban, or dabigatran may be preferred to vitamin K antagonists in patients without cancer or renal failure, more so after the development of reversal agents such as idarucizumab and andexanet alfa.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1464,
                "text": "dabigatran"
            }
        },
        {
            "context": "The management of cornea blindness from severe corneal scarring, with the Athens Protocol (transepithelial topography-guided PRK therapeutic remodeling, combined with same-day, collagen cross-linking). PURPOSE: To evaluate the safety and efficacy of combined transepithelial topography-guided photorefractive keratectomy (PRK) therapeutic remodeling, combined with same-day, collagen cross-linking (CXL). This protocol was used for the management of cornea blindness due to severe corneal scarring. METHODS: A 57-year-old man had severe corneal blindness in both eyes. Both corneas had significant central scars attributed to a firework explosion 45 years ago, when the patient was 12 years old. Corrected distance visual acuity (CDVA) was 20/100 both eyes (OU) with refraction: +4.00, -4.50 at 135° in the right eye and +3.50, -1.00 at 55° in the left. Respective keratometries were: 42.3, 60.4 at 17° and 35.8, 39.1 at 151.3°. Cornea transplantation was the recommendation by multiple cornea specialists as the treatment of choice. We decided prior to considering a transplant to employ the Athens Protocol (combined topography-guided partial PRK and CXL) in the right eye in February 2010 and in the left eye in September 2010. The treatment plan for both eyes was designed on the topography-guided wavelight excimer laser platform. RESULTS: Fifteen months after the right eye treatment, the right cornea had improved translucency and was topographically stable with uncorrected distance visual acuity (UDVA) 20/50 and CDVA 20/40 with refraction +0.50, -2.00 at 5°. We noted a similar outcome after similar treatment applied in the left eye with UDVA 20/50 and CDVA 20/40 with -0.50, -2.00 at 170° at the 8-month follow-up. CONCLUSION: In this case, the introduction of successful management of severe cornea abnormalities and scarring with the Athens Protocol may provide an effective alternative to other existing surgical or medical options.",
            "question": "Which eye condition is managed by the athens protocol?",
            "answers": {
                "answer_start": 450,
                "text": "cornea blindness due to severe corneal scarring"
            }
        },
        {
            "context": "Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73gamma in lung cancer. The p73 gene possesses an extrinsic P1 promoter and an intrinsic P2 promoter, resulting in TAp73 and DeltaNup73 isoforms, respectively. The ultimate effect of p73 in oncogenesis is thought to depend on the apoptotic TA to antiapoptotic DeltaN isoforms' ratio. This study was aimed at identifying novel transcription factors that affect TA isoform synthesis. With the use of bioinformatics tools, in vitro binding assays, and chromatin immunoprecipitation analysis, a region extending -233 to -204 bp upstream of the transcription start site of the human p73 P1 promoter, containing conserved Sp1-binding sites, was characterized. Treatment of cells with Sp1 RNAi and Sp1 inhibitor functionally suppress TAp73 expression, indicating positive regulation of P1 by the Sp1 protein. Notably Sp1 inhibition or knockdown also reduces DeltaNup73 protein levels. Therefore, Sp1 directly regulates TAp73 transcription and affects DeltaNup73 levels in lung cancer. TAp73gamma was shown to be the only TA isoform overexpressed in several lung cancer cell lines and in 26 non-small cell lung cancers, consistent with Sp1 overexpression, thereby questioning the apoptotic role of this specific p73 isoform in lung cancer.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 217,
                "text": "7"
            }
        },
        {
            "context": "SEA0400, a specific inhibitor of the Na+-Ca2+ exchanger, attenuates sodium nitroprusside-induced apoptosis in cultured rat microglia. 1. Using SEA0400, a potent and selective inhibitor of the Na+-Ca2+ exchanger (NCX), we examined whether NCX is involved in nitric oxide (NO)-induced disturbance of endoplasmic reticulum (ER) Ca2+ homeostasis followed by apoptosis in cultured rat microglia. 2. Sodium nitroprusside (SNP), an NO donor, decreased cell viability in a dose- and time-dependent manner with apoptotic cell death in cultured microglia. 3. Treatment with SNP decreased the ER Ca2+ levels as evaluated by measuring the increase in cytosolic Ca2+ level induced by exposing cells to thapsigargin, an irreversible inhibitor of ER Ca2+-ATPase. 4. The treatment with SNP also increased mRNA expression of CHOP and GPR78, makers of ER stress. 5. SEA0400 at 0.3-1.0 microM protected microglia against SNP-induced apoptosis. 6. SEA0400 blocked not only the SNP-induced decrease in ER Ca2+ levels but also SNP-induced increase in CHOP and GRP78 mRNAs. 7. SEA0400 did not affect capacitative Ca2+ entry in the presence and absence of SNP. 8. SNP increased Na+-dependent 45Ca2+ uptake and this increase was blocked by SEA0400. 9. These results suggest that SNP induces apoptosis via the ER stress pathway and SEA0400 attenuates SNP-induced apoptosis via suppression of the ER stress in cultured microglia. Our findings imply that NCX plays a role in ER Ca2+ depletion under pathological conditions.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 212,
                "text": "NCX"
            }
        },
        {
            "context": "In silico analysis of DosR regulon proteins of Mycobacterium tuberculosis. One of the challenges faced by Mycobacterium tuberculosis (M. tuberculosis) in dormancy is hypoxia. DosR/DevR of M. tuberculosis is a two component dormancy survival response regulator which induces the expression of 48 genes. In this study, we have used DosR regulon proteins of M. tuberculosis H37Rv as the query set and performed a comprehensive homology search against the non-redundant database. Homologs were found in environmental mycobacteria, environmental bacteria and archaebacteria. Analysis of genomic context of DosR regulon revealed that they are distributed as nine blocks in the genome of M. tuberculosis with many transposases and integrases in their vicinity. Further, we classified DosR regulon proteins into eight functional categories. One of the hypothetical proteins Rv1998c could probably be a methylisocitrate lyase or a phosphonomutase. Another hypothetical protein, Rv0572 was found only in mycobacteria. Insights gained in this study can potentially aid in the development of novel therapeutic interventions.",
            "question": "How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?",
            "answers": {
                "answer_start": 292,
                "text": "48 genes"
            }
        },
        {
            "context": "[Imatinib therapy for patients with chronic myelogenous leukemia]. Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 351,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Homology-independent discovery of replicating pathogenic circular RNAs by deep sequencing and a new computational algorithm. A common challenge in pathogen discovery by deep sequencing approaches is to recognize viral or subviral pathogens in samples of diseased tissue that share no significant homology with a known pathogen. Here we report a homology-independent approach for discovering viroids, a distinct class of free circular RNA subviral pathogens that encode no protein and are known to infect plants only. Our approach involves analyzing the sequences of the total small RNAs of the infected plants obtained by deep sequencing with a unique computational algorithm, progressive filtering of overlapping small RNAs (PFOR). Viroid infection triggers production of viroid-derived overlapping siRNAs that cover the entire genome with high densities. PFOR retains viroid-specific siRNAs for genome assembly by progressively eliminating nonoverlapping small RNAs and those that overlap but cannot be assembled into a direct repeat RNA, which is synthesized from circular or multimeric repeated-sequence templates during viroid replication. We show that viroids from the two known families are readily identified and their full-length sequences assembled by PFOR from small RNAs sequenced from infected plants. PFOR analysis of a grapevine library further identified a viroid-like circular RNA 375 nt long that shared no significant sequence homology with known molecules and encoded active hammerhead ribozymes in RNAs of both plus and minus polarities, which presumably self-cleave to release monomer from multimeric replicative intermediates. A potential application of the homology-independent approach for viroid discovery in plant and animal species where RNA replication triggers the biogenesis of siRNAs is discussed.",
            "question": "Which are the smallest known subviral pathogens of plants?",
            "answers": {
                "answer_start": 1158,
                "text": "viroids"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 383,
                "text": "TYR"
            }
        },
        {
            "context": "Frequency of infectious agents for vaginitis in patients with a cytological diagnosis of atypical squamous cells of undetermined significance. AIM: To evaluate the presence of infectious agents for vaginitis in patients with ASCUS. METHODS: 33,388 patients who underwent cervical-vaginal cytology from 08/1993 to 05/2002 were included in the study, and 1,104 (3.4%) presented positive ASCUS. The appraised infectious agents were Coccobacilli, Candida sp, Trichomonas vaginalis, and clue cells (Gardnerella vaginalis). RESULTS: In the group with ASCUS a larger frequency of Coccobacilli (22.37%) and Trichomonas vaginalis (5.25%) was found when compared with the group with negative ASCUS (17.79% and 3.98%, respectively; p < 0.05). Cytolysis occurred more frequently in patients with ASCUS (3.8 vs 6.3%, first phase and 4.5 vs 10%, second phase). CONCLUSIONS: We believe that some diagnoses of ASCUS can be induced by the presence of infectious agents for vaginitis, mainly cocci and coccoides. ASCUS occurs more frequently in the first phase of the menstrual cycle, therefore in less acid vaginal pH.",
            "question": "Clue cells are characteristics to which causative bacteria of vaginitis?",
            "answers": {
                "answer_start": 494,
                "text": "Gardnerella vaginalis"
            }
        },
        {
            "context": "Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. OBJECTIVES: The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial. BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials. METHODS: Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C)  > 100 and <190 mg/dl and Framingham risk scores  < 10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly. RESULTS: A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2]; NCT01763827).",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 364,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer's disease. Alzheimer's disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI's) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD. Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials. Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI's and NMDA receptor antagonists for the symptomatic treatment of AD.",
            "question": "What does intepirdine target?",
            "answers": {
                "answer_start": 847,
                "text": "5-HT6"
            }
        },
        {
            "context": "TFEB regulates lysosomal proteostasis. Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 839,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5'-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3' in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 152,
                "text": "FSHD"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 1341,
                "text": "telomerase"
            }
        },
        {
            "context": "Serotonin: The Anti-SuddenDeathAmine? Sudden unexpected death in epilepsy (SUDEP) is an exceptionally difficult condition to study in humans. Therefore, translational research in animal models has been very important in defining pathophysiological mechanisms of death and identifying potential treatments. These models are helping define whether the primary mechanism of death is cardiac or respiratory. They have also identified a link to the serotonergic system of the brainstem; this, in turn, led to recognition that SUDEP and sudden infant death syndrome (SIDS) may share a common final pathway in the sequence of events that lead to death.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 38,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Histone variant H2A.Z regulates centromere silencing and chromosome segregation in fission yeast. The incorporation of histone variant H2A.Z into nucleosomes plays essential roles in regulating chromatin structure and gene expression. A multisubunit complex containing chromatin remodeling protein Swr1 is responsible for the deposition of H2A.Z in budding yeast and mammals. Here, we show that the JmjC domain protein Msc1 is a novel component of the fission yeast Swr1 complex and is required for Swr1-mediated incorporation of H2A.Z into nucleosomes at gene promoters. Loss of Msc1, Swr1, or H2A.Z results in loss of silencing at centromeres and defective chromosome segregation, although centromeric levels of CENP-A, a centromere-specific histone H3 variant that is required for setting up the chromatin structure at centromeres, remain unchanged. Intriguingly, H2A.Z is required for the expression of another centromere protein, CENP-C, and overexpression of CENP-C rescues centromere silencing defects associated with H2A.Z loss. These results demonstrate the importance of H2A.Z and CENP-C in maintaining a silenced chromatin state at centromeres.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 499,
                "text": "Swr1"
            }
        },
        {
            "context": "Using MRSA Screening Tests To Predict Methicillin Resistance in Staphylococcus aureus Bacteremia. Bloodstream infections with Staphylococcus aureus are clinically significant and are often treated with empirical methicillin resistance (MRSA, methicillin-resistant S. aureus) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in S. aureus bacteremia and could help determine the requirement for empirical vancomycin therapy. We reviewed consecutive S. aureus bacteremias over a 5-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-day criterion), as tested within 30 days but accounting for any prior positive results (ever-positive criterion), or as tested in known-positive patients, with patients with unknown MRSA status being labeled negative (known-positive criterion). There were 409 S. aureus bacteremias: 302 (73.8%) methicillin-susceptible S. aureus (MSSA) and 107 (26.2%) MRSA bacteremias. In the 167 patients with MSSA bacteremias, 7.2% had a positive MRSA test within 30 days. Of 107 patients with MRSA bacteremia, 68 were tested within 30 days (54 positive; 79.8%), and another 21 (19.6%) were previously positive. The 30-day criterion provided negative predictive values (NPV) exceeding 90% and 95% if the prevalence of MRSA in S. aureus bacteremia was less than 33.4% and 19.2%, respectively. The same NPVs were predicted at MRSA proportions below 39.7% and 23.8%, respectively, for the ever-positive criterion and 34.4% and 19.9%, respectively, for the known-positive criterion. In MRSA-colonized patients, positive predictive values exceeded 50% at low prevalence. MRSA screening could help avoid empirical vancomycin therapy and its complications in stable patients and settings with low-to-moderate proportions of MRSA bacteremia.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 236,
                "text": "MRSA"
            }
        },
        {
            "context": "Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism. BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. This response requires the presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To better understand the genetic basis of this response, we utilized a controlled in vitro system and Next Generation sequencing to determine and compare RNA expression profiles of the parental strain and an isogenic AtxA-deficient strain in a 2 × 2 factorial design with growth environments containing or lacking carbon dioxide. RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were strongly regulated by the separate or synergistic actions of AtxA and carbon dioxide. The majority of the regulated genes responded to both AtxA and carbon dioxide rather than to just one of these factors. Interestingly, we identified two previously unrecognized small RNAs that are highly expressed under physiological carbon dioxide concentrations in an AtxA-dependent manner. Expression levels of the two small RNAs were found to be higher than that of any other gene differentially expressed in response to these conditions. Secondary structure and small RNA-mRNA binding predictions for the two small RNAs suggest that they may perform important functions in regulating B. anthracis virulence. CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are regulated by the presence of either CO2 or AtxA separately are also regulated synergistically in the presence of both. These results also elucidate novel pXO1-encoded small RNAs that are associated with virulence conditions.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 75,
                "text": "CO2"
            }
        },
        {
            "context": "The Role of Nursing Professionals in the Management of Patients With High-Risk Neuroblastoma Receiving Dinutuximab Therapy. Neuroblastoma, an embryonic cancer of the sympathetic nervous system, is the most common extracranial solid tumor in childhood. Dinutuximab (formerly called ch14.18), a monoclonal antibody targeting the disialoganglioside GD2, has been shown to significantly improve survival rates in patients with high-risk neuroblastoma. However, the safe and effective use of dinutuximab therapy in these high-risk patients requires medical expertise in patient selection, treatment administration, and the monitoring and management of adverse events. Findings of the randomized phase III study (ANBL0032) led to the approval of dinutuximab for the treatment of children with high-risk neuroblastoma. Multi-institutional nursing approaches to implementing standard protocols ensure the effective management of high-risk neuroblastoma patients receiving dinutuximab immunotherapy. Understanding and implementing recommendations for the management of the clinically important and most common adverse events are essential to ensuring patient continuation of therapy and improving patient outcomes.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 797,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Ghrelin protects human umbilical vein endothelial cells against high glucose-induced apoptosis via mTOR/P70S6K signaling pathway. Ghrelin exhibits its biological effect through binding to the growth hormone secretagogue 1a receptor (GHS-R1a). Recently, it has been reported that ghrelin has an anti-apoptotic effect in several cell types. However, the molecule mechanisms underlying the anti-apoptotic effect of ghrelin remain poorly understood. In this study, we investigated the intracellular mechanisms responsible for anti-apoptotic effect of ghrelin on human umbilical vein endothelial cells (HUVEC). Treatment of HUVEC with ghrelin inhibited high glucose-induced cell apoptosis. Ghrelin stimulated the rapid phosphorylation of mammalian target of rapamycin (mTOR), P70S6K and S6. The GHS-R1a-specific antagonist [D-Lys3]-GHRP-6 abolished the anti-apoptotic effect and inhibited the activation of mTOR, P70S6K, S6 induced by ghrelin. Pretreatment of cells with specific inhibitor of mTOR blocked the anti-apoptotic effect of ghrelin. In addition, ghrelin protected HUVECs against high glucose induced apoptosis by increasing Bcl-2/Bax ratio. Taken together, our results demonstrate that ghrelin produces a protective effect on HUVECs through activating GHS-R1a and mTOR/P70S6K signaling pathway mediates the effect of ghrelin. These observations suggest that ghrelin may act as a survival factor in preventing HUVECs apoptosis caused by high glucose.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 733,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer. Histone variant H2A.Z-containing nucleosomes exist at most eukaryotic promoters and play important roles in gene transcription and genome stability. The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. How SWR1 catalyzes the replacement reaction is largely unknown. Here, we determined the crystal structure of the N-terminal region (599-627) of the catalytic subunit Swr1, termed Swr1-Z domain, in complex with the H2A.Z-H2B dimer at 1.78 Å resolution. The Swr1-Z domain forms a 310 helix and an irregular chain. A conserved LxxLF motif in the Swr1-Z 310 helix specifically recognizes the αC helix of H2A.Z. Our results show that the Swr1-Z domain can deliver the H2A.Z-H2B dimer to the DNA-(H3-H4)2 tetrasome to form the nucleosome by a histone chaperone mechanism.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 859,
                "text": "Swr1"
            }
        },
        {
            "context": "Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. The human dopamine transporter (DAT1) gene is localized to chromosome 5p15.3 by in situ hybridization and PCR amplification of rodent somatic cell hybrid DNA. Analysis of a 40-bp repeat in the 3' untranslated region of the message revealed variable numbers of the repeat ranging from 3 to 11 copies. These results will aid in the investigation of a role for this gene in genetic disorders of the dopaminergic system in humans.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 58,
                "text": "5p15.3"
            }
        },
        {
            "context": "Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light. Exposure to sources of UV radiation, such as sunlight, induces a number of cellular alterations that are highly dependent on its ability to affect gene expression. Among them, the rapid activation of genes coding for two subfamilies of proto-oncoproteins, Fos and Jun, which constitute the AP-1 transcription factor, plays a key role in the subsequent regulation of expression of genes involved in DNA repair, cell proliferation, cell cycle arrest, death by apoptosis, and tissue and extracellular matrix remodeling proteases. Besides being regulated at the transcriptional level, Jun and Fos transcriptional activities are also regulated by phosphorylation as a result of the activation of intracellular signaling cascades. In this regard, the phosphorylation of c-Jun by UV-induced JNK has been readily documented, whereas a role for Fos proteins in UV-mediated responses and the identification of Fos-activating kinases has remained elusive. Here we identify p38 MAPKs as proteins that can associate with c-Fos and phosphorylate its transactivation domain both in vitro and in vivo. This phosphorylation is transduced into changes in its transcriptional ability as p38-activated c-Fos enhances AP1-driven gene expression. Our findings indicate that as a consequence of the activation of stress pathways induced by UV light, endogenous c-Fos becomes a substrate of p38 MAPKs and, for the first time, provide evidence that support a critical role for p38 MAPKs in mediating stress-induced c-Fos phosphorylation and gene transcription activation. Using a specific pharmacological inhibitor for p38alpha and -beta, we found that most likely these two isoforms mediate UV-induced c-Fos phosphorylation in vivo. Thus, these newly described pathways act concomitantly with the activation of c-Jun by JNK/MAPKs, thereby contributing to the complexity of AP1-driven gene transcription regulation.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 883,
                "text": "JNK"
            }
        },
        {
            "context": "Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. Recent studies reveal that long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and lncRNA MALAT-1 expression is upregulated in some tumors. However, the contributions of MALAT-1 to bladder cancer metastasis remain largely unknown. In the present study we evaluated MALAT-1 expression in bladder cancer tissues by real-time PCR, and defined its biological functions. We verified that MALAT-1 levels were upregulated in bladder cancer tissues compared with adjacent normal tissues, and MALAT-1 expression was remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. SiRNA-mediated MALAT-1 silencing impaired in vitro bladder cancer cell migration. Downregulation of MALAT-1 resulted in a decrease of the epithelial-mesenchymal transition (EMT)-associated ZEB1, ZEB2 and Slug levels, and an increase of E-cadherin levels. We further demonstrated that MALAT-1 promoted EMT by activating Wnt signaling in vitro. These data suggest an important role for MALAT-1 in regulating metastasis of bladder cancer and the potential application of MALAT-1 in bladder cancer therapy.",
            "question": "Is the long non- coding RNA malat-1 up or downregulated in cancer?",
            "answers": {
                "answer_start": 276,
                "text": "upregulated"
            }
        },
        {
            "context": "γ-Secretase modulator in Alzheimer's disease: shifting the end. The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat (LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the γ-secretase era. γ-Secretase modulators, by definition, only block the γ-secretase cleavage of amyloid-β protein precursor (AβPP) to generate the longer, 42-residue amyloid-β (Aβ42) without changing the production of total Aβ. The first generation GSMs were shown to block Aβ42 generation while increasing Aβ38. The non-steroidal anti-inflammatory drug, Tarenflurbil, binds to AβPP and shifts the cleavage site from Aβ42 to Aβ38. In addition, Tarenflurbil does not affect the γ-secretase cleavage of Notch. Even before the failed clinical trials of Tarenflurbil, second generation GSMs had emerged, and some of these GSMs interact with presenilin, which carries the active site of the γ-secretase. While second generation GSMs are pharmacologically superior to first generation GSMs, in vivo Aβ profiles (decreased levels of Aβ38, Aβ40, and Aβ42) in animals treated with potent GSMs are strikingly different from those in cultured cells. Thus, the unique pharmacologic properties of new GSMs and their mechanisms of action need to be elucidated in order to avoid the fate of Tarenflurbil. It is critical to understand how GSMs shift the \"end\" in vivo, i.e., shifting the γ-secretase cleavage at the C-terminal end of Aβ. In view of the myriad effects of candidate GSMs on Aβ production in cells and animals, drug development would benefit from better definition of the target-GSM interaction and physiological function of shorter Aβ peptides.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 129,
                "text": "Semagacestat"
            }
        },
        {
            "context": "Intrinsic transcript cleavage in yeast RNA polymerase II elongation complexes. Transcript elongation can be interrupted by a variety of obstacles, including certain DNA sequences, DNA-binding proteins, chromatin, and DNA lesions. Bypass of many of these impediments is facilitated by elongation factor TFIIS through a mechanism that involves cleavage of the nascent transcript by the RNA polymerase II/TFIIS elongation complex. Highly purified yeast RNA polymerase II is able to perform transcript hydrolysis in the absence of TFIIS. The \"intrinsic\" cleavage activity is greatly stimulated at mildly basic pH and requires divalent cations. Both arrested and stalled complexes can carry out the intrinsic cleavage reaction, although not all stalled complexes are equally efficient at this reaction. Arrested complexes in which the nascent transcript was cleaved in the absence of TFIIS were reactivated to readthrough blocks to elongation. Thus, cleavage of the nascent transcript is sufficient for reactivating some arrested complexes. Small RNA products released following transcript cleavage in stalled ternary complexes differ depending upon whether the cleavage has been induced by TFIIS or has occurred in mildly alkaline conditions. In contrast, both intrinsic and TFIIS-induced small RNA cleavage products are very similar when produced from an arrested ternary complex. Although alpha-amanitin interferes with the transcript cleavage stimulated by TFIIS, it has little effect on the intrinsic cleavage reaction. A mutant RNA polymerase previously shown to be refractory to TFIIS-induced transcript cleavage is essentially identical to the wild type polymerase in all tested aspects of intrinsic cleavage.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 527,
                "text": "TFIIS"
            }
        },
        {
            "context": "Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 334,
                "text": "MITF"
            }
        },
        {
            "context": "Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate. Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 237,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "MMP-2 selectivity in hydroxamate-type inhibitors. Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.",
            "question": "What is needed for MMP proteins to be functional?",
            "answers": {
                "answer_start": 113,
                "text": "zinc"
            }
        },
        {
            "context": "Costello syndrome and hyperinsulinemic hypoglycemia. Costello syndrome is characterized by mental retardation, loose skin, coarse facies, skeletal abnormalities, cardiovascular abnormalities (congenital heart defects, cardiomyopathy, rhythm disturbances), and predisposition to neoplasia. Endocrine abnormalities including growth hormone deficiency, adrenal insufficiency, glucose intolerance, parathyroid adenoma with hyperprolactinemia and hypoglycemia have been described. Hypoglycemia has been documented due to growth hormone and cortisol deficiency. We report on two patients with Costello syndrome and persistent hyperinsulinemic hypoglycemia and review the endocrine manifestations of Costello syndrome. Both patients required diazoxide therapy to stop the unregulated insulin secretion and maintain normoglycemia. The mechanism of persistent hyperinsulinism in patients with Costello syndrome is unclear.",
            "question": "Which hormone deficiency is implicated in the Costello syndrome ?",
            "answers": {
                "answer_start": 323,
                "text": "growth hormone deficiency"
            }
        },
        {
            "context": "Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel. Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is in development as a microbicide for the protection of women against HIV infection. A randomized, double-blind, phase 1 trial was conducted in 36 healthy HIV-negative women to compare the pharmacokinetics of 2 dapivirine vaginal gel formulations (0.05% each) and their safety with the hydroxyethyl cellulose-based universal placebo gel. Gel was self-administered once daily for a total of 11 days. Blood and vaginal fluid samples were collected sequentially over 24 days for pharmacokinetic analysis. Safety was evaluated by pelvic examination, colposcopy, adverse events, and clinical laboratory assessments. Adverse event profiles were similar for the 3 gels. Most events were mild and not related to study gel. Headache and vaginal hemorrhage (any vaginal bleeding) were most common. Plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Steady-state conditions were reached within approximately 10 days. Dapivirine concentrations in vaginal fluids were slightly higher for Gel 4789, but Cmax values on days 1 and 14 were not significantly different. Terminal half-life was 72-73 hours in plasma and 15-17 hours in vaginal fluids. Both formulations of dapivirine gel were safe and well tolerated. Dapivirine was delivered to the lower genital tract at concentrations at least 5 logs greater than in vitro inhibitory concentrations.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 263,
                "text": "HIV"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 250,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 1856,
                "text": "positive"
            }
        },
        {
            "context": "Small, smaller, smallest: the origins and evolution of ancient dual symbioses in a Phloem-feeding insect. Many insects rely on bacterial symbionts with tiny genomes specialized for provisioning nutrients lacking in host diets. Xylem sap and phloem sap are both deficient as insect diets, but differ dramatically in nutrient content, potentially affecting symbiont genome evolution. For sap-feeding insects, sequenced symbiont genomes are available only for phloem-feeding examples from the suborder Sternorrhyncha and xylem-feeding examples from the suborder Auchenorrhyncha, confounding comparisons. We sequenced genomes of the obligate symbionts, Sulcia muelleri and Nasuia deltocephalinicola, of the phloem-feeding pest insect, Macrosteles quadrilineatus (Auchenorrhyncha: Cicadellidae). Our results reveal that Nasuia-ALF has the smallest bacterial genome yet sequenced (112 kb), and that the Sulcia-ALF genome (190 kb) is smaller than that of Sulcia in other insect lineages. Together, these symbionts retain the capability to synthesize the 10 essential amino acids, as observed for several symbiont pairs from xylem-feeding Auchenorrhyncha. Nasuia retains genes enabling synthesis of two amino acids, DNA replication, transcription, and translation. Both symbionts have lost genes underlying ATP synthesis through oxidative phosphorylation, possibly as a consequence of the enriched sugar content of phloem. Shared genomic features, including reassignment of the UGA codon from Stop to tryptophan, and phylogenetic results suggest that Nasuia-ALF is most closely related to Zinderia, the betaproteobacterial symbiont of spittlebugs. Thus, Nasuia/Zinderia and Sulcia likely represent ancient associates that have co-resided in hosts since the divergence of leafhoppers and spittlebugs >200 Ma, and possibly since the origin of the Auchenorrhyncha, >260 Ma.",
            "question": "Which bacterium has the smallest genome in base pairs yet found?",
            "answers": {
                "answer_start": 669,
                "text": "Nasuia deltocephalinicola"
            }
        },
        {
            "context": "The Genetic Cost of Neanderthal Introgression. Approximately 2-4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.",
            "question": "What percentage of Homo sapiens DNA is of Neanderthal origin?",
            "answers": {
                "answer_start": 61,
                "text": "2-4%"
            }
        },
        {
            "context": "Lysyl oxidase is downregulated by the EWS/FLI1 oncoprotein and its propeptide domain displays tumor supressor activities in Ewing sarcoma cells. Ewing sarcoma is the second most common bone malignancy in children and young adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as aberrant transcription factors that upregulate and downregulate target genes, leading to cellular transformation. Thus, identificating these target genes and understanding their contribution to Ewing sarcoma tumorigenesis are key for the development of new therapeutic strategies. In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is downregulated by the EWS/FLI1 oncoprotein and in consequence it is not expressed in Ewing sarcoma cells and primary tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we showed that LOX displays tumor suppressor activities. Interestingly, we showed that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Expression of LOX-PP reduced cell proliferation, cell migration, anchorage-independent growth in soft agar and formation of tumors in immunodeficient mice. By contrast, the C-terminal domain of LOX, which contains the enzymatic activity, had the opposite effects, corroborating that the tumor suppressor activity of LOX is mediated exclusively by its propeptide domain. Finally, we showed that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significantly deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based on the administration of LOX propeptide or functional analogues could be useful for the treatment of this devastating paediatric cancer.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 279,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "[Dermatitis herpetiformis occuring in patients with celiac disease in childhood]. BACKGROUND: Dermatitis herpetiformis (DH) is a chronic papulovesicular immune-mediated disorder associated with gluten-sensitive enteropathy. We report eight cases in which DH appeared many years after celiac disease (CD) in child. PATIENTS AND METHODS: The diagnosis of CD was based on histological features of total or subtotal villous atrophy, full remission after withdrawal of gluten from the diet, and eventually circulating antibodies (IgA gliadin, antireticulin and antiendomysium) at the time of diagnosis and their disappearance under gluten-free diet. The diagnosis of DH was made from clinical findings, histological examination of the involved skin and direct immunofluorescence microscopy of normal or perilesional skin. HLA class II typing was performed in five patients. DRB1, DQA1, DQB1 and DBP1 alleles were studied. RESULTS: DH appeared between 3 and 22 years after the initial diagnosis of CD. Five patients did not show at that time any digestive symptoms. In three cases, a break in the gluten-free diet or a recent revival of the normal diet preceded the rash. In only one case, DH appeared while the patient was under gluten-free diet. In three patients, the rash appeared many years after the gluten-free diet had been stopped. Phenotype DR3 and/or DR7 of the celiac disease could be found in four of the five patients studied; three of them were found to bear DQW2. The DR2 allele was not found in any of the five tested patients. DISCUSSION: These eight cases illustrate the absence of precise nosological barrier between gluten-sensitive enteropathy of the DH and that observed in CD. The presence of the DR7 allele, and especially the absence of the DR2 allele, could explain the particularly severe and symptomatic course of the enteropathy in these patients. The delay in the appearance of DH, after a very variable period of normal diet, could correspond to the necessary time for progressive accumulation of IgA (or immune complex IgA-gluten) in the skin after a digestive sensitization to gluten. The preventive role of gluten-free diet is thus probable. CONCLUSION: CD and DH likely correspond to two different stages of the same disease, thus requiring a prolonged follow-up of both digestive and skin tissues. Long-term eviction of gluten to prevent eventual DH must be balanced with the demand and the cost of such a diet.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 94,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Necrobiosis lipoidica diabeticorum. Localization in surgical scars. Necrobiosis lipoidica is a skin disorders with an interesting predisposition for areas of trauma such as the anterior shins. In this report a patient with diabetes mellitus and generalized necrobiosis lipoidica diabeticorum with localization in surgical scars is described. A brief review of other skin disorders occurring in scars is also included.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 223,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 235,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 56,
                "text": "orexin"
            }
        },
        {
            "context": "Induction of protein-protein interactions in live cells using light. Protein-protein interactions are essential for many cellular processes. We have developed a technology called light-activated dimerization (LAD) to artificially induce protein hetero- and homodimerization in live cells using light. Using the FKF1 and GIGANTEA (GI) proteins of Arabidopsis thaliana, we have generated protein tags whose interaction is controlled by blue light. We demonstrated the utility of this system with LAD constructs that can recruit the small G-protein Rac1 to the plasma membrane and induce the local formation of lamellipodia in response to focal illumination. We also generated a light-activated transcription factor by fusing domains of GI and FKF1 to the DNA binding domain of Gal4 and the transactivation domain of VP16, respectively, showing that this technology is easily adapted to other systems. These studies set the stage for the development of light-regulated signaling molecules for controlling receptor activation, synapse formation and other signaling events in organisms.",
            "question": "Which G protein is essential in the formation and function of lamellipodia?",
            "answers": {
                "answer_start": 546,
                "text": "Rac1"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 117,
                "text": "tyr"
            }
        },
        {
            "context": "Seipin promotes adipose tissue fat storage through the ER Ca²⁺-ATPase SERCA. Adipose tissue is central to the regulation of lipid metabolism. Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), one of the most severe lipodystrophy diseases, is caused by mutation of the Seipin gene. Seipin plays an important role in adipocyte differentiation and lipid homeostasis, but its exact molecular functions are still unknown. Here, we show that Seipin physically interacts with the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in both Drosophila and man. SERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen. Like dSeipin, dSERCA cell-autonomously promotes lipid storage in Drosophila fat cells. dSeipin affects dSERCA activity and modulates intracellular calcium homeostasis. Adipose tissue-specific knockdown of the ER-to-cytosol calcium release channel ryanodine receptor (RyR) partially restores fat storage in dSeipin mutants. Our results reveal that Seipin promotes adipose tissue fat storage by regulating intracellular calcium homeostasis.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 525,
                "text": "SERCA"
            }
        },
        {
            "context": "Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: microcephaly, developmental delay and delayed bone age. Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors. Here, we report on a 14-month-old boy with a reverse phenotype of Sotos syndrome due to the reciprocal duplication of the 5q35.3 region, including the NSD1 gene, detected by array CGH. The phenotype includes delayed bone age, microcephaly, seizures, and failure to thrive. Our case suggests that the gene dosage effect of the NSD1 gene is the likely cause for the reversed phenotype of Sotos syndrome in this patient.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 184,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Opposing actions of heat shock protein 90 and 70 regulate nicotinamide adenine dinucleotide phosphate oxidase stability and reactive oxygen species production. OBJECTIVE: Excessive reactive oxygen species contribute to vascular dysfunction. We have previously shown that heat shock protein (Hsp90) inhibitors potently suppress Nox 1 to 3 and 5, and the goals of this study were to identify how molecular chaperones regulate Nox function. METHODS AND RESULTS: In vitro, protein expression of Nox 1 to 2, 5 was decreased by Hsp90 inhibitors in multiple cell types (human pulmonary artery endothelial cells, neutrophils, macrophages, and human saphenous vein). In mice treated with Hsp90 inhibitors, Nox1 expression was reduced in lung along with reduced reactive oxygen species from leukocytes. Elevated reactive oxygen species production in obese (db/db) aorta was suppressed by Hsp90 inhibition. Hsp90 inhibitors did not alter Nox5 micro RNA levels, and proteasome inhibition prevented Nox2 and 5 protein degradation and increased ubiquitin incorporation. Inhibition of Hsp90 upregulated the expression of Hsp70 and Hsp70-bound Nox2, 5 and promoted degradation. Silencing Hsp70 prevented Hsp90 inhibitor-mediated degradation of Nox5. The Hsp70-regulated ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP), also bound Nox5 and promoted increased Nox5 ubiquitination and degradation. The chaperone binding and ubiquitination domains of CHIP were required, and the silencing of CHIP blunted Hsp90 inhibitor-mediated degradation of Nox2 and 5. CONCLUSIONS: We conclude that Hsp90 binds to and regulates Nox protein stability. These actions are opposed by Hsp70 and CHIP, which promote the ubiquitination and degradation of Nox proteins and reduce reactive oxygen species production.",
            "question": "Which heat shock protein is found to be upregulated during Hsp90 inhibition?",
            "answers": {
                "answer_start": 1116,
                "text": "Hsp70"
            }
        },
        {
            "context": "Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. AIMS: The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. METHODS: This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. RESULTS: Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax ) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT-opicapone complex. CONCLUSION: Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 273,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. The p53 tumor suppressor protein has long been recognized as the central factor protecting humans from cancer. It has been famously dubbed \"the guardian of the genome\" due to its ability to respond to genotoxic stress, such as DNA damage and other stress signals, and to protect the genome by inducing a variety of biological responses including DNA repair, cell cycle arrest, and apoptosis. However, the tumor suppressive effects of p53 go far beyond its roles in mediating these three processes. There is growing evidence that p53 also exerts its effects on multiple aspects of tumor formation, including suppression of metastasis and, as summarized in this review, inhibition of new blood vessel development (angiogenesis). The p53 protein has been shown to limit angiogenesis by at least three mechanisms: (1) interfering with central regulators of hypoxia that mediate angiogenesis, (2) inhibiting production of proangiogenic factors, and (3) directly increasing the production of endogenous angiogenesis inhibitors. The combination of these effects allows p53 to efficiently shut down the angiogenic potential of cancer cells. Inactivation of p53, which occurs in approximately half of all tumors, reverses these effects; as a consequence, tumors carrying p53 mutations appear more vascularized and are often more aggressive and correlate with poor prognosis for treatment. Thus, the loss of functional p53 during tumorigenesis likely represents an essential step in the switch to an angiogenic phenotype that is displayed by aggressive tumors.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 36,
                "text": "p53"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "A cytochrome c methyltransferase from Crithidia oncopelti. The mitochondrial cytochrome c-557 of Crithidia oncopelti contains two lysine residues and an N-terminal proline residue that are methylated in vivo by the methyl group of methionine. The purified cytochrome can act as a methyl acceptor for a methyltransferase activity in the cell extract that uses S-adenosylmethionine as methyl donor. Crithidia cytochrome c-557 is by far the best substrate for this methyltransferase of those tested, in spite of the fact that methylation sites are already almost fully occupied. The radioactive uptake of [14C]methyl groups from S-adenosylmethionine occurred only at a lysine residue (-8) and the N-terminal proline residue. This methyltransferase appears to differ from that of Neurospora and yeast [Durban, Nochumson, Kim, Paik & Chan (1978) J. Biol. Chem. 253, 1427-1435; DiMaria, Polastro, DeLange, Kim & Paik (1979) J. Biol. Chem. 254, 4645-4652] in that lysine-72 of horse cytochrome c is a poor acceptor. Also, the Crithidia methyltransferase appears to be stable to carry lysine methylation much further to completion than do the enzymes from yeast and Neurospora, which produce very low degrees of methylation in native cytochromes c.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 359,
                "text": "S-adenosylmethionine"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 838,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Two asymptomatic cases with sarcoidosis demonstrated sequential evolution from radiographic stage I to III within five years. There are no guidelines regarding the treatment of pulmonary sarcoidosis. Generally, oral corticosteroids are considered the first-line treatment for symptomatic patients with pulmonary sarcoidosis. We report here two Japanese cases with pulmonary sarcoidosis who demonstrated sequential evolution from radiographic stage I to III within five years. Although these two cases had no symptoms, persistent, progressive pulmonary involvements were observed on chest X-ray. Considering the effectiveness of corticosteroids on patients with radiographic type II or III sarcoidosis reported by the British Thoracic Society, corticosteroid therapy might be a choice even in asymptomatic cases, if they demonstrate developing pulmonary involvement.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 216,
                "text": "corticosteroids"
            }
        },
        {
            "context": "Opposing actions of heat shock protein 90 and 70 regulate nicotinamide adenine dinucleotide phosphate oxidase stability and reactive oxygen species production. OBJECTIVE: Excessive reactive oxygen species contribute to vascular dysfunction. We have previously shown that heat shock protein (Hsp90) inhibitors potently suppress Nox 1 to 3 and 5, and the goals of this study were to identify how molecular chaperones regulate Nox function. METHODS AND RESULTS: In vitro, protein expression of Nox 1 to 2, 5 was decreased by Hsp90 inhibitors in multiple cell types (human pulmonary artery endothelial cells, neutrophils, macrophages, and human saphenous vein). In mice treated with Hsp90 inhibitors, Nox1 expression was reduced in lung along with reduced reactive oxygen species from leukocytes. Elevated reactive oxygen species production in obese (db/db) aorta was suppressed by Hsp90 inhibition. Hsp90 inhibitors did not alter Nox5 micro RNA levels, and proteasome inhibition prevented Nox2 and 5 protein degradation and increased ubiquitin incorporation. Inhibition of Hsp90 upregulated the expression of Hsp70 and Hsp70-bound Nox2, 5 and promoted degradation. Silencing Hsp70 prevented Hsp90 inhibitor-mediated degradation of Nox5. The Hsp70-regulated ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP), also bound Nox5 and promoted increased Nox5 ubiquitination and degradation. The chaperone binding and ubiquitination domains of CHIP were required, and the silencing of CHIP blunted Hsp90 inhibitor-mediated degradation of Nox2 and 5. CONCLUSIONS: We conclude that Hsp90 binds to and regulates Nox protein stability. These actions are opposed by Hsp70 and CHIP, which promote the ubiquitination and degradation of Nox proteins and reduce reactive oxygen species production.",
            "question": "Which heat shock protein is found to be upregulated during Hsp90 inhibition?",
            "answers": {
                "answer_start": 1106,
                "text": "Hsp70"
            }
        },
        {
            "context": "Transducer of erbB2.1 is a potential cellular target of gefitinib in lung cancer therapy. Gefitinib, the specific inhibitor of the epidermal growth factor receptor (EGFR), may cause growth delay in cancer cell lines. Thorough understanding of the downstream cellular signaling of gefitinib will facilitate the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies, and provide information for key targets for therapeutic intervention. In this study, we investigated the role of transducer of erbB2.1 (TOB1) in gefitinib therapy. Using the lung carcinoma cell lines A549 and NCI-H1975, the results suggested that gefitinib might mediate cell cycle arrest in lung cancer cells at least by targeting TOB1 expression. Gefitinib treatment caused cell cycle arrest predominantly at the G1 phase, which is associated with TOB1 nuclear translocation and its interaction with cyclin D1. We also showed that knockdown of TOB1 expression by RNAi rescued lung cancer cells from gefitinib-induced cell-proliferative arrest. These results suggest that TOB1 interaction with cyclin D1 and nuclear translocation is directly involved in the gefitinib-induced anti-proliferative cell cycle arrest.",
            "question": "Which is the cellular target of gefitinib?",
            "answers": {
                "answer_start": 131,
                "text": "epidermal growth factor receptor (EGFR)"
            }
        },
        {
            "context": "SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts. Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 125,
                "text": "PLN"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 405,
                "text": "Xa"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 641,
                "text": "7"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 646,
                "text": "ZEB2"
            }
        },
        {
            "context": "Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes: A Clinical Update of Safety and Efficacy. INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. METHODS: A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized. RESULTS: Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events. CONCLUSION: GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer.",
            "question": "Which disease is treated with semaglutide?",
            "answers": {
                "answer_start": 222,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Nonsteroidal therapy of sarcoidosis. PURPOSE OF REVIEW: None of the medications used in clinical practice to treat sarcoidosis have been approved by the regulatory authorities. Understanding how to use disease-modifying antisarcoid drugs, however, is essential for physicians treating patients with sarcoidosis. This review summarizes the recent studies of medications used for sarcoidosis with a focus on nonsteroidal therapies. Studies from 2006 to 2013 were considered for review to update clinicians on the most relevant literature published over the last few years. RECENT FINDINGS: Several recently published pieces of evidence have helped expand our ability to more appropriately sequence second-line and third-line therapies for sarcoidosis. For instance, methotrexate and azathioprine may be useful and well tolerated medications as second-line treatment. Mycophenolate mofetil might have a role in neurosarcoidosis. TNF-α blockers and other biologics seem to be well tolerated medications for the most severely affected patients. SUMMARY: Corticosteroids remain the first-line therapy for sarcoidosis as many patients never require treatment or only necessitate a short treatment duration. Second-line and third-line therapies described in this article should be used in patients with progressive or refractory disease or when life-threatening complications are evident at the time of presentation.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 1049,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "L-leucine increases [3H]-thymidine incorporation in chicken hepatocytes: involvement of the PKC, PI3K/Akt, ERK1/2, and mTOR signaling pathways. This study examined how L-leucine affected DNA synthesis and cell cycle regulatory protein expression in cultured primary chicken hepatocytes. L-Leucine promoted DNA synthesis in a dose- and time-dependent manner, with concomitant increases in cyclin D1 and cyclin E expression. Phospholipase C (PLC) and protein kinase C (PKC) mediated the L-leucine-induced increases in [3H]-thymidine incorporation and cyclin D1/CDK4 and cyclin E/CDK2 expression, as U73122 (a PLC inhibitor) or bisindolylmaleimide I (a PKC blocker) inhibited these effects. L-Leucine also increased PKC phosphorylation and intracellular Ca2+ levels. L-Leucine-mediated increases in [3H]-thymidine incorporation and cyclin/CDK expression were sensitive to LY 294002 (PI3K inhibitor), Akt inhibitor, PD 98059 (MEK inhibitor). It was also observed that L-leucine-induced increases of cyclin/CDK expression were inhibited by PI3K siRNA and ERK siRNA; L-leucine increased extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt phosphorylation levels. Bisindolylmaleimide I attenuated L-leucine-induced phosphorylation of ERK1/2 but did not influence Akt phosphorylation, and PI3K siRNA and LY 294002 inhibited L-leucine-induced ERK1/2 phosphorylation, suggesting some cross-talk between the PKC and ERK1/2 or PI3K/Akt and ERK1/2 pathways. L-Leucine also increased the levels of phosphorylated molecular target of rapamycin (mTOR) and two of its targets, ribosomal protein S6 kinase (p70S6K), and 4E binding protein 1 (4E-BP1); furthermore, rapamycin (an mTOR inhibitor) blocked all of the mitogenic effects of L-leucine. In addition, Akt inhibitor blocked L-leucine-induced mTOR phosphorylation. In conclusion, L-leucine stimulated DNA synthesis and promoted cell cycle progression in primary cultured chicken hepatocytes through PKC, ERK1/2, PI3K/Akt, and mTOR.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 1538,
                "text": "mTOR"
            }
        },
        {
            "context": "McLeod syndrome resulting from a novel XK mutation. McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1323,
                "text": "XK"
            }
        },
        {
            "context": "Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Although most eukaryotic genomes lack operons, they contain some physical clusters of genes that are related in function despite being unrelated in sequence. How these clusters are formed during evolution is unknown. The DAL cluster is the largest metabolic gene cluster in yeast and consists of six adjacent genes encoding proteins that enable Saccharomyces cerevisiae to use allantoin as a nitrogen source. We show here that the DAL cluster was assembled, quite recently in evolutionary terms, through a set of genomic rearrangements that happened almost simultaneously. Six of the eight genes involved in allantoin degradation, which were previously scattered around the genome, became relocated to a single subtelomeric site in an ancestor of S. cerevisiae and Saccharomyces castellii. These genomic rearrangements coincided with a biochemical reorganization of the purine degradation pathway, which switched to importing allantoin instead of urate. This change eliminated urate oxidase, one of several oxygen-consuming enzymes that were lost by yeasts that can grow vigorously in anaerobic conditions. The DAL cluster is located in a domain of modified chromatin involving both H2A.Z histone exchange and Hst1-Sum1-mediated histone deacetylation, and it may be a coadapted gene complex formed by epistatic selection.",
            "question": "Which is the largest metabolic gene cluster in yeast?",
            "answers": {
                "answer_start": 289,
                "text": "The DAL cluster"
            }
        },
        {
            "context": "Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China. PURPOSE: To assess whether vancomycin minimum inhibitory concentration (MIC) creeps among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in a regional hospital in China. Furthermore, to analyze the causes of vancomycin MIC creeps and the relationship between vancomycin MICs and the outcome among patients with MRSA infection. MATERIALS AND METHODS: All clinical isolates of MRSA from 2006-2010 were retrieved and tested by the broth microdilution procedure to determine their vancomycin MIC. Meanwhile, related patient records were analyzed. RESULTS: While all isolates were susceptive to vancomycin, the percentage of isolates with a vancomycin MIC = 1 mg/L increased significantly from 2006 (37.0%) to 2010 (75.7%). Meanwhile, vancomycin usage density (DDDs/1000 bed-days) had increased significantly from 2006-2010. Mean linear correlation analysis showed a statistically significant positive correlation (r = 0.905, P < 0.05) between the consumption of vancomycin and the percentage of MRSA isolates with a vancomycin MIC = 1 mg/L. Clinical records revealed high vancomycin MIC was associated with a higher microbiologic failure rate in MRSA bloodstream infections. CONCLUSIONS: The data demonstrated vancomycin MIC creep among clinical isolates in our hospital, and the MIC creep may be caused by the increasing usage of vancomycin. Furthermore, the analysis strongly suggested this shift of vancomycin MIC within the susceptible range may be associated with an increasing probability of treatment failure.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 282,
                "text": "MRSA"
            }
        },
        {
            "context": "The incidence of cystic fibrosis in Caucasian populations. Estimates of the newborn frequency of cystic fibrosis in different Caucasian groups range from 4 times more to 40 times less common than the generally accepted figure of 1:2000. Current meconium screening trials which may be effective in populations with the incidence equal to or greater than 1:2000, may be useful for populations with an incidence as low as 1:7000 only after maximum improvement of the methods. Once the true incidence or the variable incidence is proven for Caucasian populations, screening trails in Negro, Oriental and Indian populations will be required.",
            "question": "What is the incidence of cystic fibrosis in the caucasian population?",
            "answers": {
                "answer_start": 229,
                "text": "1:2000"
            }
        },
        {
            "context": "New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 104,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Genetics of pituitary adenomas. Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 957,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 288,
                "text": "NCX"
            }
        },
        {
            "context": "Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. OBJECTIVES: Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. DESIGN: Prospective analysis. PATIENTS: 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses. SETTING: All analyses were performed in a large German laboratory specialised in genetic diagnostics. RESULTS: 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. CONCLUSIONS: On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1917,
                "text": "MITF"
            }
        },
        {
            "context": "[Ehlers-Danlos syndromes. Clinical, genetic and molecular aspects]. The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. Considerable clinical and genetic heterogeneity exists, and more than nine separate forms have been recognized. Recent advances in the molecular analysis of EDS have identify defects responsible for EDS VI (homozygous and compound heterozygous mutations in the lysyl-hydroxylase gene), EDS VIIA and EDS VIIB (mutations in the type I collagene genes), EDS VIIC (deficiency of procollagen N-proteinase), EDS IX (mutations in the MNK gene), and EDS IV (mutations in the type III collagen gene). Of the various types of Ehlers-Danlos syndrome the most severe is type IV (EDS IV). Early studies showed that fibroblasts from EDS IV patients secreted lower than normal amounts of type III procollagen (Pope et al., 1975). Later, the disease was linked to COL3A1, the gene encoding this protein. More recently, with the publication of full length cDNA and partial characterisation of the gene structure, detailed analysis of mutations in EDS IV patients has become possible. Nineteen different mutations in the type III procollagen gene have been reported in different families with EDS IV. Recent results support the hypothesis that in EDS IV, dominant inheritance should be assumed, in sporadic cases also, unless proven otherwise. Very little is known about the genetics or biochemicals defects responsible for the others EDS subtypes, but with the applications of the tools of molecular biology, analysis of these defects if now within reach.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 127,
                "text": "connective tissue"
            }
        },
        {
            "context": "[Dermatitis herpetiformis occuring in patients with celiac disease in childhood]. BACKGROUND: Dermatitis herpetiformis (DH) is a chronic papulovesicular immune-mediated disorder associated with gluten-sensitive enteropathy. We report eight cases in which DH appeared many years after celiac disease (CD) in child. PATIENTS AND METHODS: The diagnosis of CD was based on histological features of total or subtotal villous atrophy, full remission after withdrawal of gluten from the diet, and eventually circulating antibodies (IgA gliadin, antireticulin and antiendomysium) at the time of diagnosis and their disappearance under gluten-free diet. The diagnosis of DH was made from clinical findings, histological examination of the involved skin and direct immunofluorescence microscopy of normal or perilesional skin. HLA class II typing was performed in five patients. DRB1, DQA1, DQB1 and DBP1 alleles were studied. RESULTS: DH appeared between 3 and 22 years after the initial diagnosis of CD. Five patients did not show at that time any digestive symptoms. In three cases, a break in the gluten-free diet or a recent revival of the normal diet preceded the rash. In only one case, DH appeared while the patient was under gluten-free diet. In three patients, the rash appeared many years after the gluten-free diet had been stopped. Phenotype DR3 and/or DR7 of the celiac disease could be found in four of the five patients studied; three of them were found to bear DQW2. The DR2 allele was not found in any of the five tested patients. DISCUSSION: These eight cases illustrate the absence of precise nosological barrier between gluten-sensitive enteropathy of the DH and that observed in CD. The presence of the DR7 allele, and especially the absence of the DR2 allele, could explain the particularly severe and symptomatic course of the enteropathy in these patients. The delay in the appearance of DH, after a very variable period of normal diet, could correspond to the necessary time for progressive accumulation of IgA (or immune complex IgA-gluten) in the skin after a digestive sensitization to gluten. The preventive role of gluten-free diet is thus probable. CONCLUSION: CD and DH likely correspond to two different stages of the same disease, thus requiring a prolonged follow-up of both digestive and skin tissues. Long-term eviction of gluten to prevent eventual DH must be balanced with the demand and the cost of such a diet.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 94,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 639,
                "text": "telomerase"
            }
        },
        {
            "context": "Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. BACKGROUND: Diamond-Blackfan anemia is a rare, clinically heterogeneous, congenital red cell aplasia: 40% of patients have congenital abnormalities. Recent studies have shown that in western countries, the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes in about 50% of patients. There have been no studies to determine the incidence of these mutations in Asian patients with Diamond-Blackfan anemia. DESIGN AND METHODS: We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A. RPS14 was also examined due to its implied involvement in 5q- syndrome. RESULTS: Mutations in RPS19, RPL5, RPL11 and RPS17 were identified in five, four, two and one of the probands, respectively. In total, 12 (27%) of the Japanese Diamond-Blackfan anemia patients had mutations in ribosomal protein genes. No mutations were detected in RPS14, RPS24 or RPL35A. All patients with RPS19 and RPL5 mutations had physical abnormalities. Remarkably, cleft palate was seen in two patients with RPL5 mutations, and thumb anomalies were seen in six patients with an RPS19 or RPL5 mutation. In contrast, a small-for-date phenotype was seen in five patients without an RPL5 mutation. CONCLUSIONS: We observed a slightly lower frequency of mutations in the ribosomal protein genes in patients with Diamond-Blackfan anemia compared to the frequency reported in western countries. Genotype-phenotype data suggest an association between anomalies and RPS19 mutations, and a negative association between small-for-date phenotype and RPL5 mutations.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 17,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "Iron, brain and restless legs syndrome. Iron is the most important transitional metal in the body, as it is implicated in many metabolic processes, mostly related to its capacity as an electron donor/acceptor. Iron deficiency has been long been known to cause anaemia, iron excess to cause haemochromatosis. As excess free iron can cause oxidative damage, it is important that the levels of iron in the body are tightly regulated which appears to be done only by digestive absorption, as there is no known regulating mechanism for elimination of iron. The amount of free iron is also kept to a minimum thanks to binding to transferrin for transport, and to ferritin for storage. Recent research has put emphasis on the possible role of excess iron in the brain in several degenerative diseases. Iron deficiency in the central nervous system is known to cause motor impairment and cognitive deficits; more recently, it has been suggested that it may play a role in the pathophysiology of the restless leg syndrome. 2001 Harcourt Publishers Ltd",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 795,
                "text": "Iron"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 574,
                "text": "FSHD"
            }
        },
        {
            "context": "Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 35,
                "text": "Neuroblastoma"
            }
        },
        {
            "context": "Cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome) in childhood: clinicoradiological analysis of 19 cases. BACKGROUND: The purpose of this study was to emphasize the clinical and imaging findings of 19 child cases of cerebral hemiatrophy. METHODS: A total of 11 male and eight female patients underwent assessment with computed tomography and magnetic resonance imaging. The patients ranged from 1 to 17 years in age. The evaluated parameters were: location of the lesions, midline structural shift effect, ipsilateral calvarial and parenchymal changes. RESULTS: Left cerebral hemiatrophy was seen in 14 of the cases while right cerebral hemiatrophy was observed in five cases. Unilateral calvarial thickening was seen in 11 cases, hyperpneumatization of paranasal sinuses in five, and hypoplasia of the middle frontal cranial fossa in three patients. Cerebral peduncle atrophy was noted in seven cases. In total, 11 patients had thalamic atrophy and lentiform nucleus hypoplasia. In one case, cerebral hemiatrophy was associated with ipsilateral large schizencephalic cleft and absence of the septum pellucidum, whereas in another case, there was diffuse cerebellar atrophy associated with cerebral hemiatrophy. CONCLUSION: Computed tomography and, in particular, magnetic resonance imaging are the procedures of choice with respect to assessment of the etiology and extent of cerebral parenchymal involvement in cerebral hemiatrophy.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 0,
                "text": "Cerebral hemiatrophy"
            }
        },
        {
            "context": "Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 517,
                "text": "CD38"
            }
        },
        {
            "context": "McLeod neuroacanthocytosis: genotype and phenotype. McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 407,
                "text": "XK"
            }
        },
        {
            "context": "Recurrent necrobiosis lipoidica diabeticorum associated with venous insufficiency in an adolescent with poorly controlled type 2 diabetes mellitus. Type 2 diabetes mellitus and associated long-term complications have become a significant health problem in adolescents. We report a 16-year-old girl with poorly controlled type 2 diabetes mellitus who had recurrent necrobiosis lipoidica diabeticorum associated with venous insufficiency.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 129,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Idarucizumab for dabigatran overdose. CONTEXT: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds dabigatran with high affinity. It reverses the anticoagulant effect of dabigatran within minutes and is approved for the reversal of dabigatran during emergency situations. CASE DETAILS: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking dabigatran 150 mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5 g of intravenous idarucizumab promptly and completely reversed the anticoagulant activity of dabigatran as assessed by routine and specific coagulation assays (aPTT from to 75 to 26 s, PT from 26 to 11 s and diluted thrombin time from 92 to 27 s). The initially planned emergency hemodialysis was canceled. DISCUSSION: This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 415,
                "text": "dabigatran"
            }
        },
        {
            "context": "Chromosome condensation and sister chromatid pairing in budding yeast. We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 740,
                "text": "chromosome XII"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 73,
                "text": "RADAR"
            }
        },
        {
            "context": "Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Neurobiology of speech and language has previously been studied in the KE family, in which half of the members have severe impairment in both speech and language. The gene responsible for the phenotype was mapped to chromosome 7q31 and identified as the FOXP2 gene, coding for a transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain. Because of linkage studies implicating 7q31 in autism, where language impairment is a component of the disorder, and in specific language impairment, FOXP2 has also been considered as a potential susceptibility locus for the language deficits in autism and/or specific language impairment. In this study, we characterized mice with a disruption in the murine Foxp2 gene. Disruption of both copies of the Foxp2 gene caused severe motor impairment, premature death, and an absence of ultrasonic vocalizations that are elicited when pups are removed from their mothers. Disruption of a single copy of the gene led to modest developmental delay but a significant alteration in ultrasonic vocalization in response to such separation. Learning and memory appear normal in the heterozygous animals. Cerebellar abnormalities were observed in mice with disruptions in Foxp2, with Purkinje cells particularly affected. Our findings support a role for Foxp2 in cerebellar development and in a developmental process that subsumes social communication functions in diverse organisms.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 331,
                "text": "FOXP2"
            }
        },
        {
            "context": "Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 203,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Benzodiazepine intoxication treated with flumazenil (Anexate, RO 15-1788). The efficacy and safety of flumazenil were assessed in comparison to placebo in a double-blind randomised study of 31 adults intoxicated with benzodiazepines. The criteria of efficacy were the degree of sedation, and orientation in time and space. Patients who received flumazenil awoke within minutes but central depression returned partly one hour later, which reflects the short elimination half-life of the drug. Side effects were few and the results indicate that flumazenil is effective in the primary management of benzodiazepine overdose and in states where benzodiazepines have been taken with other drugs.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 544,
                "text": "flumazenil"
            }
        },
        {
            "context": "A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 286,
                "text": "dabigatran"
            }
        },
        {
            "context": "New anticoagulants for atrial fibrillation. Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 592,
                "text": "Xa"
            }
        },
        {
            "context": "Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 1618,
                "text": "Huntington disease"
            }
        },
        {
            "context": "The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation. Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here, we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2, and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 146,
                "text": "FOXP2"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. INTRODUCTION: Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. METHODS: General clinical assessment, sural nerve biopsy, and genetic analysis were performed. RESULTS: Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular-like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. CONCLUSION: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 212,
                "text": "GAN gene"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 874,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Increasing awareness of sudden unexpected death in epilepsy. Epilepsy affects about 1 in 130 people in the UK and most have a normal life expectancy. Sudden unexpected death in epilepsy (SUDEP) is a - probably heterogeneous - condition where patients with epilepsy die suddenly, almost certainly during a seizure and with no other identified cause of death. The mechanism(s) of SUDEP remain uncertain, but with a growing international scientific interest, there is reason to be optimistic that eventually most of the likely several causes will be identified. Increasing awareness of SUDEP has generated efforts to understand the underlying pathophysiology of SUDEP better to direct the search for effective preventative measures. This review addresses the epidemiology of SUDEP, its possible underlying mechanisms, risk factors, clinical implications and future directions for research.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 150,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Effect of moderate liver impairment on the pharmacokinetics of opicapone. PURPOSE: Opicapone (OPC) is a novel catechol-O-methyltransferase (COMT) inhibitor to be used as adjunctive therapy in levodopa-treated patients with Parkinson's disease. The purpose of this study was to evaluate the effect of moderate liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD; effect on COMT activity) of OPC. METHODS: An open-label, parallel-group study in patients (n = 8) with moderate liver impairment (Child-Pugh category B, score of 7 to 9) and matched healthy subjects (n = 8, control) with normal liver function. All subjects received a single 50-mg oral dose of OPC, with plasma and urine concentrations of opicapone and its metabolites measured up to 72 h post-dose, including soluble COMT (S-COMT) activity. A one-way analysis of variance (ANOVA) was used to compare the main PK and PD parameters between groups. Point estimates (PE) of geometric mean ratios (GMR) and corresponding 90 % confidence intervals (90%CI) for the ratio hepatic/control subjects of each parameter were calculated and compared with the reference interval (80-125 %). RESULTS: Exposure to opicapone (AUC and Cmax) increased significantly in patients with moderate hepatic impairment (PE [90%CI]: AUC0-∞, 184 % [135-250 %]; Cmax, 189 % [144-249 %]). Although apparent total clearance (CL/F) of opicapone was decreased by ∼35 %, similar elimination half-life and unbound/bound fractions of opicapone were observed between the two groups. Both rate and extent of exposure to BIA 9-1103 were higher in the hepatically impaired group, but not statistically significant compared with the control group. Similar to the parent (opicapone), the observed increase in exposure to BIA 9-1106 was statistically significant in the hepatically impaired group over the control group. BIA 9-1106 was the only metabolite detected in urine and its urine PK parameters were in accordance with plasma data. Maximum S-COMT inhibition (Emax) occurred earlier for the hepatically impaired group with values of 100 % and 91.2 % for the hepatically impaired and control groups respectively. Both Emax and AUEC for the hepatically impaired group reached statistical significance over the control group. OPC was well tolerated in both hepatically impaired and control groups. CONCLUSION: The bioavailability of an orally administered single dose of 50 mg OPC was significantly higher in patients with moderate chronic hepatic impairment, perhaps by a reduced first-pass effect. As the tolerability profile of OPC was favourable under the conditions of this study and its exposure is completely purged from systemic circulation before the subsequent dose administration, no OPC dose adjustment is needed in patients with mild to moderate chronic hepatic impairment. However, as OPC is under clinical development for use as adjunctive therapy in levodopa-treated patients with Parkinson's disease, an adjustment of levodopa and/or OPC regimens in patients should be carefully considered based on a potentially enhanced levodopa dopaminergic response and the associated tolerability.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 110,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 465,
                "text": "ADAR"
            }
        },
        {
            "context": "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2778,
                "text": "5-HT2A"
            }
        },
        {
            "context": "The incidence of cystic fibrosis in Caucasian populations. Estimates of the newborn frequency of cystic fibrosis in different Caucasian groups range from 4 times more to 40 times less common than the generally accepted figure of 1:2000. Current meconium screening trials which may be effective in populations with the incidence equal to or greater than 1:2000, may be useful for populations with an incidence as low as 1:7000 only after maximum improvement of the methods. Once the true incidence or the variable incidence is proven for Caucasian populations, screening trails in Negro, Oriental and Indian populations will be required.",
            "question": "What is the incidence of cystic fibrosis in the caucasian population?",
            "answers": {
                "answer_start": 353,
                "text": "1:2000"
            }
        },
        {
            "context": "Monitoring plasma levels of factor Xa inhibitors: how, why and when? New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed. Several available anti-FXa assays are used for monitoring anticoagulant activity of heparins and fondaparinux. They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). The use of calibrators (lyophilized plasma with a known concentration of drug) allows an expression of the results in ng per ml of plasma. Two categories of assays - endogenous and exogenous assays are available. Endogenous assays are useful in pharmaceutical research, while exogenous assays are used in clinical laboratories. The preferred anti-FXa assay is a specific method in contrast to prothrombin time and activated partial thromboplastin time, but it is not available everywhere at any time. A specific measurement of direct FXa inhibitors is feasible with the use of a new test developed by the authors' group. The physicians must be aware of the possibility to measure the plasma concentration of FXa inhibitors in patients at high risk of bleeding and in several other special clinical situations.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 678,
                "text": "xa"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1338,
                "text": "MARS"
            }
        },
        {
            "context": "Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 312,
                "text": "orally"
            }
        },
        {
            "context": "Update on Treatment in Cardiac Sarcoidosis. The prevalence of cardiac sarcoidosis has exponentially increased over the past decade, primarily due to increased awareness and diagnostic modalities for the disease entity. Despite an expanding patient cohort, the optimal management of cardiac sarcoidosis remains yet to be established with a significant lack of prospective trials to support current practice. Corticosteroids remain first-line treatment of this disorder, and we recommend that immunosuppressive therapy should be initiated in all patients diagnosed with cardiac sarcoidosis. Additional pharmacotherapy may be necessary based on disease manifestations and response to treatment. The use of nuclear imaging with fluorodeoxyglucose (FDG) positron emission tomography (PET) to guide treatment has become more common, but lacks rigorous data from larger cohorts. Whether an improvement in inflammatory burden as assessed by FDG-PET is correlated with clinical outcomes is as yet unproven. Device therapy with implantable-cardioverter defibrillators should be considered in all cardiac sarcoidosis patients for either primary or secondary prevention of ventricular arrhythmias and cardiac death.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 407,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "PPADS, a P2X receptor antagonist, as a novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger in guinea pig airway smooth muscle. The Na(+)/Ca(2+)exchanger (NCX) principal function is taking 1 Ca(2+) out of the cytoplasm and introducing 3 Na(+). The increase of cytoplasmic Na(+) concentration induces the NCX reverse mode (NCX(REV)), favoring Ca(2+) influx. NCX(REV) can be inhibited by: KB-R7943 a non-specific compound that blocks voltage-dependent and store-operated Ca(2+) channels; SEA0400 that appears to be selective for NCX(REV), but difficult to obtain and SN-6, which efficacy has been shown only in cardiomyocytes. We found that PPADS, a P2X receptor antagonist, acts as a NCX(REV) inhibitor in guinea pig tracheal myocytes. In these cells, we characterized the NCX(REV) by substituting NaCl and NaHCO(3) with LiCl, resulting in the increase of the intracellular Ca(2+) concentration ([Ca(2+)]i) using fura 2-AM. We analyzed 5 consecutive responses of the NCX(REV) every 10 min, finding no differences among them. To evaluate the effect of different NCX(REV) blockers, concentration response curves to KB-R7943 (1, 3.2 and 10 μM), and SN-6 (3.2, 10 and 30 μM) were constructed, whereas PPADS effect was characterized as time- and concentration-dependent (1, 3.2, 10 and 30 μM). PPADS had similar potency and efficacy as KB-R7943, whereas SN-6 was the least effective. Furthermore, KCl-induced contraction, sensitive to D600 and nifedipine, was blocked by KB-R7943, but not by PPADS. KCl-induced [Ca(2+)]i increment in myocytes was also significantly decreased by KBR-7943 (10 μM). Our results demonstrate that PPADS can be used as a reliable pharmacological tool to inhibit NCX(REV), with the advantage that it is more specific than KB-R7943 because it does not affect L-type Ca(2+) channels.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 313,
                "text": "NCX"
            }
        },
        {
            "context": "Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating enzyme inhibitor, MLN4924, using AlphaScreen. Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct. The inhibited enzyme can no longer transfer Nedd8 downstream to modify and activate the E3 cullin-RING ligases. This results in the stabilization of proteins regulated by the proteasome, leading to cell death. These studies monitored the endogenous cellular changes to NAE∼Nedd8 thioester, the formation of the Nedd8-MLN4924 adduct, and the reduction in the Cul1-Nedd8. Lysates derived from MLN4924-treated HCT116 cells showed that whereas the β-subunit of NAE remained constant, reductions of both NAE∼Nedd8 thioester and Cul1-Nedd8 levels occurred with a concomitant rise of the adduct. Moreover, the formation of the Nedd8-MLN4924 adduct was approximately stoichiometric with the concentration of NAEβ. Higher density 384-well cell-based assays illustrated the kinetics of enzyme inactivation across a wider range of MLN4924 concentrations, showing a rapid loss of NAE∼Nedd8 thioester and Cul1-Nedd8. The reduction of NAE∼Nedd8 thioester precedes the loss of Cul1-Nedd8 at twice the rate. Finally, these results clearly demonstrate the utility of the homogeneous assay for quantitative assessment of these endogenous cellular components in a 384-well plate in response to inhibition of NAE by MLN4924.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 143,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α. Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 794,
                "text": "miR-138"
            }
        },
        {
            "context": "Necrobiosis lipoidica and diabetic control revisited. Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 290,
                "text": "diabetes mellitus"
            }
        }
    ],
    "test": [
        {
            "context": "Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 100,
                "text": "EGFR"
            }
        },
        {
            "context": "Mood disorders in restless legs syndrome (Willis-Ekbom disease). OBJECTIVE: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. This narrative review provides an overview of RLS diagnosis and reports epidemiologic evidence for an association between RLS and mood disorders. Possible links between RLS, sleep disturbances, and mood disorders are considered, and theoretical pathophysiologic pathways are discussed. Finally, pharmacologic therapies for RLS are summarized. DATA SOURCES: A PubMed search was performed using the search term restless legs syndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety disorder, attention deficit hyperactivity disorder, depression/depressive disorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, psychiatric disorder, and psychosis. English-language articles published between January 1993 and May 2013 were retrieved. Additional studies were identified from the reference lists of relevant publications. STUDY SELECTION: 173 publications were retrieved. Articles related to the association between idiopathic RLS and depression, anxiety, and mood disorders were reviewed. In total, 32 epidemiologic studies were identified. These studies were reviewed in detail and ranked according to quality. DATA EXTRACTION: Data were extracted on the basis of relevance to the topic. Epidemiologic studies were assessed using 3 parameters: methodology, data quality, and generalizability of the results. Each factor was scored from 1 (high quality) to 4 (low quality), giving a total score of between 3 and 12 for each study. RESULTS AND CONCLUSIONS: RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 76,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in spinocerebellar ataxia type 3. The C-terminal region of the protein includes a polyglutamine stretch that is expanded in spinocerebellar ataxia type 3. Here, we report on the analysis of an ataxin-3 mutant mouse that has been obtained by gene trap integration. The ataxin-3 fusion protein encompasses 259 N-terminal amino acids including the Josephin domain and an ubiquitin-interacting motif but lacks the C-terminus with the polyglutamine stretch, the valosin-containing protein binding region and part of the ubiquitin-interacting motif 2. Homozygous ataxin-3 mutant mice were viable and showed no apparent anatomical defects at birth. However, at the age of 9 months, homozygous and heterozygous mutant mice revealed significantly altered behaviour and progressing deficits of motor coordination followed by premature death at ∼12 months. At this time, prominent extranuclear protein aggregates and neuronal cell death was found in mutant mice. This was associated with disturbances of the endoplasmic reticulum-mediated unfolded protein response, consistent with the normal role of ataxin-3 in endoplasmic reticulum homeostasis. Thus, the ataxin-3 gene trap model provides evidence for a contribution of the non-polyglutamine containing ataxin-3 N-terminus, which mimics a calpain fragment that has been observed in spinocerebellar ataxia type 3. Consistent with the disease in humans, gene trap mice develop cytoplasmic inclusion bodies and implicate impaired unfolded protein response in the pathogenesis of spinocerebellar ataxia type 3.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 129,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Lessons Learned From an Untreated \"Benign\" Thoracic Tumor. We describe a patient with Doege-Potter syndrome (solitary fibrous tumor of the pleura presenting with hypoglycemia) and illustrate several important lessons learned from the case. Seven years after the initial diagnosis, the tumor showed significant growth and developed a high-grade undifferentiated component. Solitary fibrous tumors do grow and cannot be deemed benign. Resection should be considered in all patients who are candidates for operation upon diagnosis. Our case also serves as a reminder of this rare syndrome, inasmuch as early recognition of the association of hypoglycemia with these tumors may have allowed for earlier diagnosis and avoidance of extensive tests in our patient.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 162,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Heterologous expression of the C-terminal antigenic domain of the malaria vaccine candidate Pfs48/45 in the green algae Chlamydomonas reinhardtii. Malaria is a widespread and infectious disease that is a leading cause of death in many parts of the world. Eradication of malaria has been a major world health goal for decades, but one that still remains elusive. Other diseases have been eradicated using vaccination, but traditional vaccination methods have thus far been unsuccessful for malaria. Infection by Plasmodium species, the causative agent of malaria, is currently treated with drug-based therapies, but an increase in drug resistance has led to the need for new methods of treatment. A promising strategy for malaria treatment is to combine transmission blocking vaccines (TBVs) that prevent spread of disease with drug-based therapies to treat infected individuals. TBVs can be developed against surface protein antigens that are expressed during parasite reproduction in the mosquito. When the mosquito ingests blood from a vaccinated individual harboring the Plasmodium parasite, the antibodies generated by vaccination prevent completion of the parasites life-cycle. Animal studies have shown that immunization with Pfs48/45 results in the production of malaria transmission blocking antibodies; however, the development of this vaccine candidate has been hindered by poor expression in both prokaryotic and eukaryotic hosts. Recently, the chloroplast of Chlamydomonas reinhardtii has been used to express complex recombinant proteins. In this study, we show that the C-terminal antigenic region of the Pfs48/45 antigen can be expressed in the chloroplast of the green algae C. reinhardtii and that this recombinant protein has a conformation recognized by known transmission blocking antibodies. Production of this protein in algae has the potential to scale to the very large volumes required to meet the needs of millions at risk for contracting malaria.",
            "question": "Which is the causative agent of malaria?",
            "answers": {
                "answer_start": 511,
                "text": "Plasmodium species"
            }
        },
        {
            "context": "SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing. A primary step in activating the alternative nuclear factor-kappaB (NF-kappaB) pathway requires NF-kappaB2/p100 processing to generate p52. In most cases, stimuli-induced p100 processing is dependent on NF-kappaB-inducing kinase/IkappaB kinase alpha-mediated phosphorylation and ubiquitination. Here, we report that post-translational modification of p100 at specific sites by the small ubiquitin-like modifier (SUMO) is another determining factor for stimuli-induced p100 processing. The results show that basal SUMO modification is required for stimuli-induced p100 phosphorylation and that blocking SUMOylation of p100, either by site-directed mutation or by short interfering RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various physiological stimuli-induced p100 processing and ultimate activation of the alternative NF-kappaB pathway. Together, these findings show the crucial role of SUMO1 modification in p100 processing and provide mechanistic insights into the participation of SUMO1 modification in the regulation of signal transduction.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 818,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 119,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "The metal chelating and chaperoning effects of clioquinol: insights from yeast studies. Clioquinol (CQ), a once popular antibiotic, was used to inhibit the growth of microorganisms. Recently, CQ and its analog PBT2 have shown encouraging effects in the animal and clinical trials for Alzheimer's disease (AD). However, the mechanism by which this class of molecules works remains controversial. In this work, we used the yeast Saccharomyces cerevisiae as a model to study how CQ affects molecular and cellular functions and particularly, copper, iron, and zinc homeostasis. We observed a CQ-induced inhibition of yeast growth, which could be slightly relieved by supplementation of copper or iron. Microarray results indicated that yeast cells treated with CQ sense a general deficiency in metals, despite elevated total cellular contents of copper and iron. Consistent with this, reduced activities of some metal-sensitive enzymes were observed. Intriguingly, CQ can increase the SOD1 activity, likely through Ccs1's accessibility to CQ-bound copper ions. Further studies revealed that CQ sequestrates copper and iron at the cellular membrane, likely the plasma membrane, resulting overall metal accumulation but cytosolic metal depletion. CQ's effects on metal-sensitive metalloenzymes were also verified in mammalian cell line SH-SY5Y. Together, our results revealed that CQ can regulate metal homeostasis by binding metal ions, resulting the cell sensing a state of deficiency of bioavailable metal ions while simultaneously increasing available metals to SOD1 (via Ccs1) and possibly some other metalloproteins that can access CQ-bound metals. We hope this regulation of metal homeostasis may be helpful in explaining the therapeutic effects of CQ used in disease treatment.",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 284,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Livestock-Associated MRSA: The Impact on Humans. During the past 25 years an increase in the prevalence of methicillin-resistant Staphylococcus aureus (HA-MRSA) was recorded worldwide. Additionally, MRSA infections may occur outside and independent of hospitals, caused by community associated MRSA (CA-MRSA). In Germany, we found that at least 10% of these sporadic infections are due to livestock-associated MRSA (LA-MRSA), which is initially associated with livestock. The majority of these MRSA cases are attributed to clonal complex CC398. LA-MRSA CC398 colonizes the animals asymptomatically in about half of conventional pig farms. For about 77%-86% of humans with occupational exposure to pigs, nasal carriage has been reported; it can be lost when exposure is interrupted. Among family members living at the same farms, only 4%-5% are colonized. Spread beyond this group of people is less frequent. The prevalence of LA-MRSA in livestock seems to be influenced by farm size, farming systems, usage of disinfectants, and in-feed zinc. LA-MRSA CC398 is able to cause the same kind of infections in humans as S. aureus and MRSA in general. It can be introduced to hospitals and cause nosocomial infections such as postoperative surgical site infections, ventilator associated pneumonia, septicemia, and infections after joint replacement. For this reason, screening for MRSA colonization at hospital admittance is recommended for farmers and veterinarians with livestock contacts. Intrahospital dissemination, typical for HA-MRSA in the absence of sufficient hygiene, has only rarely been observed for LA-MRSA to date. The proportion of LA-MRSA among all MRSA from nosocomial infections is about 3% across Germany. In geographical areas with a comparatively high density of conventional farms, LA-MRSA accounts for up to 10% of MRSA from septicemia and 15% of MRSA from wound infections. As known from comparative genome analysis, LA-MRSA has evolved from human-adapted methicillin-susceptible S. aureus, and the jump to livestock was obviously associated with several genetic changes. Reversion of the genetic changes and readaptation to humans bears a potential health risk and requires tight surveillance. Although most LA-MRSA (>80%) is resistant to several antibiotics, there are still sufficient treatment options.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 155,
                "text": "MRSA"
            }
        },
        {
            "context": "Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy. Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 731,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1675,
                "text": "FSHD"
            }
        },
        {
            "context": "Correlation of transcription of MALAT-1, a novel noncoding RNA, with deregulated expression of tumor suppressor p53 in small DNA tumor virus models. Although metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies, little is known about its function or regulation. We therefore examined the relationship between MALAT-1 expression and candidate modulators such as DNA tumor virus oncoproteins human papillomavirus (HPV)-16 E6 and E7, BK virus T antigen (BKVTAg), mouse polyoma virus middle T antigen (MPVmTAg) and tumor suppressor genes p53 and pRb. Using suppressive subtractive hybridization (SSH) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays, MALAT-1 was shown to be increased in viral oncongene-expressing salivary gland biopsies from humans and mice. The results also indicated that MALAT-1 transcripts and promoter activity were increased in vitro when viral oncongene-expressing plasmids were introduced into different cell types. These same viral oncogenes in addition to increasing MALAT-1 transcription have also been shown to inhibit p53 and/or pRb function. In p53 mutant or inactive cell lines MALAT-1 was also shown to be highly upregulated. We hypothesize that there is a correlation between MALAT-1 over-expression and p53 deregulation. In conclusion, we show that disruption of p53, by both polyoma and papilloma oncoproteins appear to play an important role in the up-regulation of MALAT-1. MALAT-1 might therefore represent a biomarker for p53 deregulation within malignancies.",
            "question": "Is the long non- coding RNA malat-1 up or downregulated in cancer?",
            "answers": {
                "answer_start": 249,
                "text": "upregulated"
            }
        },
        {
            "context": "BHLHB3: a candidate tumor suppressor in lung cancer. BHLHB3 is a basic helix-loop-helix (bHLH) domain-containing protein that acts as a transcriptional repressor. We found that BHLHB3 transcript levels were low in three human lung cancer cell lines and downregulated in human lung adenocarcinomas as compared to normal lung tissue. BHLHB3 gene overexpression inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. The reduced colony growth was likely due to inhibition of cell proliferation as suggested by the downregulation of cyclin D1 (CCND1) expression in NCI-H520 cells transfected to overexpress the BHLHB3 gene; no evidence of apoptosis was observed. These results point to the potential role of the BHLHB3 protein as a tumor suppressor for lung cancer.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 417,
                "text": "lung"
            }
        },
        {
            "context": "Lumbosacral transitional vertebra causing Bertolotti's syndrome: a case report and review of the literature. INTRODUCTION: Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. The association of that variant with low back pain and the change in the biomechanical properties of the lumbar spine is called Bertolotti's syndrome. CASE PRESENTATION: We report a case of a 40-year-old male patient with chronic low back pain extending to the left buttock, just above the ipsilateral sacroiliac joint. Radiographic investigation revealed an anomalous enlargement of the left transverse process of the fifth lumbar vertebra forming a pseudarthrosis with the infrajacent ala of the sacrum. CONCLUSION: In young patients with back pain the possibility of Bertolotti's syndrome should always be taken in account.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 123,
                "text": "Lumbosacral"
            }
        },
        {
            "context": "Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum. Myotonic dystrophy (DM) is caused by a CTG expansion in the 3'-untranslated region of a protein kinase gene (DMPK). Cardiovascular disease is one of the most prevalent causes of death in DM patients. Electrophysiological studies in cardiac muscles from DM patients and from DMPK(-/-) mice suggested that DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity. However, there are no data regarding the molecular signaling pathways involved in DM heart failure. Here we show that DMPK expression in cardiac myocytes is highly enriched in the sarcoplasmic reticulum (SR) where it colocalizes with the ryanodine receptor and phospholamban (PLN), a muscle-specific SR Ca(2+)-ATPase (SERCA2a) inhibitor. Coimmunoprecipitation studies showed that DMPK and PLN can physically associate. Furthermore, purified wild-type DMPK, but not a kinase-deficient mutant (K110A DMPK), phosphorylates PLN in vitro. Subsequent studies using the DMPK(-/-) mice demonstrated that PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice compared with wild-type mice both in vitro and in vivo. Finally, we show that Ca(2+) uptake in SR is impaired in ventricular homogenates from DMPK(-/-) mice. Together, our data suggest the existence of a novel regulatory DMPK pathway for cardiac contractility and provide a molecular mechanism for DM heart pathology.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 820,
                "text": "phospholamban"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 228,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Multilocus outbreak of foodborne botulism linked to contaminated sausage in Hebei province, China. In 2007, an outbreak of foodborne botulism occurred in Hebei province, China. An epidemiological investigation and laboratory detection studies showed that sausage contaminated by type A Clostridium botulinum caused this outbreak of food poisoning. Its clinical and epidemiological features were different from previous reports of food poisoning.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 286,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study. OBJECTIVES: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. METHODS: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. RESULTS: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. CONCLUSIONS: BMI appears to be associated with RA disease activity in women, but not in men.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 866,
                "text": "women"
            }
        },
        {
            "context": "Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation. Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases encoded by the largest uninterrupted cluster of protease-encoding genes within the human genome. Recent studies, mostly relying on in vitro proteolysis of recombinant proteins, have suggested that KLK activities are regulated by proteolytic activation cascades that can operate in a tissue-specific manner, such as the semen liquefaction and skin desquamation cascades. The validity of KLK activation cascades in vivo largely remains to be demonstrated. Here, we focus on recent investigations showing that KLKs represent interesting players in the broader field of immunology based on their ability to bridge their inherent ability to degrade the extracellular matrix with major functions of the immune system. More specifically, KLKs assist in the infiltration of immune cells through the skin and the blood brain barrier, whereas they catalyze the generation of antimicrobial peptides by proteolytic activation and further processing of protein precursors. In an attempt to integrate current knowledge, we propose KLK-mediated pathways that are putatively involved in inflammation associated with skin wounding and central nervous system disorders, including multiple sclerosis. Finally, we present evidence of KLK participation in autoimmune diseases and allergies.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 162,
                "text": "15"
            }
        },
        {
            "context": "PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin. UNLABELLED: [18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 22,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Successful treatment with nilotinib after imatinib failure in a CML patient with a four-way Ph chromosome translocation and point mutations in BCR/ABL gene. Chronic myelogenous leukemia (CML) is characterized by Philadelphia (Ph) chromosome with a chimeric gene BCR-ABL created by reciprocal t(9:22) (q34;q11) translocation. Variant Ph chromosome translocations involving chromosomes other than 9 and 22 are found in 5-10% of CML cases. We here report a CML patient who carries a four-way Ph chromosome translocation, t(9;22;15;19) (q34;q11;q15;q13). The patient was diagnosed in 1997 and initially treated with hydroxyurea. In 2002, treatment with imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained at the levels of 42-65%, indicating imatinib failure. In 2006, the point mutations of F359I and L387M were detected in BCR/ABL gene, which may be related to imatinib failure. Treatment with nilotinib, a TKI with high target specificity, was then started which resulted in durable major molecular response. Administration of nilotinib offered an effective treatment in a CML patient with variant Ph chromosome translocations and BCR-ABL point mutations after imatinib failure.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 671,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Gemin proteins are required for efficient assembly of Sm-class ribonucleoproteins. Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of spinal motor neurons. The gene encoding the survival of motor neurons (SMN) protein is mutated in >95% of SMA cases. SMN is the central component of a large oligomeric complex, including Gemins2-7, that is necessary and sufficient for the in vivo assembly of Sm proteins onto the small nuclear (sn)RNAs that mediate pre-mRNA splicing. After cytoplasmic assembly of the Sm core, both SMN and splicing snRNPs are imported into the nucleus, accumulating in Cajal bodies for additional snRNA maturation steps before targeting to splicing factor compartments known as \"speckles.\" In this study, we analyzed the function of individual SMN complex members by RNA interference (RNAi). RNAi-mediated knockdown of SMN, Gemin2, Gemin3, and Gemin4 each disrupted Sm core assembly, whereas knockdown of Gemin5 and Snurportin1 had no effect. Assembly activity was rescued by expression of a GFP-SMN construct that is refractive to RNAi but not by similar constructs that contain SMA patient-derived mutations. Our results also demonstrate that Cajal body homeostasis requires SMN and ongoing snRNP biogenesis. Perturbation of SMN function results in disassembly of Cajal bodies and relocalization of the marker protein, coilin, to nucleoli. Moreover, in SMN-deficient cells, newly synthesized SmB proteins fail to associate with U2 snRNA or accumulate in Cajal bodies. Collectively, our results identify a previously uncharacterized function for Gemin3 and Gemin4 in Sm core assembly and correlate the activity of this pathway with SMA.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1375,
                "text": "coilin"
            }
        },
        {
            "context": "Drug development based on the metals hypothesis of Alzheimer's disease. The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-beta to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2 is a once per day, orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer's disease.",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 1470,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790: implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8%. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 276,
                "text": "EGFR"
            }
        },
        {
            "context": "Direct comparison of [(18) F]MH.MZ and [(18) F] altanserin for 5-HT2A receptor imaging with PET. Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 132,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B). MWS has been reported in association with Hirschsprung disease (HSCR). MWS is sometimes difficult to diagnose clinically, especially when HSCR is absent. Thus, it is necessary to detect gene abnormalities at the molecular level. Here we report two Japanese girls with MWS, who showed a distinct facial phenotype, severe intellectual disability and epileptic seizures. Major congenital anomalies of the patients were very different. Patient 1 suffered from severe congenital heart disease, but did not show apparent HSCR. Patient 2 suffered from typical HSCR and underwent surgical treatment, but did not have congenital heart disease. According to the gene analysis using white blood cells, they had nonsense mutations in ZFHX1B, R695X and Q433X, respectively. In conclusion, molecular genetic analysis of ZFHX1B is important for a definite diagnosis of MWS which has a wide phenotypic spectrum of congenital anomalies.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 234,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Coilin, more than a molecular marker of the cajal (coiled) body. The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 694,
                "text": "coilin"
            }
        },
        {
            "context": "Genetic variation within coat color genes of MC1R and ASIP in Chinese brownish red Tibetan pigs. Melanocortin receptor 1 (MC1R) and agouti signaling protein (ASIP) are two major genes affecting coat color phenotypes in mammals, and inactivation mutations in the MC1R gene are responsible for red coat color in European pig breeds. Conversely, the gain-of-function ASIP mutations block MC1R signaling and lead to the production of red pheomelanin. Chinese Tibetan pigs have three types of coat color phenotypes, including brownish red, solid black and black with patches of brownish red and white. Herein, we investigated variations of the MC1R and ASIP genes in Tibetan pigs. The results showed that the brownish red Tibet pig had the dominant black MC1R allele (E(D1)). No loss-of-function mutation in MC1R responsible for red coat color in European breeds was observed in this breed. No causal mutation for the red coat color phenotype was found in the coding sequence of the ASIP gene. A novel missense mutation c.157G > A was firstly identified in exon 2 of ASIP, which was further genotyped in 285 pigs from five Chinese breeds and three Western breeds having different coat color phenotypes. Nearly all pigs were GG homozygotes. In conclusion, no functional variant responsible for brownish red coloration was found in the coding region of MC1R and ASIP in Tibetan pigs.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 803,
                "text": "MC1R"
            }
        },
        {
            "context": "Retrovirus-mediated gene transfer and galactocerebrosidase uptake into twitcher glial cells results in appropriate localization and phenotype correction. Galactocerebrosidase (GALC) is deficient in all tissues from human patients and animal models with globoid cell leukodystrophy (GLD) or Krabbe disease. The deficiency results in decreased lysosomal catabolism of certain galactolipids including galactosylceramide and psychosine that are synthesized maximally during myelination. According to current theories, the accumulation of psychosine in humans and animals with GLD induces oligodendrocyte degeneration and myelination ceases. Transduction of oligodendrocytes from twitcher mice with a retroviral vector containing the GALC cDNA can correct the enzyme deficiency in these cells. Our data show that twitcher astrocytes and oligodendrocytes can internalize exogenous GALC, as well as donate the enzyme to the mutant glial cells. Antibodies against human GALC localized the GALC antigen in retrovirally transduced cells and cells receiving enzyme via cell to cell secretion and uptake to the lysosomal fraction. In fact immunocytochemical studies in transduced oligodendrocytes revealed that the GALC colocalizes in vesicles lysosomal-associated membrane protein-2 (LAMP2) (+). Moreover, labeling cells with anti-GALC and a marker for oligodendrocytes demonstrated that, upon differentiation, transduced, twitcher oligodendrocytes attained the normal branched process configuration, while untransduced cells show only abnormal morphology. Phenotype correction in mutant oligodendrocytes has also been observed after enzyme transfer. These studies indicate that GALC activity supplied to cultured oligodendrocytes from twitcher mice by different methods can correct the pathological phenotype of these cells.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 154,
                "text": "Galactocerebrosidase"
            }
        },
        {
            "context": "Stress Responses in Alfalfa (Medicago sativa L.) : V. Constitutive and Elicitor-Induced Accumulation of Isoflavonoid Conjugates in Cell Suspension Cultures. The isoflavonoid conjugates medicarpin-3-O-glucoside-6''-O-malonate (MGM), afrormosin-7-O-glucoside (AG), and afrormosin-7-O-glucoside-6''-O-malonate (AGM) were isolated and characterized from cell suspension cultures of alfalfa (Medicago sativa L.), where they were the major constitutive secondary metabolites. They were also found in alfalfa roots but not in other parts of the plant. The phytoalexin medicarpin accumulated rapidly in suspension cultured cells treated with elicitor from Colletotrichum lindemuthianum, and this was subsequently accompanied by an increase in the levels of MGM. In contrast, net accumulation of afrormosin conjugates was not affected by elicitor treatment. Labeling studies with [(14)C]phenylalanine indicated that afrormosin conjugates were the major de novo synthesized isoflavonoid products in unelicited cells. During elicitation, [(14)C]phenylalanine was incorporated predominantly into medicarpin, although a significant proportion of the newly synthesized medicarpin was also conjugated. Treatment of (14)C-labeled, elicited cells with l-alpha-aminooxy-beta-phenylpropionic acid, a potent inhibitor of PAL activity in vivo, resulted in the initial appearance of labeled medicarpin of very low specific activity, suggesting that the phytoalexin could be released from a preformed conjugate under these conditions. Our data draw attention to the involvement of isoflavone hydroxylases during the constitutive and elicitor-induced accumulation of isoflavonoids and their conjugates in alfalfa cell cultures.",
            "question": "Which is the major phytoalexin in alfalfa (Medicago sativa L.)?",
            "answers": {
                "answer_start": 185,
                "text": "medicarpin"
            }
        },
        {
            "context": "Stable carbon isotopes and the study of prehistoric human diet. Mass spectrometric analysis of the stable carbon isotope composition (13C/12C or delta 13C) of bone collagen from human remains recovered at archaeological sites provides a direct chemical method for investigating dietary patterns of prehistoric human populations. This methodology is based on the facts that (1) different food items within the human diet have distinct delta 13C values, and (2) the delta 13C value of human bone collagen is determined by the delta 13C value of the diet. Studies of the development of subsistence patterns based on corn agriculture, one of the most significant developments in North American prehistory, can benefit from the use of stable carbon isotope techniques because corn has a high delta 13C value relative to other components of the human diet. Measurements of delta 13C of bone collagen from prehistoric human skeletal remains from southeastern Missouri and northeastern Arkansas indicate that intensive corn agriculture began in this region around A.D. 1000, that the incorporation of corn into the human diet was a rapid phenomenon, and that 35 to 77% of the human diet from A.D. 1000 to A.D. 1600 consisted of corn. Results from an isochronous population in southeastern South Dakota (A.D. 1400) suggest that 78 to 90% of the diet of this group consisted of corn, with no difference between males and females. Coupled with more traditional archaeological methods, stable carbon isotope analysis of bone collagen can significantly enhance reconstruction of dietary patterns of prehistoric humans.",
            "question": "Which bone protein is used in archaelogy for dating and species identification?",
            "answers": {
                "answer_start": 164,
                "text": "collagen"
            }
        },
        {
            "context": "Fanconi anemia: at the crossroads of DNA repair. Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations. The FA pathway comprises 13 disease-causing genes involved in maintaining genomic stability. The fast pace of study of the novel DNA damage network has led to the constant discovery of new FA-like genes involved in the pathway that when mutated lead to similar disorders. A majority of the FA proteins act as signal transducers and scaffolding proteins to employ other pathways to repair DNA. This review discusses what is known about the FA proteins and other recently linked FA-like proteins. The goal is to clarify how the proteins work together to carry out interstrand crosslink repair and homologous recombination-mediated repair of damaged DNA.",
            "question": "What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?",
            "answers": {
                "answer_start": 49,
                "text": "Fanconi anemia"
            }
        },
        {
            "context": "Cracking the histone code: one, two, three methyls, you're out! In this issue of Molecular Cell, Zhang et al. report the structure of a ternary complex between the SET domain histone methyltransferase DIM-5, its cofactor, and a histone H3 peptide. The insight gained from analysis of a key amino acid provides an exciting opportunity to dissect the possible functional meaning of mono-, di-, and trimethylation of histone lysine residues in vivo that will complement existing approaches in the quest to crack the histone methylation code.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 164,
                "text": "SET domain"
            }
        },
        {
            "context": "Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model. BACKGROUND & AIMS: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity.",
            "question": "Hy's law measures failure for what organ?",
            "answers": {
                "answer_start": 58,
                "text": "Liver"
            }
        },
        {
            "context": "Naltrexone/bupropion for the treatment of obesity and obesity with Type 2 diabetes. Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification. Its safety and efficacy were assessed in four randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies demonstrated statistically significant and clinically meaningful weight loss following up to 52 weeks of treatment with naltrexone/bupropion compared with placebo. The average weight loss from baseline across the four studies was approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for weight loss, as well as significant improvements in cardiometabolic markers. This review focuses on the four studies, their outcomes and the mechanism of action of Contrave.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 224,
                "text": "obesity"
            }
        },
        {
            "context": "Epidemiology of Clostridium difficile in Germany based on a single center long-term surveillance and German-wide genotyping of recent isolates provided to the advisory laboratory for diagnostic reasons. Epidemiology of Clostridium difficile is characterized by worldwide increase of C. difficile infections (CDI) and the emergence of new epidemic outbreak strains with the capacity for global spreading. Long-term local surveillance at the University of Saarland Medical Center between 2000 and 2013 shows that the incidence rate of laboratory-confirmed CDI was influenced by local epidemiology as well as by testing strategies. Since 2008, molecular typing of C. difficile was regularly performed for symptomatic hospitalized patients by surface-layer protein A sequence typing (slpAST), which is an established highly standardized technique for genotyping of C. difficile. The results were assigned to known ribotypes for better comparison to international data. It could be demonstrated that distribution of genotypes was different between age groups. Older patients were predominantly infected with ribotype 001 and 027, whereas ribotype 027 was not detected in the pediatric population. Molecular typing of German isolates sent to the advisory laboratory between 2011 and 2013 revealed that ribotype 027 is present with high percentages in most German regions except for the very North. In conclusion, optimized testing of all hospitalized patients with diarrhea should be generally implemented to avoid under-diagnosis of C. difficile infection. Ribotype 027 is highly prevalent in Germany, but its infections are restricted to older patients, while absent in children. Molecular typing of suspected hospital outbreaks and of patients with severe or recurrent disease may help to better understand virulence and epidemic spreading of C. difficile.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 1552,
                "text": "Ribotype 027"
            }
        },
        {
            "context": "Deciphering transcription dysregulation in FSH muscular dystrophy. DUX4, a homeobox-containing gene present in a tandem array, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant autosomal disease. New findings about DUX4 have raised as many fundamental questions about the molecular pathology of this unique disease as they have answered. This review discusses recent studies addressing the question of whether there is extensive FSHD-related transcription dysregulation in adult-derived myoblasts and myotubes, the precursors for muscle repair. Two models for the role of DUX4 in FSHD are presented. One involves transient pathogenic expression of DUX4 in many cells in the muscle lineage before the myoblast stage resulting in a persistent, disease-related transcription profile ('Majority Rules'), which might be enhanced by subsequent oscillatory expression of DUX4. The other model emphasizes the toxic effects of inappropriate expression of DUX4 in only an extremely small percentage of FSHD myoblasts or myotube nuclei ('Minority Rules'). The currently favored Minority Rules model is not supported by recent studies of transcription dysregulation in FSHD myoblasts and myotubes. It also presents other difficulties, for example, explaining the expression of full-length DUX4 transcripts in FSHD fibroblasts. The Majority Rules model is the simpler explanation of findings about FSHD-associated gene expression and the DUX4-encoded homeodomain-type protein.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 184,
                "text": "FSHD"
            }
        },
        {
            "context": "The p73 tumor suppressor is targeted by Pirh2 RING finger E3 ubiquitin ligase for the proteasome-dependent degradation. The p73 gene, a homologue of the p53 tumor suppressor, is expressed as TA and ΔN isoforms. TAp73 has similar activity as p53 and functions as a tumor suppressor whereas ΔNp73 has both pro- and anti-survival functions. While p73 is rarely mutated in spontaneous tumors, the expression status of p73 is linked to the sensitivity of tumor cells to chemotherapy and prognosis for many types of human cancer. Thus, uncovering its regulators in tumors is of great interest. Here, we found that Pirh2, a RING finger E3 ubiquitin ligase, promotes the proteasome-dependent degradation of p73. Specifically, we showed that knockdown of Pirh2 up-regulates, whereas ectopic expression of Pirh2 down-regulates, expression of endogenous and exogenous p73. In addition, Pirh2 physically associates with and promotes TAp73 polyubiquitination both in vivo and in vitro. Moreover, we found that p73 can be degraded by both 20 S and 26 S proteasomes. Finally, we showed that Pirh2 knockdown leads to growth suppression in a TAp73-dependent manner. Taken together, our findings indicate that Pirh2 promotes the proteasomal turnover of TAp73, and thus targeting Pirh2 to restore TAp73-mediated growth suppression in p53-deficient tumors may be developed as a novel anti-cancer strategy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 292,
                "text": "7"
            }
        },
        {
            "context": "Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma:: final time-to-event results from the SUMMIT trial. BACKGROUND: Bortezomib, a first-in-class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase II trial, SUMMIT. METHODS: Patients received bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 followed by a 10-day rest period for up to 8 cycles. Dexamethasone 20 mg on the day of and the day after bortezomib was permitted for suboptimal response. Extended treatment beyond 8 cycles was offered to patients whose physicians felt they would benefit from additional therapy. Follow-up was conducted in all patients for a median of 23 months, an additional 13 months from the original report. RESULTS: Of 202 patients enrolled in SUMMIT, 193 were evaluable for response. Seven (4%) patients achieved a complete response, 12 (6%) achieved a nearly complete response, 34 (18%) achieved a partial response, and 14 (7%) had a minimal response while on bortezomib. The updated median duration of response to bortezomib alone was 12.7 months. The median overall time to progression for all SUMMIT patients was 7 months. For responding patients, the median time to progression was 13.9 months, whereas for those with progressive disease (PD) or who were not evaluable, the median time to progression was 1.3 months. The median overall survival (OS) for all SUMMIT patients was 17.0 months. Whereas the median OS for patients with PD or who were not evaluable was 8 months, the median OS for responding patients was not reached at 23 months of follow-up. CONCLUSIONS: These data demonstrate that treatment with bortezomib results in meaningful long-term benefit for patients with relapsed and refractory myeloma.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 248,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. BACKGROUND: Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. METHODS: Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. FINDINGS: 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. INTERPRETATION: A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. FUNDING: Orexigen Therapeutics.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 463,
                "text": "Obesity"
            }
        },
        {
            "context": "Focal cortical dysplasia - review. Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults.Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed - from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes.New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life.Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias.THE MOST COMMON FINDINGS ON MRI IMAGING INCLUDE: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure-free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy.However, in type I cortical dysplasia, MR imaging is often normal, and also in both types the lesion seen on MRI may be smaller than the seizure-generating region seen in the EEG. The abnormalities may also involve vital for life brain parts, where curative surgery will not be an option. Therefore, other diagnostic imaging techniques such as FDG PET, MEG, DTI and intra-cranial EEG are widely used to establish the diagnosis and to decide on management.With advances in both genetics and neuroimaging, we may develop a better understanding of patients with drug-resistant epilepsy, which will help us to provide more successful pharmacological and/or surgical treatment in the future.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 656,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Incorporating body-type (apple vs. pear) in STOP-BANG questionnaire improves its validity to detect OSA. STUDY OBJECTIVE: The aim of this study is to evaluate whether adding the item of \"apple body type\" to the STOP-BANG questionnaire enhances diagnostic performance of the questionnaire for detecting obstructive sleep apnea (OSA). DESIGN: Cross-sectional study. SETTING: Sleep center setting. PATIENTS: Two hundred and eight subjects who were referred for an evaluation of possible OSA at Tulane Comprehensive Sleep Center. The exclusion criteria were age<18years old, incomplete or absent questionnaire, incomplete body type identification, polysomnography (PSG) refusal, and pregnant women. INTERVENTIONS: STOP-BANG items and body type data were collected on the initial clinic visit. An overnight PSG was performed on every participant. MEASUREMENTS: Descriptive analyses of the demographic data and PSG variables were performed. The predictive parameters of STOP and STOP-BANG without and with body type score (STOP-Apple and STOPBANG-Apple) were compared. MAIN RESULTS: The STOP questionnaire's sensitivity/specificity/positive likelihood ratio (+LR) (cut-off=2) was 96%/11%/1.1, respectively whereas the STOP-Apple questionnaire (cut-off=3) was 88%/39%/1.5. The STOP-BANG's sensitivity/specificity/+LR (cut-off=3) was 96%/19%/1.2, respectively whereas the STOP-BANG-Apple questionnaire (cut-off=4) was 90%/39%/1.5. The area under the Receiver Operating Characteristic (ROC) curve of STOP-Apple was comparable to the STOP-BANG (P=0.25). The addition of the apple body type item to the STOP-BANG questionnaire in participants with a score > 3 led to increased specificity (67.4%), increased the odds ratio of having OSA of 2.5 (95% CI, 1.2-5.3) and odds ratio of having moderate-severe OSA of 4.7 (95% CI, 2.5-8.7). CONCLUSION: In the sleep center setting, adding the body type item to the STOP-BANG questionnaire improves not only clinical prediction for PSG confirmed OSA but also predicts moderate to severe of OSA.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 302,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 133,
                "text": "CD38"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 286,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1276,
                "text": "CD38"
            }
        },
        {
            "context": "A cascade of genes related to Waardenburg syndrome. On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 181,
                "text": "MITF"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1613,
                "text": "XK"
            }
        },
        {
            "context": "Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders. The Marfan syndrome is an autosomal dominant disorder with pleiotropic manifestations that involve the cardiovascular, ocular, and skeletal systems. Through a number of investigational approaches, the gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with elastin in connective tissue. Mutational analysis of defects in the FBN1 gene in patients with the Marfan syndrome has revealed that most mutations are private or unique in an affected individual or family. Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations. In addition, fibroblast cell strains from a subset of patients with idiopathic scoliosis have fibrillin protein defects. Last, fibroblasts from calves affected with bovine Marfan syndrome display defects in the fibrillin protein. These studies have wide-ranging implications in the diagnosis, treatment, and prevention of Marfan syndrome and related disorders.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 357,
                "text": "FBN1"
            }
        },
        {
            "context": "Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression. The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ~50%; p<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (p<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer > 1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 115,
                "text": "SERCA2"
            }
        },
        {
            "context": "Classification schemes of cranial dural arteriovenous fistulas. The clinical presentation of dural arteriovenous fistulas (DAVFs), in particular the associated risk of intracranial hemorrhage, shows a strong correlation with their pattern of venous drainage. The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage. A revised classification that grades DAVFs through a combination of angiographic and clinical features has also been proposed. This article offers a review of these various classification schemes, and discusses their application to treatment decision making.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 310,
                "text": "DAVF"
            }
        },
        {
            "context": "[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 567,
                "text": "xa"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1494,
                "text": "XK"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 304,
                "text": "BRG1"
            }
        },
        {
            "context": "Novel anticoagulants for stroke prevention in atrial fibrillation: current clinical evidence and future developments. Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 662,
                "text": "Xa"
            }
        },
        {
            "context": "Heme and FLVCR-related transporter families SLC48 and SLC49. Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.",
            "question": "Which SLC family is FLVCR1 a member of?",
            "answers": {
                "answer_start": 265,
                "text": "SLC49"
            }
        },
        {
            "context": "Incidence of sudden unexpected death in nocturnal frontal lobe epilepsy: a cohort study. OBJECTIVE: Most cases of sudden unexpected death in epilepsy (SUDEP) follow a seizure, and most deaths occur while people are in bed, presumably sleeping. Nocturnal seizures are reported to be a risk factor for SUDEP. People with nocturnal frontal lobe epilepsy (NFLE) have seizures predominantly or exclusively during sleep, often many times per night. The present study aimed to assess whether NFLE represents a high-risk condition for SUDEP. METHODS: The present study retrospectively assessed the incidence of SUDEP in a cohort reconstructed from a dedicated database of consecutive patients referred to the Epilepsy and Sleep Centres of the Institute of Neurological Sciences of Bologna from 1980 to 2012 with: (1) a diagnosis of NFLE, (2) at least 90% of seizures during sleep, and (3) at least one-year of follow-up. RESULTS: One hundred and three people were included. The median time from seizure onset to last observation was 26 years, equal to a follow-up of 2789 person-years. One person died of SUDEP during the follow-up period. The incidence rate of SUDEP was 0.36 per 1000 person-years (95% CI 0.01 to 2.0). CONCLUSIONS: The incidence of SUDEP in the participant population was not higher than the rates previously reported in prevalent epilepsy populations (0.4 to 2.3 per 1000 person-years). The low prevalence of SUDEP might reflect the low occurrence of generalised tonic-clonic seizures in people with NFLE.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 114,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "S100A4 interacts with p53 in the nucleus and promotes p53 degradation. S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.",
            "question": "Where in the cell does the proteins S100A4 and p53 interact ?",
            "answers": {
                "answer_start": 33,
                "text": "nucleus"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 544,
                "text": "early"
            }
        },
        {
            "context": "Days weaving the lagging strand synthesis of DNA - A personal recollection of the discovery of Okazaki fragments and studies on discontinuous replication mechanism. At DNA replication forks, the overall growth of the antiparallel two daughter DNA chains appears to occur 5'-to-3' direction in the leading-strand and 3'-to-5' direction in the lagging-strand using enzyme system only able to elongate 5'-to-3' direction, and I describe in this review how we have analyzed and proved the lagging strand multistep synthesis reactions, called Discontinuous Replication Mechanism, which involve short RNA primer synthesis, primer-dependent short DNA chains (Okazaki fragments) synthesis, primer removal from the Okazaki fragments and gap filling between Okazaki fragments by RNase H and DNA polymerase I, and long lagging strand formation by joining between Okazaki fragments with DNA ligase.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 168,
                "text": "DNA replication"
            }
        },
        {
            "context": "Calcium and vitamin D in sarcoidosis: is supplementation safe? Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.",
            "question": "What is the first line treatment for sarcoidosis?",
            "answers": {
                "answer_start": 346,
                "text": "Corticosteroids"
            }
        },
        {
            "context": "The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs that are found in plants and animals (for recent reviews, see ). miRNAs are expressed in a developmentally and tissue-specific manner and regulate the translational efficiency and stability of partial or fully sequence-complementary mRNAs. miRNAs are excised in a stepwise process from double-stranded RNA precursors that are embedded in long RNA polymerase II primary transcripts (pri-miRNA). Drosha RNase III catalyzes the first excision event, the release in the nucleus of a hairpin RNA (pre-miRNA), which is followed by export of the pre-miRNA to the cytoplasm and further processing by Dicer to mature miRNAs. Here, we characterize the human DGCR8, the DiGeorge syndrome critical region gene 8, and its Drosophila melanogaster homolog. We provide biochemical and cell-based readouts to demonstrate the requirement of DGCR8 for the maturation of miRNA primary transcripts. RNAi knockdown experiments of fly and human DGCR8 resulted in accumulation of pri-miRNAs and reduction of pre-miRNAs and mature miRNAs. Our results suggest that DGCR8 and Drosha interact in human cells and reside in a functional pri-miRNA processing complex.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 523,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome. Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 221,
                "text": "FBN1"
            }
        },
        {
            "context": "Barth syndrome. First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 1593,
                "text": "Xq28"
            }
        },
        {
            "context": "Genetics of pituitary adenomas. Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 957,
                "text": "aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability.",
            "question": "Which technique led to the elucidation of the role of HOXD10 in regulating lymphatic endothelial responses to VEGF-C?",
            "answers": {
                "answer_start": 0,
                "text": "DeepCAGE"
            }
        },
        {
            "context": "[STI571 (Glivec)--a new drug for the treatment of chronic myeloid leukemia]. Chronic myeloid leukaemia (CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase. In the chronic phase of the disease, normal peripheral blood values are achieved within the first month of treatment in the large majority of patients and in many patients also a cytogenic response within the following months. The results in the advanced phase are far less favourable, which is explained by the development of resistance owing to reactivation of the BCR-ABL signal transduction. Side effects are primarily nausea, vomiting, various rashes, oedema, most often in the periorbital region, and musculoskeletal symptoms, including muscle cramps. Perspectives for treatment with STI571 are described, as are combinations with alpha-interferon and other cytostatics with a synergistic profile.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 299,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein. A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 435,
                "text": "tyr"
            }
        },
        {
            "context": "MicroRNA genes are transcribed by RNA polymerase II. MicroRNAs (miRNAs) constitute a large family of noncoding RNAs that function as guide molecules in diverse gene silencing pathways. Current efforts are focused on the regulatory function of miRNAs, while little is known about how these unusual genes themselves are regulated. Here we present the first direct evidence that miRNA genes are transcribed by RNA polymerase II (pol II). The primary miRNA transcripts (pri-miRNAs) contain cap structures as well as poly(A) tails, which are the unique properties of class II gene transcripts. The treatment of human cells with alpha-amanitin decreased the level of pri-miRNAs at a concentration that selectively inhibits pol II activity. Furthermore, chromatin immunoprecipitation analyses show that pol II is physically associated with a miRNA promoter. We also describe, for the first time, the detailed structure of a miRNA gene by determining the promoter and the terminator of mir-23a approximately 27a approximately 24-2. These data indicate that pol II is the main, if not the only, RNA polymerase for miRNA gene transcription. Our study offers a basis for understanding the structure and regulation of miRNA genes.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 407,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment. Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 615,
                "text": "CDK4/6"
            }
        },
        {
            "context": "A genetic risk factor for low serum ferritin levels in Danish blood donors. BACKGROUND: Iron deficiency is a frequent side effect of blood donation. In recent years, several studies have described genetic variants associated with iron concentrations. However, the impact of these variants on iron levels is unknown in blood donors. Knowledge of genetic variants that predispose donors to iron deficiency would allow bleeding frequency and iron supplementation to be tailored to the individual donor. STUDY DESIGN AND METHODS: The genotypes of five specific single-nucleotide polymorphisms (SNPs) in three genes that have been previously associated with iron status and/or restless leg syndrome (RLS) were investigated in two groups of female blood donors. The first group had low iron stores (serum ferritin < 12 µg/L, n = 657), and the second group had normal to high iron stores (serum ferritin > 30 µg/L, n = 645). Genotype distribution for each of the SNPs was compared between the two groups. RESULTS: Homozygosity for the T-allele of BTBD9 rs9296249 was associated with lower serum ferritin. The odds ratio for low serum ferritin was 1.35 (95% confidence interval, 1.02-1.77; p = 0.03) when comparing donors with the TT genotype with donors with the CT genotype. CONCLUSION: A frequent polymorphism in BTBD9 was significantly associated with serum ferritin. This polymorphism has previously been associated with RLS, but not low iron stores in blood donors.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1435,
                "text": "iron"
            }
        },
        {
            "context": "Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases. Heme (iron protoporphyrin IX) is an essential molecule for numerous living organisms. Not only does it serve as a prosthetic group in enzymes, it also acts as a signaling molecule that controls diverse molecular and cellular processes ranging from signal transduction to protein complex assembly. Deficient heme synthesis or function impacts the hematopoietic, hepatic and nervous systems in humans. Recent studies have revealed a series of heme-regulated transcription factors and signal transducers including Hap1, a heme-activated transcription factor that mediates the effects of oxygen on gene transcription in the yeast Saccharomyces cerevisiae; Bach1, a transcriptional repressor that is negatively regulated by heme in mammalian cells; IRR, an iron regulatory protein that mediates the iron-dependant regulation of heme synthesis in the bacterium Bradyrhizobium japonicum; and heme-regulated inhibitor, an eucaryotic initiation factor 2alpha kinase that coordinates protein synthesis with heme availability in reticulocytes. In this review, we summarize the current knowledge about how heme controls the activity of these transcriptional regulators and signal transducers, and discuss diseases associated with defective heme synthesis, degradation and function.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 814,
                "text": "repressor"
            }
        },
        {
            "context": "Delamanid for multidrug-resistant pulmonary tuberculosis. BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).",
            "question": "Which disease can be treated with Delamanid?",
            "answers": {
                "answer_start": 309,
                "text": "tuberculosis"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 900,
                "text": "GBshape"
            }
        },
        {
            "context": "Proton pump inhibitors and pain. There may be a relationship between proton pump inhibitors (PPIs) and iron absorption. PPIs may decrease the amount of iron absorbed gastrointestinally specifically due to alteration of the pH in the duodenum. Restless legs syndrome (RLS) is a sensorimotor disorder that includes an urge to move legs, accompanied or caused by uncomfortable and unpleasant sensations in the legs; the urge to move begins or worsens during periods of rest or inactivity, the urge to move is partially or totally relieved by movement, and the urge is worse or only occurs at night. In the majority of the restless leg syndrome population, the sensation is deep seated, often described as being in the shin bones, and most commonly felt between the knee and ankle. It may be described as a creepy, shock-like, tense, electric, buzzing, itchy, or even numb sensation. A subpopulation of this restless leg syndrome patient population experiences restless leg syndrome associated pain (RLSAP) that has been described as a deep \"achy pain.\" This pain has not been found to be relieved by many of the typical over the counter analgesics. Often, constant movement of the legs appears to be the only remedy, as these sensations usually appear during periods of rest. Furthermore, there appears to be an association between iron deficiency and those suffering from Restless Leg Syndrome (RLS). The authors theorize that there may be a possible correlation between PPIs and the symptoms (e.g. pain) associated with RLS. The authors propose that PPIs, such as omeprazole, may interfere with iron absorption in certain patients and that a subpopulation of patients who develop significant iron deficiency characterized by low serum ferritin levels while on PPIs may also develop RLS-like symptoms (including RLSAP). While there is no robust direct evidence to support any associations of PPIs and iron deficiency or PPIs associated with RLS-like symptoms (including RLSAP), it is hoped that this manuscript may spark research efforts on this issue.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1329,
                "text": "iron"
            }
        },
        {
            "context": "Direct interaction between Tks proteins and the N-terminal proline-rich region (PRR) of NoxA1 mediates Nox1-dependent ROS generation. NADPH oxidase (Nox) family enzymes are one of the main sources of cellular reactive oxygen species (ROS), which have been implicated in several physiological and pathophysiological processes. To date seven members of this family have been reported, including Nox1-5 and Duox1 and 2. With the exception of Nox2, the regulation of the Nox enzymes is still poorly understood. Nox1 is highly expressed in the colon, and requires two cytosolic regulators, the organizer subunit NoxO1 and the activator subunit NoxA1, as well as the binding of Rac1 GTPase, for its activity. Recently, we identified the c-Src substrate proteins Tks4 and Tks5 as functional members of a p47(phox)-related organizer superfamily. As a functional consequence of this interaction, Nox1 localizes to invadopodia, actin-rich membrane protrusions of cancer cells which facilitate pericellular proteolysis and invasive behavior. Here, we report that Tks4 and Tks5 directly bind to NoxA1. Moreover, the integrity of the N-terminal PRR of NoxA1 is essential for this direct interaction with the Tks proteins. When the PRR in NoxA1 is disrupted, Tks proteins cannot bind NoxA1 and lose their ability to support Nox1-dependent ROS generation. Consistent with this, Tks4 and Tks5 are unable to act as organizers for Nox2 because of their inability to interact with p67(phox), which lacks the N-terminal PRR, thus conferring a unique specificity to Tks4 and 5. Taken together, these results clarify the molecular basis for the interaction between NoxA1 and the Tks proteins and may provide new insights into the pharmacological design of a more effective anti-metastatic strategy.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 507,
                "text": "Nox1"
            }
        },
        {
            "context": "RET proto-oncogene mutations are restricted to codon 618 in Cypriot families with multiple endocrine neoplasia 2. BACKGROUND: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset ofMEN2. AIM: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. SUBJECTS AND METHODS: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. RESULTS: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. CONCLUSIONS: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1407,
                "text": "RET"
            }
        },
        {
            "context": "Effect of the mutant microphthalmia-associated transcription factor found in Tietz syndrome on the in vitro development of mast cells. Mutations in microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome type 2 (WS2), a dominantly inherited disorder involving hearing loss and pigment disturbances caused by a lack of melanocytes. On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. The MITF gene is the human homolog of the mouse microphthalmia (mi) gene in some families. Mi/mi mice show decreased numbers and an abnormal phenotype of mast cells (MC). In contrast, the number and phenotype of MC in WS2/TS patients who also have an alteration in their MITF gene are unclear. In this study, we identified a mutation in the MITF gene, delR217, which was equivalent to that found in mi/mi mice, in a case of TS. None of the MITF isoforms with the mutation were able to transactivate the tyrosinase gene promoter. In addition, mutant MITF-M showed dominant negative activity toward wild-type MITF-M, inhibiting its transactivation of the tyrosinase gene promoter. The patient's peripheral blood CD34 cells showed no differences with respect to total cell number or their expression levels of tryptase mRNA in a serum-deprived liquid culture system for 6 weeks when compared with normal control cells. These findings suggest that MITF does not play a critical role in MC development in humans.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 390,
                "text": "MITF"
            }
        },
        {
            "context": "Immunolocalization of DNMT1 and DNMT3a in salivary gland neoplasms. OBJECTIVE: Salivary gland neoplasms pathogenesis has not been well established. DNA methylation occurs when methyl groups are added to cytosine nucleotides in specific areas of the gene by the enzyme DNA methyltransferase (DNMT). This chemical modification can alter gene expression without altering DNA sequence. While DNMT3a is mostly involved in de novo methylation, DNMT1 acts as a maintenance methyltransferase. We aimed to investigate the immunoexpression of DNMT3a and DNMT1 in minor salivary gland neoplasms, comparing it with normal tissue. MATERIAL: Forty-four formalin-fixed and paraffin-embedded samples of pleomorphic adenoma, adenoid cystic carcinoma, mucoepidermoid carcinoma and polymorphous low-grade adenocarcinoma were included in the study. The DNMT1 and DNMT3a proteins were identified by using a highly sensitive polymer-based system. RESULTS: Positive nuclear and cytoplasmic labeling for DNMT1 was observed in all samples, including the controls. Positive nuclear labeling for DNMT3a was found only in few neoplasms: 1 pleomorphic adenoma (9.0%), 2 adenoid cystic carcinoma (16.6%) and 1 mucoepidermoid (9.0%) cases. CONCLUSION: Our results were not able to demonstrate a clear correlation between DNMT1 and DNMT3a immunoexpression and salivary gland neoplasms development.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 438,
                "text": "DNMT1"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 894,
                "text": "malaria"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1245,
                "text": "53BP1"
            }
        },
        {
            "context": "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 34,
                "text": "FOXP2"
            }
        },
        {
            "context": "[Tyrosine kinase inhibitors for the treatment of CML]. Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. After transcription and translation the constitutively activated p210 BCR-ABL oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL transformed cells is the result. Expression of the BCR-ABL oncoprotein is sufficient and necessary for the development of a CML phenotype. Imatinib mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and blocks downstream signalling events. Imatinib is very effective in the treatment of CML in all stages of the disease. Patients with newly diagnosed chronic phase CML were randomized to imatinib or to interferon plus cytarabine in the IRIS trial. Imatinib showed significantly superior tolerability, hematologic and cytogenetic resposes and increased time to progression. In patients with advanced phase CML, imatinib is less effective and response duration is short. Median overall survival of blast crisis patients is 6.9 months only. Additional BCR-ABL independent chromosomal abnormalities are common in advanced phase CML and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are frequently found in imatinib resistant patients and confer diminished sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, which are effective against most of the known mutations are currently tested in clinical trials.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 264,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Mutation characterization and genotype-phenotype correlation in Barth syndrome. Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. We have now evaluated 14 Barth syndrome pedigrees for mutations in G4.5 and have identified unique mutations in all, including four splice-site mutations, three deletions, one insertion, five missense mutations, and one nonsense mutation. Nine of the 14 mutations are predicted to significantly disrupt the protein products of G4.5. The occurrence of missense mutations in exons 3 and 8 suggests that these exons encode essential portions of the G4. 5 proteins, whose functions remain unknown. We found no correlation between the location or type of mutation and any of the clinical or laboratory abnormalities of Barth syndrome, which suggests that additional factors modify the expression of the Barth phenotype. The characterization of mutations of the G4.5 gene will be useful for carrier detection, genetic counseling, and the identification of patients with Barth syndrome who do not manifest all of the cardinal features of this disorder.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 224,
                "text": "Xq28"
            }
        },
        {
            "context": "Dapagliflozin: a review of its use in type 2 diabetes mellitus. Dapagliflozin (Forxiga®) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a reduction in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action. A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10 mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated haemoglobin values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycaemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clinical trials, dapagliflozin was associated with reductions in body weight that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to = 2 years. Dapagliflozin was generally well tolerated in clinical trials of 24 or 52 weeks duration and in extension studies of up to = 2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycaemia, especially when used alone or in combination with metformin, although the incidence of hypoglycaemic events reported with dapagliflozin in clinical trials varied depending on the background therapy. Longer-term tolerability/safety data with dapagliflozin are awaited with interest. In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addition to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy.",
            "question": "What is the drug forxiga used for?",
            "answers": {
                "answer_start": 225,
                "text": "treatment of patients with type 2 diabetes."
            }
        },
        {
            "context": "Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease. Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in α-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in α-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified α-synuclein species in vivo. For this purpose, we used two mutated forms of human α-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type α-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the α-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type α-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A α-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D α-synuclein appeared earlier than the other two forms of α-synuclein. Conversely, S129A α-synuclein showed significantly larger pathological α-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of α-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three α-synuclein forms resulted in pathological accumulations of α-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of α-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state.",
            "question": "Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?",
            "answers": {
                "answer_start": 183,
                "text": "serine 129"
            }
        },
        {
            "context": "Ackee (Blighia sapida) hypoglycin A toxicity: dose response assessment in laboratory rats. Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome. Hypoglycin A toxicity in this study was determined by feeding male and female Sprague-Dawley rats a control diet and ackee diets that contained 4-3840 ppm of hypoglycin. The fixed dose method was used to quantify the acute toxic dose of hypoglycin A and was determined by feeding a diet consisting of the lowest hypoglycin A concentration; this was increased to the next highest dose after 24h until toxicity was observed. The maximum tolerated dose (MTD) of hypoglycin A was determined by feeding rats the ackee and control diets over a 30-day period. The acute toxic dose for male and female rats was 231.19+/-62.5 5mg hypoglycinA/kgBW and 215.99+/-63.33 mg hypoglycinA/kgBW, respectively. This was considerably greater than the dose of 100 mg hypoglycin/kgBW reported in a previous study when aqueous hypoglycin was administered orally. The MTD of hypoglycin A in both male and female rats was 1.50+/-0.07 mg hypoglycinA/kgBW/day. These findings suggest that the form in which hypoglycin in ackee is administered could affect the toxicological properties it exhibits. Therefore, for the purpose of a hazard assessment, it may be best administered within the matrix of the fruit, which is the form that humans consume it.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 128,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Allan-Herndon-Dudley syndrome. Allan-Herndon-Dudley Syndrome (AHDS) is a rare X-linked disorder caused by mutation in the gene encoding the monocarboxylate transporter-8. Abnormal transport function is reflected by elevated free T3 and decreased free T4 levels along with clinical features characterized by neurological abnormalities including global developmental delay, central hypotonia, rotatory nystagmus, impaired hearing, spasticity and contractures of joints. We report a child with classical clinical features along with confirmatory deranged thyroid levels in blood.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 552,
                "text": "thyroid"
            }
        },
        {
            "context": "Regulation of heme oxygenase-1 by transcription factor Bach1 in the mouse brain. Oxidative stress has been implicated in tissue damage from traumatic brain injury. Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades prooxidant heme to radical-scavenging biliverdin/bilirubin in order to protect cells from oxidative stress. Although HO-1 is induced after induction of brain damage, the regulatory mechanism of HO-1 in the brain is still unclear. Bach1 is a transcriptional repressor of the HO-1 gene, and plays a critical role in tissue protection from oxidative stress by reperfusion injury of the myocardium. In this study, we examined the role of Bach1 in HO-1 regulation of the various brain sites by investigating the expression of Bach1 and HO-1 in brain tissues of mice bearing Bach1-deficient (Bach1(-/-)) or wild-type (Bach1(+/+)) genes. While the expression levels of Bach1 mRNA in the olfactory bulb were significantly higher than other brain areas, those at the cortex showed the lowest activity. Bach1(-/-) mice showed significantly higher HO-1 mRNA expression levels than Bach1(+/+) mice in all brain sites studied. Moreover, higher induction of HO-1 was observed around damaged tissues after cold injury in Bach1(-/-) than Bach1(+/+) mice. Thus, Bach1 plays an important role in regulating the constitutive and inducible expression levels of HO-1 in the brain. Although a significantly higher level of HO-1 was observed in Bach1(-/-) than Bach1(+/+) mice, genetic ablation of the Bach1 gene failed to show any tissue protective effect after cold injury was inflicted on the cortex.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 482,
                "text": "repressor"
            }
        },
        {
            "context": "Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BACKGROUND: Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM-levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI. METHODS: We used data of 1359 patients with LRTI enrolled in a multicenter study. We chose two ProADM cut-off values by assessing the association between ProADM levels and the risk of adverse events and mortality. A composite score (CURB65-A) was created combining CURB65 classes with ProADM cut-offs to further risk-stratify patients. RESULTS: CURB65 and ProADM predicted both adverse events and mortality similarly well in CAP and non-CAP-LRTI. The combined CURB65-A risk score provided better prediction of death and adverse events than the CURB65 score in the entire cohort and in CAP and non-CAP-LRTI patients. Within each CURB65 class, higher ProADM-levels were associated with an increased risk of adverse events and mortality. Overall, risk of adverse events (3.9%) and mortality (0.65%) was low for patients with CURB65 score 0-1 and ProADM < 0.75 nmol/l (CURB65-A risk class I); intermediate (8.6% and 2.6%, respectively) for patients with CURB65 score of 2 and ProADM < 1.5 nmol/l or CURB classes 0-1 and ProADM levels between 0.75-1.5 nmol/L (CURB65-A risk class II), and high (21.6% and 9.8%, respectively) for all other patients (CURB65-A risk class III). If outpatient treatment was recommended for CURB65-A risk class I and short hospitalization for CURB65-A risk class II, 17.9% and 40.8% of 1217 hospitalized patients could have received ambulatory treatment or a short hospitalization, respectively. CONCLUSIONS: The new CURB65-A risk score combining CURB65 risk classes with ProADM cut-off values accurately predicts adverse events and mortality in patients with CAP and non-CAP-LRTI. Additional prospective cohort or intervention studies need to validate this score and demonstrate its safety and efficacy for the management of patients with LRTI. TRIAL REGISTRATION: Procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections: the prohosp study; isrctn.org Identifier: ISRCTN: ISRCTN95122877.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 446,
                "text": "pneumonia"
            }
        },
        {
            "context": "Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.",
            "question": "With which cancers has the loss of SMARCB1 been associated?",
            "answers": {
                "answer_start": 204,
                "text": "childhood chordomas"
            }
        },
        {
            "context": "Thyroid anomalies in Williams syndrome: investigation of 95 patients. Thyroid involvement in Williams syndrome (WS) was recently reported in two small groups of patients, both showing an increased prevalence of elevation of TSH serum concentration; in one of the two reports, 70% of the patients demonstrated a hypoplasia of thyroid gland as well. In our institution, we currently follow a large population of WS patients who periodically undergo a multispecialist clinical evaluation that includes ultrasound evaluation of the thyroid gland, and levels of FT3, FT4, TSH, and anti-thyroid antibodies. Here, we report on the prevalence of thyroid structural and functional anomalies, in a population of 95 WS patients, half of them followed for more than 5 years. Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample) and thyroid gland hypoplasia (74.7%). Moreover, we demonstrated that TSH elevation declines with age. For this reason, we suggest that a complete thyroid evaluation be performed in every patient with WS, and that this medical complication should be periodically searched for in follow-up visits.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 325,
                "text": "thyroid"
            }
        },
        {
            "context": "Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 924,
                "text": "CD38"
            }
        },
        {
            "context": "[New kinase inhibitors]. Treatment of rheumatoid arthritis (RA) has dramatically changed during the last 15 years. A limited number of conventional disease-modifying antirheumatic drugs (DMARD) in combination with non-steroid anti-inflammatory drugs (NSAID) and corticosteroids are facing a variety of biologics that are increasingly being used. Because of the high costs of biologics as well as the necessity for subcutaneous or intravenous administration, there is currently a growing interest in new and potent oral compounds such as the small molecules. Inflammatory pathways and mechanisms in signal transduction have been characterized in detail. Instead of neutralizing the action of a proinflammatory cytokine by antagonizing its biologic effect by an antibody, these small molecules interfere with the intracellular pathways of the inflammatory cascade. Intracellular kinases are among these enzymes which are crucially involved in intracellular signal transduction. Kinase inhibitors have been successfully used within the last few years in the treatment of various hematological malignancies, such as imatinib in patients with chronic myeloid leukemia. More recently, the Janus kinase (JAK) inhibitor tofacitinib has been evaluated as a potential new treatment option in RA and is awaiting approval. While an overview about JAK inhibition will be given elsewhere, other inhibitors such as spleen tyrosine kinase (Syk) inhibitor, mitogen-activated protein kinase (MAPK) inhibitor and Bruton's tyrosine kinase (Btk) inhibitor are currently in preclinical and clinical development.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 1212,
                "text": "tofacitinib"
            }
        },
        {
            "context": "PU.1 positively regulates GATA-1 expression in mast cells. Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1(-/-) fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages.",
            "question": "Which gene controls the expression of GATA-1 isoforms?",
            "answers": {
                "answer_start": 1112,
                "text": "PU.1"
            }
        },
        {
            "context": "Clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis from a center with a high MRSA prevalence. BACKGROUND: We describe the clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis (CF) from the U.S. CF center with the highest MRSA prevalence. METHODS: Medical records of children with CF were retrospectively reviewed from 1997-2009. MRSA clinical isolates from 2007-2009 were analyzed by polymerase chain reaction and pulsed field gel electrophoresis. RESULTS: The prevalence of MRSA was 1% in 1997 and 49% in 2009. Fifty-five children (26%) had persistent MRSA infection. Sixty-eight percent of MRSA isolates were hospital-associated (HA) MRSA, of which 52% were pulsed-field type USA 100. Ninety-three percent of HA MRSA isolates were clindamycin resistant. Twelve children acquired MRSA before 1 year of age, 83% of whom were hospitalized prior to acquisition of MRSA. Ten of 11 sibling pairs carried indistinguishable MRSA strains. Children with persistent MRSA were hospitalized more often (P = .01), required inhaled medications more frequently (P = .01), and had higher rates of Pseudomonas aeruginosa coinfection (P < .001). CONCLUSION: MRSA prevalence in children with CF is increasing, and most children are infected with HA MRSA. Exposure to health care facilities and gastrointestinal surgeries may facilitate early acquisition of MRSA. Siblings carry indistinguishable MRSA strains, indicating household transmission of MRSA. Children with persistent MRSA had worse pulmonary morbidity. Coinfection with MRSA and P aeruginosa is likely associated with further increased pulmonary morbidity.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 90,
                "text": "MRSA"
            }
        },
        {
            "context": "Extension of the clinical range of facioscapulohumeral dystrophy: report of six cases. Consensual diagnostic criteria for facioscapulohumeral dystrophy (FSHD) include onset of the disease in facial or shoulder girdle muscles, facial weakness in more than 50% of affected family members, autosomal dominant inheritance in familial cases, and evidence of myopathic disease in at least one affected member without biopsy features specific to alternative diagnoses. Six patients did not meet most of these criteria but were diagnosed as FSHD by DNA testing, which showed small EcoRI fragments on chromosome 4q. Their clinical signs and symptoms and results of auxiliary investigations are reported. The patients presented with foot extensor, thigh, or calf muscle weakness. None of them had apparent facial weakness, only one complained of weakness in the shoulders, none had a positive family history. Expert physical examination, however, showed a typical facial expression, an abnormal shoulder configuration on lifting the arms, or scapular winging. This raised the suspicion of FSHD, whereupon DNA analysis was done. In conclusion, the clinical expression of FSHD is much broader than indicated by the nomenclature. The possibility to perform DNA tests is likely to greatly expand the clinical range of FSHD.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 287,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. BACKGROUND: Endovascular or intra-arterial treatment (IAT) increases the likelihood of recanalization in patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion. However, a beneficial effect of IAT on functional recovery in patients with acute ischemic stroke remains unproven. The aim of this study is to assess the effect of IAT on functional outcome in patients with acute ischemic stroke. Additionally, we aim to assess the safety of IAT, and the effect on recanalization of different mechanical treatment modalities. METHODS/DESIGN: A multicenter randomized clinical trial with blinded outcome assessment. The active comparison is IAT versus no IAT. IAT may consist of intra-arterial thrombolysis with alteplase or urokinase, mechanical treatment or both. Mechanical treatment refers to retraction, aspiration, sonolysis, or use of a retrievable stent (stent-retriever). Patients with a relevant intracranial proximal arterial occlusion of the anterior circulation, who can be treated within 6 hours after stroke onset, are eligible. Treatment effect will be estimated with ordinal logistic regression (shift analysis); 500 patients will be included in the trial for a power of 80% to detect a shift leading to a decrease in dependency in 10% of treated patients. The primary outcome is the score on the modified Rankin scale at 90 days. Secondary outcomes are the National Institutes of Health stroke scale score at 24 hours, vessel patency at 24 hours, infarct size on day 5, and the occurrence of major bleeding during the first 5 days. DISCUSSION: If IAT leads to a 10% absolute reduction in poor outcome after stroke, careful implementation of the intervention could save approximately 1% of all new stroke cases from death or disability annually. TRIAL REGISTRATION: NTR1804 (7 May 2009)/ISRCTN10888758 (24 July 2012).",
            "question": "Treatment of which disease was investigated in the MR CLEAN study?",
            "answers": {
                "answer_start": 80,
                "text": "acute ischemic stroke"
            }
        },
        {
            "context": "ZFHX1B mutations in patients with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). It is caused by de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22. ZFHX1B encodes Smad-interacting protein-1 (SMADIP1 or SIP1), a transcriptional corepressor involved in the transforming growth factor-beta signaling pathway. It is a highly evolutionarily conserved gene, widely expressed in embryological development. Over 100 mutations have been described in patients with clinically typical MWS, who almost always have whole gene deletions or truncating mutations (nonsense or frameshift) of ZFHX1B, suggesting that haploinsufficiency is the basis of MWS pathology. No obvious genotype-phenotype correlation could be identified so far, but atypical phenotypes have been reported with missense or splice mutations in the ZFHX1B gene. In this work we describe 40 novel mutations and we summarize the various mutational reports published since the identification of the causative gene.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 0,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Sinonasal teratocarcinosarcoma with rhabdoid features. Sinonasal teratocarcinosarcoma (SNTCS) is a very rare tumor developed in the nasal cavity and paranasal sinuses. The rhabdoid phenotype represents an aggressive biological behavior, but the rhabdoid feature has hitherto not been reported in cases of SNTCS. A 46-year-old man complained of a 1-month history of left-sided nasal obstruction. Computed tomography scan and magnetic resonance imaging showed a tumor mass involving the left nasal cavity, ethmoid sinus, and ethmoid bone with extension to the left frontal lobe of the brain. A gross total resection of the mass was performed and postoperative radiation therapy administered. Seven weeks later, several recurring masses were detected in the left frontotemporal lobe of the brain. A gross total resection of the mass was performed and postoperative chemotherapy administered. Histopathologically, the tumor showed benign and malignant epithelial, mesenchymal, neural, and immature elements. In addition, diffuse sheets of rhabdoid cells were immunopositive for vimentin, nestin, neuron-specific enolase, and INI1. Ultrastructurally, rhabdoid cells showed paranuclear aggregates and whorls of intermediate filaments with a 9-10 nm diameter. In conclusion, we report first case of rhabdoid features in SNTCS. The present case showed an advanced stage and early recurrence; the rhabdoid component was probably responsible for this aggressive behavior.",
            "question": "What is the average diameter of intermediate filaments?",
            "answers": {
                "answer_start": 1237,
                "text": "10 nm"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1403,
                "text": "xa"
            }
        },
        {
            "context": "PTEN: a new guardian of the genome. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT signaling pathway and suppresses cell survival as well as cell proliferation. PTEN is the second most frequently mutated gene in human cancer after p53. Germline mutations of PTEN have been found in cancer susceptibility syndromes, such as Cowden syndrome, in which over 80% of patients have mutations of PTEN. Homozygous deletion of Pten causes embryonic lethality, suggesting that PTEN is essential for embryonic development. Mice heterozygous for Pten develop spontaneous tumors in a variety of organs comparable with the spectrum of its mutations in human cancer. The mechanisms of PTEN functions in tumor suppression are currently under intense investigation. Recent studies demonstrate that PTEN plays an essential role in the maintenance of chromosomal stability and that loss of PTEN leads to massive alterations of chromosomes. The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death. Through completely different mechanisms, PTEN also protects the genome from instability. Thus, we propose that PTEN is a new guardian of the genome. In this review, we will discuss new discoveries on the role of PTEN in tumor suppression and explore mechanisms by which PTEN maintains genomic stability.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 1045,
                "text": "p53"
            }
        },
        {
            "context": "Genetic and family study of the Apert syndrome. Of 119 patients with the Apert syndrome, 94 pedigrees are available for study. Selected family histories and recorded events during pregnancy are also reported. The sex ratio is 1:1 (60 males, 59 females). All 94 pedigrees except one (an affected father and daughter) represent sporadic instances. Combining our cases with those available in the literature, only nine familial instances are known to date. The familial cases, the equal number of affected males and females, and the increased paternal age in sporadic cases strongly suggest autosomal dominant inheritance. The rarity of familial instances can be explained by reduced genetic fitness of affected individuals because severe malformations and the presence of mental deficiency, found in many cases, diminish desirability as mates. The variability of the syndrome has been defined mainly on the basis of sporadic cases. High resolution banding was normal in five recently studied cases.",
            "question": "What is the inheritance pattern of Apert syndrome?",
            "answers": {
                "answer_start": 588,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 919,
                "text": "GBshape"
            }
        },
        {
            "context": "New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome. The authors report a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, \"coarse\" face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high (>50 microU/ml; normal value 0.2-4 microU/ml), while serum free T(3) (FT3) and free T(4) (FT4) levels were normal (FT3 3.6 pg/ml, normal value 2.8-5.6 pg/ml; FT4 11.6 pg/ml, normal value 6.6-14 pg/ml); antithyroid autoantibodies were absent. Thyroid scintigraphy with sodium 99m Tc pertechnetate showed a small ectopic thyroid located in sublingual position, so treatment with L-thyroxine 37.5 microg/24 hr was started with rapid improvement of the clinical picture. At 17 months of age the patient developed the complete characteristic phenotype of Williams syndrome (WS); the clinical diagnosis was proven by fluorescent in situ hybridization (FISH) analysis which showed hemizygous deletion of the elastin gene on chromosome 7. Recently a case of thyroid hemiagenesis in a child with WS has been reported; our patient underscores the association of hypothyroidism and WS. Moreover, our case shows that clinical manifestations of hypothyroidism may be present and the treatment may be necessary as it is in isolated congenital hypothyroidism.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 751,
                "text": "thyroid"
            }
        },
        {
            "context": "Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.",
            "question": "What is the mode of inheritance of  long QT  Jervell and Lange-Nielsen syndrome?",
            "answers": {
                "answer_start": 129,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "The cyclic pattern of blood alcohol levels during continuous ethanol feeding in rats: the effect of feeding S-adenosylmethionine. S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver. The following parameters were studied to determine the effects of SAMe; liver histology, the blood alcohol cycle (BAL), changes in gene expression mined from microarray analysis, changes in histone methylation, changes in liver SAMe levels and its metabolites and ADH. SAMe changed the type of fatty liver, reduced liver ALT levels and prevented the BAL cycle caused by intragastric ethanol feeding. Microarray analysis showed that SAMe feeding prevented most of the changes in gene expression induced by ethanol feeding, presumably by inducing H3K27me3 and gene silencing. H3K27me3 was significantly increased by SAMe with or without ethanol feeding. It is concluded that SAMe feeding stabilized global gene expression so that the changes in gene expression involved in the blood alcohol cycle were prevented.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 152,
                "text": "SAM"
            }
        },
        {
            "context": "Angeborene hämophagozytische Lymphohistiozytose (HLH). Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal immune disorder characterized by uncontrolled lymphocyte- and macrophage-activation. The resulting hypercytokinemia and cell infiltration of organs lead to the clinical and laboratory features of HLH. Viral infections and other triggers can induce both, inherited and acquired forms of HLH. Disease-causing mutations in the genes encoding perforin (PRF1, FHL2), munc13-4 (UNC13D, FHL3), syntaxin 11 (STX11, FHL4), and munc18-2 (UNC18-2/STXBP2, FHL5) have been previously identified in Familial Hemophagocyic Lymphohistiocytosis (FHL), whereas mutation in RAB27A and LYST account for Griscelli syndome type 2 and Chediak-Higashi syndrome, respectively. These genes all encode proteins which are involved in the cytotoxic activity of lymphocytes. The inability of activated cytotoxic cells to clear antigen-presenting targets results in sustained immune stimulation, likely accounting for the unremitting polyclonal CD8 T-cell activation and hyperimmune reaction which characterizes FHL. Treatment of HLH consists of elimination of the trigger and immunosuppressive treatment in order to induce remission from the uncontrolled inflammation. Allogeneic hematopoietic stem cell transplantation can be indicated in the inherited forms of HLH.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 731,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Trends in novel treatments for hemophilia. The principle of hemophilia treatment is replacement therapy with factor VIII and factor IX concentrates. Recently, extended half-life factor VIII and factor IX concentrates have been developed. With these concentrates, improvements in patient QOL can be expected. More recently, a novel hemophilia therapy based on a very new concept was developed. ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function. The half-life is reportedly 4-5 weeks and remarkably decreased annual bleeding rates have been achieved with subcutaneous weekly injections in the phase 1 clinical trial. Clinical trials of anti-antithrombin therapeutics based on siRNA (ALN-AT3) and anti-TFPI antibody are currently ongoing and the results are eagerly anticipated.",
            "question": "What is emicizumab?",
            "answers": {
                "answer_start": 393,
                "text": "ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function."
            }
        },
        {
            "context": "MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 765,
                "text": "MC1R"
            }
        },
        {
            "context": "Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 101,
                "text": "Thyroid transcription factor 1"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 652,
                "text": "7"
            }
        },
        {
            "context": "Lack of immune responses to Mycobacterium tuberculosis DosR regulon proteins following Mycobacterium bovis BCG vaccination. Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.",
            "question": "How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?",
            "answers": {
                "answer_start": 819,
                "text": "48 genes"
            }
        },
        {
            "context": "Nasal MRSA screening for surgical patients: predictive value for postoperative infections caused by MRSA. PURPOSE: Postoperative methicillin-resistant Staphylococcus aureus (MRSA) infections are occasionally fatal. We hypothesized that nasal MRSA screening might predict the risk of postoperative MRSA infections. The aim of the current study was to elucidate the relationship between the positivity of nasal MRSA screening and postoperative MRSA infections. METHODS: Six hundred and fourteen surgical patients who were admitted to the intensive care unit and underwent nasal MRSA screening between April 2006 and March 2011 were divided into MRSA-positive and -negative groups. The incidence of postoperative MRSA infections in the MRSA-positive and MRSA-negative groups were compared, and various risk factors for MRSA infections were evaluated. RESULTS: The incidence of postoperative MRSA infections, such as pneumonia and enteritis, in the MRSA-positive group was significantly higher than that in the MRSA-negative group (41.9 vs. 3.1 %). The significant independent risk factors for postoperative MRSA infections were a positive MRSA screening, an operation lasting more than 300 min and an emergency operation. A positive MRSA screening was the most statistically significant risk factor for postoperative MRSA pneumonia and enteritis, but was not a risk factor for MRSA surgical site infections. CONCLUSION: Nasal MRSA screening can help to identify patients who have an increased risk of developing postoperative MRSA infections, and would enable physicians to take a prompt action if these complications occur.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 174,
                "text": "MRSA"
            }
        },
        {
            "context": "Posterior cruciate ligament injuries of the knee joint. Posterior cruciate ligament (PCL) injuries have a reported incidence of between 3 and 37%, depending on the clinical setting. The most common mechanism of injury in motor vehicle accidents is a dashboard injury or direct force to the proximal anterior tibia. Sports related injuries result from hyperflexion of the knee with the foot typically plantarflexed. The latter mechanism is the most common cause of isolated PCL injuries, while in the trauma population as many as 95% of patients with knee injuries have combined ligamentous damage. Improved knowledge at an anatomical, biomechanical and clinical level has provided the orthopaedist with a more defined treatment algorithm. Isolated, partial PCL injuries (grades I and II) can best be treated nonoperatively while complete injuries (grade III) may require operative treatment based on clinical symptoms. All combined ligamentous injuries usually respond best with surgical management.",
            "question": "Which ligament is most commonly injured in dashboard injury?",
            "answers": {
                "answer_start": 56,
                "text": "Posterior cruciate ligament"
            }
        },
        {
            "context": "Sushi.R: flexible, quantitative and integrative genomic visualizations for publication-quality multi-panel figures. Interpretation and communication of genomic data require flexible and quantitative tools to analyze and visualize diverse data types, and yet, a comprehensive tool to display all common genomic data types in publication quality figures does not exist to date. To address this shortcoming, we present Sushi.R, an R/Bioconductor package that allows flexible integration of genomic visualizations into highly customizable, publication-ready, multi-panel figures from common genomic data formats including Browser Extensible Data (BED), bedGraph and Browser Extensible Data Paired-End (BEDPE). Sushi.R is open source and made publicly available through GitHub (https://github.com/dphansti/Sushi) and Bioconductor (http://bioconductor.org/packages/release/bioc/html/Sushi.html).",
            "question": "Which R/bioconductor package is used for integrative genomics visualizations?",
            "answers": {
                "answer_start": 706,
                "text": "Sushi.R"
            }
        },
        {
            "context": "Origin of human chromosome 2: an ancestral telomere-telomere fusion. We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 853,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR. Imatinib mesylate (Glivec) is a selective inhibitor of bcr-abl tyrosine kinase, the product of the Philadelphia chromosome, which is the hallmark of chronic myeloid leukaemia (CML). With imatinib, complete cytogenetic response (CCR) can be achieved in over 70% of newly diagnosed patients with CML. However, the optimal long-term management of patients who achieve CCR after imatinib is unknown. With longer follow-up, it is anticipated that some patients are likely to progress and become candidates for autologous transplantation. We studied filgrastim (r-metHuG-CSF) mobilisation of peripheral blood stem cells (PBSC) in 32 patients who have achieved CCR with imatinib. Our data demonstrate that (1) the target CD34(+) cell yields of >/=2.0 x 10(6)/kg were attained with filgrastim 10 microg/kg/day, in 9/18 (50%) of patients during uninterrupted imatinib therapy, and in 10/14 (70%) when imatinib was temporarily withheld. The median CD34(+) cell yield per aphaeresis was 0.70 x 10(6)/kg (range 0.14-2.18) and 2.90 x 10(6)/kg (range 0.15-8.71) in the two groups, respectively (P&<0.005). (2) The cell yields did not correlate with the duration of imatinib administration. (3) There was no impact of the mobilisation procedure on the level of leukaemia as measured by serial blood bcr-abl levels using real-time quantitative PCR with either protocol. (4) bcr-abl remained detectable at low levels in the harvests in most but not all patients. In conclusion, filgrastim can safely be used to mobilise PBSC in patients who have achieved CCR with imatinib, but CD34(+) cell yields are significantly improved when imatinib is temporarily withheld.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 297,
                "text": "bcr-abl"
            }
        },
        {
            "context": "Characterization and functional expression of cDNAs encoding methionine-sensitive and -insensitive homocysteine S-methyltransferases from Arabidopsis. Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy). These reactions comprise the SMM cycle. Two Arabidopsis cDNAs specifying enzymes that mediate the SMM --> Met reaction (SMM:Hcy S-methyltransferase, HMT) were identified by homology and authenticated by complementing an Escherichia coli yagD mutant and by detecting HMT activity in complemented cells. Gel blot analyses indicate that these enzymes, AtHMT-1 and -2, are encoded by single copy genes. The deduced polypeptides are similar in size (36 kDa), share a zinc-binding motif, lack obvious targeting sequences, and are 55% identical to each other. The recombinant enzymes exist as monomers. AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM. Both enzymes also use either methyl donor in vivo because both restore the ability to utilize AdoMet or SMM to a yeast HMT mutant. However, AtHMT-1 is strongly inhibited by Met, whereas AtHMT-2 is not, a difference that could be crucial to the control of flux through the HMT reaction and the SMM cycle. Plant HMT is known to transfer the pro-R methyl group of SMM. This enabled us to use recombinant AtHMT-1 to establish that the other enzyme of the SMM cycle, AdoMet:Met S-methyltransferase, introduces the pro-S methyl group. These opposing stereoselectivities suggest a way to measure in vivo flux through the SMM cycle.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 199,
                "text": "S-adenosylmethionine"
            }
        },
        {
            "context": "Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations. BACKGROUND: Cystic fibrosis (CF) is the most common inherited disorder in Caucasian populations, with over 1400 mutations identified in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Mutations in the CFTR gene may be also causative for CBAVD (Congenital Bilateral Absence of the Vas Deferens). The type and distribution of mutations varies widely between different countries and/or ethnic groups, and is relatively unknown in Iran. We therefore performed a comprehensive analysis of the CFTR gene in Iranian CF patients. METHODS: 69 Iranian CF patients, and 1 CBAVD patient, were analysed for mutations in the complete coding region, and its exon/intron junctions, of their CFTR genes, using different methods, such as ARMS (amplification refractory mutation system)-PCR, SSCP (single stranded conformation polymorphism) analysis, restriction enzyme digestion analysis, direct sequencing, and MLPA (Multiplex Ligation-mediated Probe Amplification). RESULTS: CFTR mutation analysis revealed the identification of 37 mutations in 69 Iranian CF patients. Overall, 81.9% (113/138) CFTR genes derived from Iranian CF patients could be characterized for a disease-causing mutation. The CBAVD patient was found to be homozygous for the p.W1145R mutation. The most common mutations were p.F508del (DeltaF508) (18.1%), c.2183_2184delAAinsG (2183AA>G) (6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5G>A (4.3%), p.G542X (3.6%), c.3120+1G>A (3.6%), p.R334W (2.9%) and c.3130delA (2.9%). These 9 types of mutant CFTR genes totaled for 52% of all CFTR genes derived from the 69 Iranian CF patients. Eight mutations, c.406-8T>C, p.A566D, c.2576delA, c.2752-1_2756delGGTGGCinsTTG, p.T1036I, p.W1145R, c.3850-24G>A, c.1342-?_1524+?del, were found for the first time in this study. CONCLUSIONS: We identified 37 CFTR mutations in 69 well characterized Iranian CF patients, obtaining a CFTR mutation detection rate of 81.9%, the highest detection rate obtained in the Iranian population so far. These findings will assist in genetic counseling, prenatal diagnosis and future screening of CF in Iran.",
            "question": "Which is the most common CFTR mutation in Caucasians?",
            "answers": {
                "answer_start": 1416,
                "text": "DeltaF508"
            }
        },
        {
            "context": "Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011. Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD--consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease--is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular\ndystrophy (FSHD)?",
            "answers": {
                "answer_start": 180,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 312,
                "text": "orally"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 85,
                "text": "xa"
            }
        },
        {
            "context": "Mutation analysis of an Ashkenazi Jewish family with Gaucher disease in three successive generations. Seven members of an Ashkenazi Jewish family with Gaucher disease in 3 successive generations were tested for the presence of the 2 common mutations known to occur in the glucocerebrosidase gene. Genomic DNA from blood or skin fibroblasts of relatives was amplified by using the PCR technique and individual mutations identified by oligonucleotides specific to the mutated sequences. Four individuals were homozygous for a mutation at amino acid 370 (370 mutation) known to occur only in type 1 disease. The other 3 affected relatives were compound heterozygotes for this mutation and for a mutation at amino acid 444 (NciI mutation) which, in the homozygous state, is associated with neurological disease. Clinical severity was more marked in the compound heterozygotes than in the homozygotes. Since the mutation is present in Ashkenazim, molecular diagnosis in families which carry the NciI mutation should prove useful in assessing their risk of the neurologic forms of Gaucher disease.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 272,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 924,
                "text": "IL-1β"
            }
        },
        {
            "context": "Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Dementia with Lewy bodies (DLB) is characterized by the widespread presence of Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is expressed as two main isoforms (112 and 140), but little is known about their differential expression in the brain. We compared alpha-synuclein 112 and alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB patients, eight Alzheimer disease (AD) patients, and six control subjects. Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were determined by real-time polymerase chain reaction with competimer technology using a LightCycler System. Whereas total alpha-synuclein levels were just marginally elevated in DLB in comparison with the other groups, alpha-synuclein 112 was seen to be markedly increased in DLB compared with AD cases and controls. In contrast, alpha-synuclein 140 levels were significantly diminished in both neurodegenerative disorders in comparison with controls. These results show differential overexpression of alpha-synuclein 112 in DLB, a finding that could be of importance in DLB pathogenesis.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 193,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 178,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 273,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Impact of training for healthcare professionals on how to manage an opioid overdose with naloxone: effective, but dissemination is challenging. BACKGROUND: Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). Training in these skills has been successfully trialled internationally with opioid users themselves. Healthcare professionals working in substance misuse are in a prime position to deliver overdose prevention training to drug users and may themselves witness opioid overdoses. The best method of training dissemination has not been identified. The study assessed post-training change in clinician knowledge for managing an opioid overdose and administering naloxone, evaluated the 'cascade method' for disseminating training, and identified barriers to implementation. METHODS: A repeated-measures design evaluated knowledge pre-and-post training. A sub-set of clinicians were interviewed to identify barriers to implementation. Clinicians from addiction services across England received training. Participants self-completed a structured questionnaire recording overdose knowledge, confidence and barriers to implementation. RESULTS: One hundred clinicians were trained initially, who trained a further 119 clinicians (n=219) and thereafter trained 239 drug users. The mean composite score for opioid overdose risk signs and actions to be taken was 18.3/26 (±3.8) which increased to 21.2/26 (±4.1) after training, demonstrating a significant improvement in knowledge (Z=9.2, p<0.001). The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation. CONCLUSIONS: Training clinicians how to manage an opioid overdose and administer naloxone was effective. However the 'cascade method' was only modestly successful for disseminating training to a large clinician workforce, with a range of clinician and service perceived obstacles. Drug policy changes and improvements to educational programmes for drug services would be important to ensure successful implementation of overdose training internationally.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 1800,
                "text": "naloxone"
            }
        },
        {
            "context": "Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 835,
                "text": "FBN1"
            }
        },
        {
            "context": "Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay. BACKGROUND: Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index. METHODS: We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsy-proven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14). RESULTS: Of thirty deregulated proteins between SLE and the healthy controls (P  < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (P  < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (P  < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (P  < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease. CONCLUSIONS: This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.",
            "question": "Which method is Proseek based on?",
            "answers": {
                "answer_start": 597,
                "text": "PEA"
            }
        },
        {
            "context": "Species-specific differences in X chromosome inactivation in mammals. In female mammals, the dosage difference in X-linked genes between XX females and XY males is compensated for by inactivating one of the two X chromosomes during early development. Since the discovery of the X inactive-specific transcript (XIST) gene in humans and its subsequent isolation of the mouse homolog, Xist, in the early 1990s, the molecular basis of X chromosome inactivation (X-inactivation) has been more fully elucidated using genetically manipulated mouse embryos and embryonic stem cells. Studies on X-inactivation in other mammals, although limited when compared with those in the mice, have revealed that, while their inactive X chromosome shares many features with those in the mice, there are marked differences in not only some epigenetic modifications of the inactive X chromosome but also when and how X-inactivation is initiated during early embryonic development. Such differences raise the issue about what extent of the molecular basis of X-inactivation in the mice is commonly shared among others. Recognizing similarities and differences in X-inactivation among mammals may provide further insight into our understanding of not only the evolutionary but also the molecular aspects for the mechanism of X-inactivation. Here, we reviewed species-specific differences in X-inactivation and discussed what these differences may reveal.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 310,
                "text": "XIST"
            }
        },
        {
            "context": "[The malaria vaccine candidate RTS,S/AS is in phase III clinical trials]. This review paper describes the development of the RTS,S/AS vaccine, from concept to phase III testing. The rationale for selection of the circumsporozoite protein (CSP) as the target antigen and the preclinical development history of the vaccine are described. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and was shown to have a favorable safety profile and to be well tolerated in both adults and children. Consistent and significant efficacy has been observed in the target population of infants and children against Plasmodium falciparum infection and disease in different transmission settings, in different age groups, with or without Expanded Program of Immunization (EPI) vaccine co-administration. The RTS,S/AS01(E) malaria vaccine candidate has recently entered phase III testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline, their partners and collaborators. If the phase III results confirm the observations made during phase II testing, the RTS,S/AS01(E) vaccine, when broadly implemented and judiciously integrated with other malaria-prevention measures, would have a major public-health impact in sub-Saharan Africa.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 836,
                "text": "malaria"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 868,
                "text": "Xa"
            }
        },
        {
            "context": "Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors. In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 220,
                "text": "EGFR"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 307,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation. Cardiolipin is a mitochondrion-specific phospholipid that stabilizes the assembly of respiratory chain complexes, favoring full-yield operation. It also mediates key steps in apoptosis. In Barth syndrome, an X chromosome-linked cardiomyopathy caused by tafazzin mutations, cardiolipins display acyl chain modifications and are present at abnormally low concentrations, whereas monolysocardiolipin accumulates. Using immortalized lymphoblasts from Barth syndrome patients, we showed that the production of abnormal cardiolipin led to mitochondrial alterations. Indeed, the lack of normal cardiolipin led to changes in electron transport chain stability, resulting in cellular defects. We found a destabilization of the supercomplex (respirasome) I+III2+IVn but also decreased amounts of individual complexes I and IV and supercomplexes I+III and III+IV. No changes were observed in the amounts of individual complex III and complex II. We also found decreased levels of complex V. This complex is not part of the supercomplex suggesting that cardiolipin is required not only for the association/stabilization of the complexes into supercomplexes but also for the modulation of the amount of individual respiratory chain complexes. However, these alterations were compensated by an increase in mitochondrial mass, as demonstrated by electron microscopy and measurements of citrate synthase activity. We suggest that this compensatory increase in mitochondrial content prevents a decrease in mitochondrial respiration and ATP synthesis in the cells. We also show, by extensive flow cytometry analysis, that the type II apoptosis pathway was blocked at the mitochondrial level and that the mitochondria of patients with Barth syndrome cannot bind active caspase-8. Signal transduction is thus blocked before any mitochondrial event can occur. Remarkably, basal levels of superoxide anion production were slightly higher in patients' cells than in control cells as previously evidenced via an increased protein carbonylation in the taz1Δ mutant in the yeast. This may be deleterious to cells in the long term. The consequences of mitochondrial dysfunction and alterations to apoptosis signal transduction are considered in light of the potential for the development of future treatments.",
            "question": "Which gene is involved in the development of Barth syndrome?",
            "answers": {
                "answer_start": 143,
                "text": "tafazzin (TAZ) gene"
            }
        },
        {
            "context": "Histone variant H2A.Z functions in sister chromatid cohesion in Saccharomyces cerevisiae. H2A.Z is a highly conserved variant of histone H2A with well-characterized roles in transcriptional regulation. We previously reported that H2A.Z and Mcd1, a subunit of the cohesin complex, regulate the establishment of transcriptional silencing at telomeres in Saccharomyces cerevisiae and that H2A.Z broadly dissociated from chromatin during the anaphase-to-telophase transition, coincident with the dissociation of Mcd1 from chromosomes and dissolution of cohesion. In this study, we show that depletion of H2A.Z causes precocious loss of sister chromatid cohesion in yeast without loss of Mcd1 from chromosomes. H2A.Z is deposited into chromatin by the SWR1 complex and is subject to acetylation of its four N-terminal tail lysine residues by the NuA4 and SAGA histone acetyltransferase complexes. We found that cells compromised for function of the SWR1 complex were defective in cohesion, as were cells expressing a form of H2A.Z not subject to acetylation. Finally, inactivation of H2A.Z in metaphase-blocked cells led immediately to cohesion defects, suggesting a direct role for H2A.Z in the maintenance of sister chromatid cohesion.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 747,
                "text": "SWR1"
            }
        },
        {
            "context": "[Restless leg syndrome. Diagnosis and treatment]. INTRODUCTION: The restless legs syndrome is characterized by an unpleasant sensation in the legs which causes an imperative need to move the legs and is therefore considered to be a disorder of movement. When it appears before going to sleep, it may interfere with falling asleep and lead to a sleep-deficit. DEVELOPMENT AND CONCLUSIONS: It is a clinical condition with a satisfactory treatment, and improvement of the associated sleep disorder. The etiology is unknown, sometimes it is familial. The syndrome is increasingly often diagnosed, particularly in association with iron deficiency, during pregnancy, in chronic renal failure and in patients with peripheral neuropathy. Polysomnography is not necessary, unless one suspects an associated disorder of periodic leg movements. Treatment is by dopaminergic, opiate, benzodiazepine, anticonvulsant drugs or clonidine.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 626,
                "text": "iron"
            }
        },
        {
            "context": "Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 403,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Perforating necrobiosis lipoidica in a girl with type 1 diabetes mellitus: a new case reported. Necrobiosis lipoidica is an idiopathic dermatological condition that is strongly associated with diabetes mellitus. It is more commonly seen in women than men. The average age of onset is 30-40 years. Necrobiosis Lipoidica diabeticorum is an extremely rare finding in childhood diabetes. We describe the case of a 13-year-old girl who has had type 1 diabetes mellitus since she was 8 years old. The patient presented with 2 well-defined, persistent plaques with a depressed central area and elevated purple peripheral ring, one on the right thigh and the other over the lateral left leg. Histopathologic evaluation of the patient's biopsy confirmed the diagnosis of necrobiosis lipoidica with transfollicular elimination. Our patient is the second pediatric case described with perforating necrobiosis lipoidica. We review the literature and discuss clinical features, several complications, and the most recent treatment options for necrobiosis lipoidica in diabetic children.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 193,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment. OBJECTIVE: The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T(3)) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan-Herndon-Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T(3) levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT(4)) or liothyronine (LT(3)) treatment intending to overcome the T(3) uptake resistance through alternative transporters. METHODS: The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT(4) treatment and two periods (3 months each) of low- and high-dose LT(3) were evaluated. RESULTS: A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T(3) at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient. CONCLUSION: We identified a 70 kb deletion encompassing exons 2-6 of the MCT8 gene in our AHDS patient. Both LT(4) and LT(3) administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 414,
                "text": "thyroid"
            }
        },
        {
            "context": "Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1. Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 320,
                "text": "repressor"
            }
        },
        {
            "context": "Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes. DNA replication is a primary mechanism for maintaining genome integrity, but it serves this purpose best by cooperating with other proteins involved in DNA repair and recombination. Unlike leading strand synthesis, lagging strand synthesis has a greater risk of faulty replication for several reasons: First, a significant part of DNA is synthesized by polymerase alpha, which lacks a proofreading function. Second, a great number of Okazaki fragments are synthesized, processed and ligated per cell division. Third, the principal mechanism of Okazaki fragment processing is via generation of flaps, which have the potential to form a variety of structures in their sequence context. Finally, many proteins for the lagging strand interact with factors involved in repair and recombination. Thus, lagging strand DNA synthesis could be the best example of a converging place of both replication and repair proteins. To achieve the risky task with extraordinary fidelity, Okazaki fragment processing may depend on multiple layers of redundant, but connected pathways. An essential Dna2 endonuclease/helicase plays a pivotal role in processing common structural intermediates that occur during diverse DNA metabolisms (e.g. lagging strand synthesis and telomere maintenance). Many roles of Dna2 suggest that the preemptive removal of long or structured flaps ultimately contributes to genome maintenance in eukaryotes. In this review, we describe the function of Dna2 in Okazaki fragment processing, and discuss its role in the maintenance of genome integrity with an emphasis on its functional interactions with other factors required for genome maintenance.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 84,
                "text": "DNA replication"
            }
        },
        {
            "context": "Phenotypic and molecular analyses of X-linked dystonia-parkinsonism (\"lubag\") in women. BACKGROUND: X-linked dystonia-parkinsonism (XDP) or \"lubag\" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 100,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 551,
                "text": "chromDraw"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1773,
                "text": "xa"
            }
        },
        {
            "context": "Turner syndrome and associated problems in Turkish children: a multicenter study. OBJECTIVE: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. METHODS: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. RESULTS: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. CONCLUSION: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 170,
                "text": "X"
            }
        },
        {
            "context": "Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models. BACKGROUND: Targeting heat shock protein 90 (HSP90) has gained great interest for cancer therapy. However, in view of novel multimodality therapy approaches for treating hepatic metastases, concerns have raised regarding the impact of targeted therapies on liver regeneration and repair. In this study, we investigated the impact of HSP90 inhibition on liver regeneration in murine models. METHODS: Effects of HSP90 inhibition on the activation of signaling intermediates, expression of vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) were investigated in primary human hepatocytes (PHHs) in vitro. Effects of HSP90 inhibition on liver regeneration and repair were determined in a murine hepatectomy model and in a model with acute carbon tetrachloride (CCl(4))-induced liver damage. RESULTS: Inhibition of HSP90 effectively diminished the constitutive phosphorylation of Akt, Erk, and STAT3 in PHHs. Conversely, inhibition of HSP90 significantly increased the expression of both VEGF and HGF mRNA, and induced HSP70 protein in PHH cultures in vitro. In vivo, HSP90 inhibition significantly upregulated constitutive VEGF mRNA and HSP70 in murine livers and did not impair liver re-growth after 70% hepatectomy. Furthermore, BrdUrd-staining and histological quantification of necrotic areas revealed that HSP90 inhibition did not impair liver regeneration following partial hepatectomy, or liver repair that occurs after toxic liver injury with CCl(4). CONCLUSION: Targeting HSP90 does not negatively affect the multifactorial process of liver regeneration and repair in vivo. Hence, the use of inhibitors to HSP90 appears to be a valid option for neoadjuvant therapy of liver metastases when subsequent surgery is intended.",
            "question": "Which heat shock protein is found to be upregulated during Hsp90 inhibition?",
            "answers": {
                "answer_start": 1163,
                "text": "HSP70"
            }
        },
        {
            "context": "Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Protein methylation is a common posttranslational modification that mostly occurs on arginine and lysine residues. Arginine methylation has been reported to regulate RNA processing, gene transcription, DNA damage repair, protein translocation, and signal transduction. Lysine methylation is best known to regulate histone function and is involved in epigenetic regulation of gene transcription. To better study protein methylation, we have developed highly specific antibodies against monomethyl arginine; asymmetric dimethyl arginine; and monomethyl, dimethyl, and trimethyl lysine motifs. These antibodies were used to perform immunoaffinity purification of methyl peptides followed by LC-MS/MS analysis to identify and quantify arginine and lysine methylation sites in several model studies. Overall, we identified over 1000 arginine methylation sites in human cell line and mouse tissues, and ∼160 lysine methylation sites in human cell line HCT116. The number of methylation sites identified in this study exceeds those found in the literature to date. Detailed analysis of arginine-methylated proteins observed in mouse brain compared with those found in mouse embryo shows a tissue-specific distribution of arginine methylation, and extends the types of proteins that are known to be arginine methylated to include many new protein types. Many arginine-methylated proteins that we identified from the brain, including receptors, ion channels, transporters, and vesicle proteins, are involved in synaptic transmission, whereas the most abundant methylated proteins identified from mouse embryo are transcriptional regulators and RNA processing proteins.",
            "question": "Name a method for enrichment of arginine-methylated peptides.",
            "answers": {
                "answer_start": 710,
                "text": "immunoaffinity purification"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 369,
                "text": "INCA"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1779,
                "text": "IL-1β"
            }
        },
        {
            "context": "Organization of conserved elements near key developmental regulators in vertebrate genomes. Sequence conservation has traditionally been used as a means to target functional regions of complex genomes. In addition to its use in identifying coding regions of genes, the recent availability of whole genome data for a number of vertebrates has permitted high-resolution analyses of the noncoding \"dark matter\" of the genome. This has resulted in the identification of a large number of highly conserved sequence elements that appear to be preserved in all bony vertebrates. Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation. This chapter describes the identification and characterization of these elements, with particular reference to their composition and organization.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 715,
                "text": "development"
            }
        },
        {
            "context": "Identification of a heteromeric complex that promotes DNA replication origin firing in human cells. Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holohelicase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.",
            "question": "Which factor interacts with Treslin/TICRR throughout the cell cycle of human cells?",
            "answers": {
                "answer_start": 403,
                "text": "MDM two binding protein (MTBP)"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2246,
                "text": "stroke"
            }
        },
        {
            "context": "Regulation and functions of ADAR in drosophila. Drosophila melanogaster has a single Adar gene encoding a protein related to mammalian ADAR2 that edits transcripts encoding glutamate receptor subunits. We describe the structure of the Drosophila Adar locus and use ModENCODE information to supplement published data on Adar gene transcription, and splicing. We discuss the roles of ADAR in Drosophila in terms of the two main types of RNA molecules edited and roles of ADARs as RNA-binding proteins. Site-specific RNA editing events in transcripts encoding ion channel subunits were initially found serendipitously and subsequent directed searches for editing sites and transcriptome sequencing have now led to 972 edited sites being identified in 597 transcripts. Four percent of D. melanogaster transcripts are site-specifically edited and these encode a wide range of largely membrane-associated proteins expressed particularly in CNS. Electrophysiological studies on the effects of specific RNA editing events on ion channel subunits do not suggest that loss of RNA editing events in ion channels consistently produce a particular outcome such as making Adar mutant neurons more excitable. This possibility would have been consistent with neurodegeneration seen in Adar mutant fly brains. A further set of ADAR targets are dsRNA intermediates in siRNA generation, derived from transposons and from structured RNA loci. Transcripts with convergent overlapping 3' ends are also edited and the first discovered instance of RNA editing in Drosophila, in the Rnp4F transcript, is an example. There is no evidence yet to show that Adar antagonizes RNA interference in Drosophila. Evidence has been obtained that catalytically inactive ADAR proteins exert effects on microRNA generation and RNA interference. Whether all effects of inactive ADARs are due to RNA-binding or to even further roles of these proteins remains to be determined.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 85,
                "text": "Adar"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 340,
                "text": "Dabigatran"
            }
        },
        {
            "context": "DNA methyltransferase 1-associated protein (DMAP1) is a co-repressor that stimulates DNA methylation globally and locally at sites of double strand break repair. Correction of double strand DNA breaks proceeds in an error-free pathway of homologous recombination (HR), which can result in gene silencing of half of the DNA molecules caused by action by DNA methyltransferase 1 (DNMT1) (Cuozzo, C., Porcellini, A., Angrisano, T., Morano, A., Lee, B., Di Pardo, A., Messina, S., Iuliano, R., Fusco, A., Santillo, M. R., Muller, M. T., Chiariotti, L., Gottesman, M. E., and Avvedimento, E. V. (2007) PLoS Genet. 3, e110). To explore the mechanism that leads to HR-induced silencing, a genetic screen was carried out based on the silencing of a GFP reporter to identify potential partners. DMAP1, a DNMT1 interacting protein, was identified as a mediator of this process. DMAP1 is a potent activator of DNMT1 methylation in vitro, suggesting that DMAP1 is a co-repressor that supports the maintenance and de novo action of DNMT1. To examine critical roles for DMAP1 in vivo, lentiviral shRNA was used to conditionally reduce cellular DMAP1 levels. The shRNA transduced cells grew poorly and eventually ceased their growth. Analysis of the tumor suppressor gene p16 methylation status revealed a clear reduction in methylated CpGs in the shRNA cells, suggesting that reactivation of a tumor suppressor gene pathway caused the slow growth phenotype. Analysis of HR, using a fluorescence-based reporter, revealed that knocking down DMAP1 also caused hypomethylation of the DNA repair products following gene conversion. DMAP1 was selectively enriched in recombinant GFP chromatin based on chromatin immunoprecipitation analysis. The picture that emerges is that DMAP1 activates DNMT1 preferentially at sites of HR repair. Because DMAP1 depleted cells display enhanced HR, we conclude that it has additional roles in genomic stability.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1019,
                "text": "DNMT1"
            }
        },
        {
            "context": "Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 480,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. BACKGROUND: The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS: We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS: Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 508,
                "text": "ibrutinib"
            }
        },
        {
            "context": "Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities. Rapid laboratory methods provide optimal support for active surveillance efforts to screen for methicillin-resistant Staphylococcus aureus (MRSA). Most laboratories struggle to determine the optimal use of resources, considering options to balance cost, speed, and diagnostic accuracy. To assess the performance of common methods, the first comparison of MRSASelect agar (MS) and CHROMagar MRSA (CA), with and without broth enrichment followed by a 24-h subculture to MS, was performed. Results were compared to those of the Xpert MRSA assay. For direct culture methods, the agreement between MS and CA was 98.8%. At 18 h, direct MS identified 93% of all positive samples from direct culture and 84% of those identified by the Xpert MRSA. For Trypticase soy broth-enriched MS culture, incubated overnight and then subcultured for an additional 24 h, the agreement with Xpert MRSA was 96%. The agreement between direct MS and Xpert MRSA was 100% when semiquantitative culture revealed a bacterial density of 2+ or greater; however, discrepancies between culture and Xpert MRSA arose for MRSA bacterial densities of 1+ or less, indicating low density as a common cause of false-negative culture results. Since 1+ or less was established as the most common MRSA carrier state, broth enrichment or PCR may be critical for the identification of all MRSA carriers who may be reservoirs for transmission. In this active-surveillance convenience sample, the use of broth enrichment followed by subculture to MS offered a low-cost but sensitive method for MRSA screening, with performance similar to that of Xpert MRSA PCR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 14,
                "text": "MRSA"
            }
        },
        {
            "context": "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.",
            "question": "What disease is the drug aducanumab targeting?",
            "answers": {
                "answer_start": 46,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 565,
                "text": "SERCA"
            }
        },
        {
            "context": "Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.",
            "question": "Which type of cells is affected in Amyotrophic Lateral Sclerosis?",
            "answers": {
                "answer_start": 212,
                "text": "motor neurons"
            }
        },
        {
            "context": "The partial 5-HT(1A) agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy. Dopamine (DA) replacement therapy with l-DOPA remains the standard pharmacotherapy for Parkinson's disease (PD). Unfortunately, chronic l-DOPA treatment is accompanied by development of motor fluctuations and l-DOPA-induced dyskinesia (LID). While serotonin (5-HT)(1A) agonists acutely reduce these complications, their prophylactic and long-term effects are not well-delineated. To test this, male Sprague-Dawley rats received unilateral 6-hydroxydopamine (6-OHDA) lesions. In experiment 1, l-DOPA-primed rats were pre-treated with Vehicle (0.9% NaCl), various doses of the partial 5-HT(1A) agonist, buspirone (0.25, 1.0 or 2.5 mg/kg, ip) or buspirone (2.5 mg/kg, ip)+the 5-HT(1A) antagonist, WAY100635 (0.5 mg/kg, ip) 5 min prior to l-DOPA (12 mg/kg+15 mg/kg benserazide, ip). Rats were tested for LID using the abnormal involuntary movements (AIMs) scale and motor performance using the forepaw adjusting steps test (FAS). In experiment 2, l-DOPA-naïve rats received co-administration of l-DOPA+buspirone (1.0 or 2.5 mg/kg, ip) for 2 weeks. AIMs and FAS were measured throughout. In l-DOPA-primed rats, buspirone dose-dependently reduced LID and improved l-DOPA-related motor performance due to action at the 5-HT(1A) receptor. In l-DOPA-naïve rats, buspirone delayed LID development while improving l-DOPA's anti-parkinsonian efficacy indicating the potential long-term benefits of 5-HT(1A) agonists for reduction of l-DOPA-related side effects.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 880,
                "text": "l-DOPA"
            }
        },
        {
            "context": "Effect of partial blockade of the Na(+)/Ca(2+)-exchanger on Ca(2+) handling in isolated rat ventricular myocytes. SEA0400 is a selective inhibitor of the Na(+)/Ca(2+) exchanger having equal potencies to suppress both the forward and reverse mode operation of the Na(+)/Ca(2+) exchanger. Present experiments were designed to study the effect of partial blockade of Na(+)/Ca(2+) exchanger on Ca(2+) handling in isolated rat ventricular myocytes. Intracellular Ca(2+) transient and cell shortening were measured in ventricular myocytes loaded with Fura-2-AM fluorescent dye. Partial blockade of Na(+)/Ca(2+) exchanger was induced by superfusion of the cells with SEA0400 at a concentration of 0.3 microM. Amplitude of the intracellular Ca(2+) transient and cell shortening was significantly increased by SEA0400 in both field stimulated and voltage clamped myocytes, without significant elevation of diastolic Ca(2+) level and the decay time constant of the Ca(2+) transient. In patch clamped myocytes the SEA0400 induced increase in the Ca(2+) transient and cell shortening was accompanied by significant reduction of peak L-type Ca(2+) current. These effects can be explained by the autoregulative nature of cardiac Ca(2+) handling, as the reduced Ca(2+) efflux from the cell results in an increased Ca(2+) load to the sarcoplasmic reticulum leading to increased Ca(2+) release, which in turn may decrease the L-type Ca(2+) current by accelaration of Ca(2+) dependent inactivation of L-type Ca(2+) current. Our results suggest that complex changes in the Ca(2+) cycling can occur after selective pharmacological inhibition of the Na(+)/Ca(2+) exchanger.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 154,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke: Design of the randomized Gore REDUCE Clinical Study. Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.",
            "question": "Treatment of which disease was studied in the Gore REDUCE Clinical Study?",
            "answers": {
                "answer_start": 0,
                "text": "Patent foramen ovale"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 151,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 218,
                "text": "tyrosinase"
            }
        },
        {
            "context": "APOBEC3B and AID have similar nuclear import mechanisms. Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 1188,
                "text": " nuclear"
            }
        },
        {
            "context": "Friedreich's ataxia: clinical aspects and pathogenesis. Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 389,
                "text": "frataxin"
            }
        },
        {
            "context": "Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. BACKGROUND: Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs). OBJECTIVE: To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors. METHODS: A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case-control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease. RESULTS: 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002). CONCLUSION: Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.",
            "question": "Which is the most widely used anti-TNF drug?",
            "answers": {
                "answer_start": 806,
                "text": "etanercept"
            }
        },
        {
            "context": "Uncoupling Mitochondrial Respiration for Diabesity. Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway to uncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibits catalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act as endogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration of PM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance by increasing energy expenditure. In short-term studies, treated animals exhibit no toxicity while experiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway may identify novel therapies for diabesity, the disease state associated with diabetes and obesity.",
            "question": "Where is the enzyme PM20D1 localized?",
            "answers": {
                "answer_start": 660,
                "text": "UCP1+ adipocytes"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1470,
                "text": "53BP1"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 1463,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 889,
                "text": "Xa"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 601,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 757,
                "text": "CD38"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 289,
                "text": "BRG1"
            }
        },
        {
            "context": "Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells. The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. Accumulating evidence suggests that certain tissue kallikreins are part of an enzymatic cascade pathway that is activated in ovarian cancer and other malignant diseases. In the present study, OV-MZ-6 ovarian cancer cells were stably co-transfected with plasmids expressing hK4, hK5, hK6, and hK7. These cells displayed similar proliferative capacity as the vector-transfected control cells (which do not express any of the four tissue kallikreins), but showed significantly increased invasive behavior in an in vitro Matrigel invasion assay (p<0.01; Mann-Whitney U-test). For in vivo analysis, the cancer cells were inoculated into the peritoneum of nude mice. Simultaneous expression of hK4, hK5, hK6, and hK7 resulted in a remarkable 92% mean increase in tumor burden compared to the vector-control cell line. Five out of 14 mice in the 'tissue kallikrein overexpressing' group displayed a tumor/situs ratio greater than 0.198, while this weight limit was not exceeded at all in the vector control group consisting of 13 mice (p=0.017; chi2 test). Our results strongly support the view that tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 191,
                "text": "15"
            }
        },
        {
            "context": "Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. PURPOSE: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. EXPERIMENTAL DESIGN: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. RESULTS: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). CONCLUSIONS: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 247,
                "text": "mTOR"
            }
        },
        {
            "context": "DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation. Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 133,
                "text": "FSHD"
            }
        },
        {
            "context": "Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Despite the recent major advancement in therapy for multiple myeloma, it remains an incurable disease. There remains an unmet need for novel therapies that target different mechanisms of action. Immunotherapy with monoclonal antibodies is a promising area of development and will expand our therapeutic armamentarium in the fight against myeloma. Daratumumab is a novel, high-affinity, therapeutic human monoclonal antibody against unique CD38 epitope with broad-spectrum killing activity. It has a favorable safety profile as monotherapy in patients with relapsed/refractory myeloma and also demonstrates significant single-agent activity. Abundant preclinical data supports its use in combination therapy and clinical studies on various exciting combinations are underway. This review focuses on the CD38 antigen and its targeting with daratumumab and provides an update on the results of recent clinical studies involving daratumumab.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 561,
                "text": "CD38"
            }
        },
        {
            "context": "Phase I study protocol for ex-vivo lentiviral gene therapy for the inherited skin disease, Netherton Syndrome. Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). Patients with NS have defective keratinization, hair shaft defects, recurrent infections, atopy and a predisposition to skin malignancies. Historically, one in ten infants has died before their first birthday. Currently there are no proven treatments to cure this condition. A SIN-lentiviral vector encoding the codon optimized SPINK5 gene under the control of a 572bp element derived from the human involucrin promoter (INVO) can confer compartment specific LEKTI expression in NS keratinocytes with restoration of normal skin architecture. Here we detail a study protocol for a phase I trial for feasibility and safety evaluations of autologous epidermal sheets generated from ex-vivo gene corrected keratinocyte stem cells, which will be grafted onto patients with mutation proven NS.",
            "question": "Which protein is causing Netherton syndrome?",
            "answers": {
                "answer_start": 298,
                "text": "LEKTI"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 1810,
                "text": "stroke"
            }
        },
        {
            "context": "Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 112,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure. Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the alphabeta fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 214,
                "text": "insulin receptor"
            }
        },
        {
            "context": "Observational, retrospective study of the effectiveness of 5-aminolevulinic acid in malignant glioma surgery in Spain (The VISIONA study). OBJECTIVE: To assess effectiveness of 5-aminolevulinic acid (5-ALA, Gliolan(®)) in patients treated for malignant glioma under typical daily practice conditions in Spain, using complete resection rate (CR) and progression free survival at 6 months (PFS6). MATERIAL AND METHODS: Retrospective review of data from 18 neurosurgery departments that were categorised as either using or not using 5-ALA. The study included adult patients with suspected malignant gliomas for whom the intended treatment plan included complete resection followed by radiotherapy and chemotherapy with temozolomide. Postoperative MRI and clinical data representing at least 6 months were required for inclusion. Rates of CR and PFS6 were compared between patients with 5-ALA treatment and those without. RESULTS: The study included 251 evaluable cases. CR and PFS6 rates were significantly higher in the group of patients treated surgically with 5-ALA: CR, 67% versus 45%, p=.000; PFS6 for patients with grade IV tumours, 69% versus 48%; p=.002. The differences retained their significance and magnitude after adjusting for all covariates including age, functional status, and whether gliomas were located in eloquent areas. CONCLUSIONS: In this retrospective series, use of 5-ALA during habitual surgical procedures in Spain was associated with a higher complete resection rate for malignant glioma and increased PFS6 for grade iv glioma.",
            "question": "What is the generic name of Gliolan?",
            "answers": {
                "answer_start": 177,
                "text": "5-aminolevulinic acid"
            }
        },
        {
            "context": "Recent developments in the diagnosis of Marfan syndrome and related disorders. Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 227,
                "text": "FBN1"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 467,
                "text": "Aurora A"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 272,
                "text": "methylKit"
            }
        },
        {
            "context": "Endoplasmic reticulum-specific BH3-only protein BNIP1 induces mitochondrial fragmentation in a Bcl-2- and Drp1-dependent manner. Bcl-2/adenovirus E1B 19-kDa interacting protein 1 (BNIP1), which is predominantly localized to the endoplasmic reticulum (ER), is a pro-apoptotic Bcl-2 homology domain 3 (BH3)-only protein. Here, we show that the expression of BNIP1 induced not only a highly interconnected ER network but also mitochondrial fragmentation in a BH3 domain-dependent manner. Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission. Both BNIP1-induced mitochondrial fission and the translocation of Drp1 were abrogated by Bcl-2 overexpression. These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 922,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 134,
                "text": "FSHD"
            }
        },
        {
            "context": "Defective lysosomal arginine transport in juvenile Batten disease. Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are responsible for the neurodegenerative disorder juvenile Batten disease. A previous study on the yeast homolog to CLN3, designated Btn1p, revealed a potential role for CLN3 in the transport of arginine into the yeast vacuole, the equivalent organelle to the mammalian lysosome. Lysosomes isolated from lymphoblast cell lines, established from individuals with juvenile Batten disease-bearing mutations in CLN3, but not age-matched controls, demonstrate defective transport of arginine. Furthermore, we show that there is a depletion of arginine in cells derived from individuals with juvenile Batten disease. We have, therefore, characterized lysosomal arginine transport in normal lysosomes and show that it is ATP-, v-ATPase- and cationic-dependent. This and previous studies have shown that both arginine and lysine are transported by the same transport system, designated system c. However, we report that lysosomes isolated from juvenile Batten disease lymphoblasts are only defective for arginine transport. These results suggest that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell. This assertion is supported by two other experimental approaches. First, an antibody to CLN3 can block lysosomal arginine transport and second, expression of CLN3 in JNCL cells using a lentiviral vector can restore lysosomal arginine transport. CLN3 may have a role in regulating intracellular levels of arginine possibly through control of the transport of this amino acid into lysosomes.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 199,
                "text": "Batten disease"
            }
        },
        {
            "context": "Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. Mgm1 is a member of the dynamin family of GTP-binding proteins. Mgm1 was first identified in yeast, where it affects mitochondrial morphology. The human homologue of Mgm1 is called OPA1. Mutations in the OPA1 gene are the prevailing cause of dominant optic atrophy, a hereditary disease in which progressive degeneration of the optic nerve can lead to blindness. Here we investigate the properties of the Mgm1/OPA1 protein in mammalian cells. We find that Mgm1/OPA1 is localized to the mitochondrial intermembrane space, where it is tightly bound to the outer surface of the inner membrane. Overexpression of wild type or mutant forms of the Mgm1/OPA1 protein cause mitochondria to fragment and, in some cases, cluster near the nucleus, whereas the loss of protein caused by small interfering RNA (siRNA) leads to dispersal of mitochondrial fragments throughout the cytosol. The cristae of these fragmented mitochondria are disorganized. At early time points after transfection with Mgm1/OPA1 siRNA, the mitochondria are not yet fragmented. Instead, the mitochondria swell and stretch, after which they form localized constrictions similar to the mitochondrial abnormalities observed during the early stages of apoptosis. These abnormalities might be the earliest effects of losing Mgm1/OPA1 protein.",
            "question": "Which is the cellular localization of the protein Opa1?",
            "answers": {
                "answer_start": 616,
                "text": "mitochondrial intermembrane space"
            }
        },
        {
            "context": "McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings. The McLeod syndrome is an X-linked disorder caused by mutations of the XK gene encoding the XK protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxy-glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X-linked trait should be examined for acanthocytosis and Kell/Kx blood group serology.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 207,
                "text": "XK"
            }
        },
        {
            "context": "Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence. Patient adherence to many osteoporosis treatments, primarily bisphosphonates, is generally poor, thus leading to a significant reduction in antifracture efficacy. Patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence, in addition to other factors, such as difficult dosing regimens and high dosing frequency. Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. It is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis. Preference and adherence to Dmab treatment were assessed in various clinical trials. Although with some limitations, available data suggest that Dmab is preferred to bisphosphonates, produces greater satisfaction than bisphosphonates, and would be preferentially chosen for long-term treatment. Moreover, patient perceptions about the necessity of Dmab treatment clearly outweigh the concerns about the injections, and positive beliefs about treatment positively influence medication-taking behavior. According to these data, Dmab may represent a reasonable alternative to bisphosphonates, particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected.",
            "question": "Which is the target of the drug Denosumab?",
            "answers": {
                "answer_start": 684,
                "text": "RANKL"
            }
        },
        {
            "context": "A rare G6490-->A substitution at the last nucleotide of exon 10 of the glucocerebrosidase gene in two unrelated Italian Gaucher patients. Mutation screening of the glucocerebrosidase gene by SSCP analysis revealed an abnormal pattern of exon 10 in two unrelated Italian Gaucher patients. Direct sequencing of the mutated samples identified a G6490-->A transition. The same mutation has been described before in a Japanese patient with Gaucher disease type III. The clinical phenotype of our patients was type I in one whose second allele carried the N370S mutation and type II in the other one with a L444P mutation. In this latter the G6490-->A substitution cancels a normal Msp I site, while on the opposite chromosome the T6433-->C mutation (L444P) introduces a new Msp I site. Thus, digestion with Msp I of the amplified exon 10 is a useful method for identifying the two mutations simultaneously.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 164,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Lewy body pathology in Alzheimer's disease. Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 1382,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 707,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 601,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa. BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 279,
                "text": "HIV"
            }
        },
        {
            "context": "Somatic cell genetic analysis of the galactocerebrosidase gene: lack of complementation in human Krabbe disease/twitcher mouse cell hybrids. The inherited deficiency of galactosylceramide beta-galactosidase (E.C. 3.2.1.46: galactocerebrosidase) activity results in globoid cell leukodystrophy in humans (Krabbe disease) and in mice (twitcher mutant). To determine whether Krabbe patients' cells complement twitcher cells to produce, in hybrid combination, greater than deficient levels of galactocerebrosidase activity, five separate crosses were made between an established twitcher mouse cell line and five cell strains from unrelated Krabbe disease patients. A total of 57 twitcher mouse/Krabbe somatic cell hybrid lines developed from all of these crosses were deficient in galactocerebrosidase activity despite the presence of human chromosomes 14 or 17, which have been previously implicated as bearing the galactocerebrosidase gene. A control cross between twitcher mouse/positive control human fibroblasts resulted in 14 of 21 independent hybrid lines that expressed higher than deficient levels of galactocerebrosidase activity. The lack of complementation between Krabbe disease patient and twitcher mutant mouse cells provides further evidence that the twitcher mouse is an authentic murine model for Krabbe disease and supports the hypothesis that the mutations in both species are within the structural gene for the galactocerebrosidase enzyme.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 223,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 249,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. The mechanism of neurodegeneration in CAG/polyglutamine repeat expansion diseases is unknown but is thought to occur at the protein level. Here, in studies of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. We further provide evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. Together with recent findings from transgenic models, our results suggest that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 364,
                "text": "ataxin-3"
            }
        },
        {
            "context": "The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib.",
            "question": "Which is the cellular target of gefitinib?",
            "answers": {
                "answer_start": 148,
                "text": "epidermal growth factor receptor (EGFR)"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 1029,
                "text": "L-dopa"
            }
        },
        {
            "context": "Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 217,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Dietary flavonoids fisetin and myricetin: dual inhibitors of Plasmodium falciparum falcipain-2 and plasmepsin II. Malaria is one of the most devastating infectious diseases in the developing world. Until now, only one candidate malaria vaccine RTS,S/AS01 has shown modest protection in phase 3 trial in African infants. Hence the treatment of malaria still depends on the current chemotherapeutic drugs. Considering the resistance of malaria parasites to almost all used antimalarial drugs, aiming at multi-targets rather than a single target will be a more promising strategy. Previous studies have shown that myricetin and fisetin exhibited in vitro antimalarial activity against Plasmodium falciparum, but very little research focused on the molecular mechanism for their parasiticidal activity. The cysteine protease falcipain-2 and aspartic protease plasmepsin II have long been considered as important antimalarial drug targets, especially combined inhibition of these two proteases. In this study, we determined that myricetin and fisetin are dual inhibitors of falcipain-2 and plasmepsin II, which might account for their antimalarial properties. Overall, the dual inhibition of falcipain-2 and plasmepsin II by myricetin and fisetin has shed light on a possible mechanism for their antimalarial activity and provided a rationale for further development as antimalarial drugs.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 228,
                "text": "malaria"
            }
        },
        {
            "context": "Therapeutics for Alzheimer's disease based on the metal hypothesis. Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral beta-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Abeta, the principle component of beta-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Abeta and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Abeta together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Abeta oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Abeta oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the \"Metal Hypothesis of Alzheimer's Disease,\" which stipulates that the neuropathogenic effects of Abeta in Alzheimer's disease are promoted by (and possibly even dependent on) Abeta-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Abeta-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Abeta-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the \"metal hypothesis.\"",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 1604,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism. BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. This response requires the presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To better understand the genetic basis of this response, we utilized a controlled in vitro system and Next Generation sequencing to determine and compare RNA expression profiles of the parental strain and an isogenic AtxA-deficient strain in a 2 × 2 factorial design with growth environments containing or lacking carbon dioxide. RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were strongly regulated by the separate or synergistic actions of AtxA and carbon dioxide. The majority of the regulated genes responded to both AtxA and carbon dioxide rather than to just one of these factors. Interestingly, we identified two previously unrecognized small RNAs that are highly expressed under physiological carbon dioxide concentrations in an AtxA-dependent manner. Expression levels of the two small RNAs were found to be higher than that of any other gene differentially expressed in response to these conditions. Secondary structure and small RNA-mRNA binding predictions for the two small RNAs suggest that they may perform important functions in regulating B. anthracis virulence. CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are regulated by the presence of either CO2 or AtxA separately are also regulated synergistically in the presence of both. These results also elucidate novel pXO1-encoded small RNAs that are associated with virulence conditions.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 270,
                "text": "CO2"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1566,
                "text": "XK"
            }
        },
        {
            "context": "Spontaneous brachial pseudo-aneurysm in a 12-year-old with kyphoscoliosis-type Ehlers-Danlos Syndrome. The Ehlers-Danlos Syndrome (EDS) is a rare connective tissue disorder characterised by fragility of the soft connective tissues and widespread manifestations in skin, ligaments, joints, blood vessels and internal organs. We report a case of a 12-year-old boy, previously diagnosed with kyphoscoliosis-type EDS (type VI), presenting with a left brachial artery pseudo-aneursym with history of multiple spontaneous and post-traumatic arterial ruptures. Surgical management of this patient was performed successfully by primary repair of brachial artery lesion.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 146,
                "text": "connective tissue"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 1350,
                "text": "PD-L1"
            }
        },
        {
            "context": "The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer. Histone variant H2A.Z-containing nucleosomes exist at most eukaryotic promoters and play important roles in gene transcription and genome stability. The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. How SWR1 catalyzes the replacement reaction is largely unknown. Here, we determined the crystal structure of the N-terminal region (599-627) of the catalytic subunit Swr1, termed Swr1-Z domain, in complex with the H2A.Z-H2B dimer at 1.78 Å resolution. The Swr1-Z domain forms a 310 helix and an irregular chain. A conserved LxxLF motif in the Swr1-Z 310 helix specifically recognizes the αC helix of H2A.Z. Our results show that the Swr1-Z domain can deliver the H2A.Z-H2B dimer to the DNA-(H3-H4)2 tetrasome to form the nucleosome by a histone chaperone mechanism.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 295,
                "text": "SWR1"
            }
        },
        {
            "context": "In vitro antifugal activity of medicinal plant extract against Fusarium oxysporum f. sp. lycopersici race 3 the causal agent of tomato wilt. Medicinal plant extracts of five plants; Adhatoda vasica, Eucalyptus globulus, Lantana camara, Nerium oleander and Ocimum basilicum collected from Cairo, Egypt were evaluated against Fusarium oxysporum f. sp. lycopersici race 3 in vitro conditions using water and certain organic solvents. The results revealed that cold distilled water extracts of O. basilicum and E. globulus were the most effective ones for inhibiting the growth of F. oxysporum f. sp. lycopersici. Butanolic and ethanolic extracts of the tested plants inhibited the pathogen growth to a higher extent than water extracts. Butanolic extract of O. basilicum completely inhibited the growth of F. oxysporum f. sp. lycopersici at concentrations 1.5 and 2.0% (v/v). Butanolic extracts (2.0%) of tested plants had a strong inhibitory effect on hydrolytic enzymes; β-glucosidase, pectin lyase and protease of F. oxysporum f. sp. lycopersici. This study has confirmed that the application of plant extracts, especially from O. basilicum for controlling F. oxysporum f. sp. lycopersici is environmentally safe, cost effective and does not disturb ecological balance. Investigations are in progress to test the efficacy of O. basilicum extract under in vivo conditions.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 128,
                "text": "tomato"
            }
        },
        {
            "context": "MLL core components give the green light to histone methylation. Trimethylation of histone H3 Lys4 (H3K4) is associated with transcriptional activation. One of the chief effectors of H3K4 methylation is mixed-lineage leukemia 1 (MLL1), a gene that is disrupted by chromosomal translocation in acute leukemia and a master regulator of Hox and other genes. In a recent paper, core components of the human MLL histone methyltransferase (MT) complex were found to form a structural platform, with one component (WDR5) mediating association between the specific histone H3K4 substrate and the MT. This novel regulatory mechanism, which is conserved from yeast to human, is required for both methylation and downstream target gene transcription.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 183,
                "text": "H3K4"
            }
        },
        {
            "context": "Dynamics, stability and iron-binding activity of frataxin clinical mutants. Friedreich's ataxia results from a deficiency in the mitochondrial protein frataxin, which carries single point mutations in some patients. In the present study, we analysed the consequences of different disease-related mutations in vitro on the stability and dynamics of human frataxin. Two of the mutations, G130V and D122Y, were investigated for the first time. Analysis by CD spectroscopy demonstrated a substantial decrease in the thermodynamic stability of the variants during chemical and thermal unfolding (wild-type > W155R > I154F > D122Y > G130V), which was reversible in all cases. Protein dynamics was studied in detail and revealed that the mutants have distinct propensities towards aggregation. It was observed that the mutants have increased correlation times and different relative ratios between soluble and insoluble/aggregated protein. NMR showed that the clinical mutants retained a compact and relatively rigid globular core despite their decreased stabilities. Limited proteolysis assays coupled with LC-MS allowed the identification of particularly flexible regions in the mutants; interestingly, these regions included those involved in iron-binding. In agreement, the iron metallochaperone activity of the Friedreich's ataxia mutants was affected: some mutants precipitate upon iron binding (I154F and W155R) and others have a lower binding stoichiometry (G130V and D122Y). Our results suggest that, in heterozygous patients, the development of Friedreich's ataxia may result from a combination of reduced efficiency of protein folding and accelerated degradation in vivo, leading to lower than normal concentrations of frataxin. This hypothesis also suggests that, although quite different from other neurodegenerative diseases involving toxic aggregation, Friedreich's ataxia could also be linked to a process of protein misfolding due to specific destabilization of frataxin.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 151,
                "text": "frataxin"
            }
        },
        {
            "context": "Predicting early mortality in acute exacerbation of chronic obstructive pulmonary disease using the CURB65 score. BACKGROUND AND OBJECTIVE: Hospitalization for exacerbation of COPD is associated with a high risk of mortality. A risk-prediction model using information easily obtained on admission could help to identify high-risk individuals. The CURB65 score was developed to predict mortality risk in community acquired pneumonia. A retrospective study found that this score was also associated with mortality in COPD exacerbations. We conducted a prospective study to assess the utility of the CURB65 score in acute COPD exacerbations. METHODS: Consecutive patients with physician diagnosed COPD exacerbations admitted to a public hospital during a 1-year period were studied prospectively. The CURB65 scores were calculated from information obtained at initial hospital presentation. CURB65 = one point each for Confusion, Urea > 7 mmol/L, Respiratory rate > 30/min, low Blood pressure, age > 65 years. RESULTS: 30-day mortality data were available for 249 of 252 patients. CURB65 scores on admission significantly predicted risk of death during the hospital admission and at 30 days. The 30-day mortality by score groups were: low risk (scores 0-1) 2.0% (2/98), moderate risk (score 2) 6.7% (6/90) and high risk (scores 3-5) 21.3% (13/61). CURB65 scores were not predictive of 1-year mortality. CONCLUSIONS: A simple 6-point score based on confusion, blood urea, respiratory rate, blood pressure and age can be used to stratify patients with COPD exacerbation into different management groups. The CURB65 score was as effective in predicting early mortality in our cohort of acute COPD exacerbations as it was in previous cohorts with community acquired pneumonia. Our findings suggest that CURB65 scores can help clinicians to assess patients with exacerbation of COPD.",
            "question": "CURB65 score is used for stratification of which disease?",
            "answers": {
                "answer_start": 422,
                "text": "pneumonia"
            }
        },
        {
            "context": "Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 101,
                "text": "Thyroid transcription factor 1"
            }
        },
        {
            "context": "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis. When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 418,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, and metformin following co-administration in healthy volunteers. OBJECTIVE: This open-label study investigated potential drug-drug interactions between empagliflozin and metformin. METHODS: 16 healthy men received treatment A (empagliflozin 50 mg q.d. for 5 days), treatment B (empagliflozin 50 mg q.d. for 4 days with metformin 1,000 mg b.i.d. for 3 days and 1,000 mg q.d. on Day 4) and treatment C (metformin 1,000 mg b.i.d. for 3 days and 1,000 mg q.d .on Day 4) in the sequence AB then C, or C then AB. RESULTS: Metformin had no clinically relevant effect on the area under the steady state plasma concentration-time curve (AUC(τ,ss) geometric mean ratio (GMR): 96.9; 90% CI: 92.3 - 101.7) or the maximum plasma concentration at steady state (C(max,ss) GMR: 100.5; 90% CI: 88.8 - 113.7) of empagliflozin. Similarly, empagliflozin had no clinically relevant effect on AUC(τ,ss) (GMR: 100.7; 90% CI: 95.9 - 105.6) or C(max,ss) (GMR: 103.6; 90% CI: 96.5 - 111.2) of metformin. The renal clearance of empagliflozin and metformin were unaffected by co-administration. Both drugs were well tolerated alone and in combination and did not cause hypoglycemia. CONCLUSIONS: These data support co-administration of empagliflozin and metformin without dose adjustment.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 69,
                "text": "SGLT2"
            }
        },
        {
            "context": "The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1008,
                "text": "NCX"
            }
        },
        {
            "context": "A nutritional perspective on UCP1-dependent thermogenesis. Uncoupling protein 1 (UCP1) is the hallmark protein responsible for cold- and diet-induced thermogenesis in brown adipose tissue (BAT). UCP1 activity is protective against body fat accumulation. UCP1 has re-gained researchers' attention in the context of obesity following the realization that BAT is present and can be activated in adult humans and of inducible UCP1-expressing cells in white fat depots. UCP1-mediated thermogenesis is activated by specific food compounds, which function by stimulating sympathetic nervous system activity to adipose tissues and/or by acting on the adipose cells directly or indirectly, through humoral factors released upon their intake. The impact, functional consequences and potential mechanism of action of macronutrients, micronutrients and bioactive compounds impinging on UCP1 expression/activity is discussed, as well as emerging links between human genetic variation and differential responses to potential thermogenic food ingredients. Advances in this field can help dietary recommendations and strategies for long-term weight loss/maintenance and improved metabolic health.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 81,
                "text": "UCP1"
            }
        },
        {
            "context": "Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 326,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease. Here we define the role of phosphorylation of Ser129 in alpha-synuclein toxicity and inclusion formation using a Drosophila model of Parkinson disease. Mutation of Ser129 to alanine to prevent phosphorylation completely suppresses dopaminergic neuronal loss produced by expression of human alpha-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances alpha-synuclein toxicity. The G protein-coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances alpha-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating alpha-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity.",
            "question": "Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?",
            "answers": {
                "answer_start": 160,
                "text": "serine 129"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 831,
                "text": "thyroid"
            }
        },
        {
            "context": "Novel details of calsequestrin gel conformation in situ. Calsequestrin (CASQ) is the major component of the sarcoplasmic reticulum (SR) lumen in skeletal and cardiac muscles. This calcium-binding protein localizes to the junctional SR (jSR) cisternae, where it is responsible for the storage of large amounts of Ca(2+), whereas it is usually absent, at least in its polymerized form, in the free SR. The retention of CASQ inside the jSR is due partly to its association with other jSR proteins, such as junctin and triadin, and partly to its ability to polymerize, in a high Ca(2+) environment, into an intricate gel that holds the protein in place. In this work, we shed some light on the still poorly described in situ structure of polymerized CASQ using detailed EM images from thin sections, with and without tilting, and from deep-etched rotary-shadowed replicas. The latter directly illustrate the fundamental network nature of polymerized CASQ, revealing repeated nodal points connecting short segments of the linear polymer.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 72,
                "text": "CASQ"
            }
        },
        {
            "context": "Yeast DNA topoisomerase II is encoded by a single-copy, essential gene. The gene TOP2 encoding yeast topoisomerase II has been cloned by immunological screening of a yeast genomic library constructed in the phage lambda expression vector, lambda gt11. The ends of the message encoded by the cloned DNA fragment were delimited by the Berk and Sharp procedure (S1 nuclease mapping) for the 5' end and mapping of the polyA tail portion of a cDNA fragment for the 3' end. The predicted size of the message agrees with the length of the message as determined by Northern blot hybridization analysis. The identity of the gene was confirmed by expressing the gene in E. coli from the E. coli promoter lac UV5 to give catalytically active yeast DNA topoisomerase II. Disruption of one copy of the gene in a diploid yeast creates a recessive lethal mutation, indicating that the single DNA topoisomerase II gene of yeast has an essential function.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 881,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2234,
                "text": "stroke"
            }
        },
        {
            "context": "Knockout of Foxp2 disrupts vocal development in mice. The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/-) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/- mice. In comparison to their WT littermates, Foxp2+/- mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/- song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene's role in general vocal motor control.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 58,
                "text": "FOXP2"
            }
        },
        {
            "context": "Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 18,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 247,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Myoclonic astatic epilepsy (Doose syndrome) - a lamotrigine responsive epilepsy? PURPOSE: Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients. PATIENTS AND METHODS: In an exploratory, retrospective study, 10 pharmacoresistant MAE patients were included who had been admitted to the Northern German Epilepsy Center between 07/2007 and 12/2010 and had been treated with LTG. Documentation was performed with the electronic seizure diary Epivista. A total observation period of 32 weeks was defined: 8-week 'pre LTG treatment phase' (before starting with LTG), 16-week 'titration phase' (starting with very low LTG doses), 8-week 'follow-up phase'. Seizure frequency, medication and adverse events were extracted from the electronic diary and evaluated in each particular patient. The individual reduction of seizure frequency per day was defined as primary outcome variable. Additionally, a dose-effect-relationship was analyzed for each patient. RESULTS: Six out of ten patients were seizure free during the follow-up phase. Statistical analysis indicated a significant seizure reduction in seven patients at follow-up compared to the pre LTG treatment phase. Seizure frequency did not significantly decrease in two patients and increased in one patient. A significant relationship between seizure frequency per day and LTG dosage during titration and follow-up phase could be demonstrated in nine patients. Group statistics using the exact Wilcoxon test revealed a significant reduction in seizure frequency (p = 0.049, two-sided). CONCLUSION: Our data provide evidence that adjunctive LTG is an eligible therapeutic option for the treatment of pharmacoresistant MAE and encourage further prospective studies to verify this observation.",
            "question": "Which is the major symptom of the Doose syndrome?",
            "answers": {
                "answer_start": 0,
                "text": "Myoclonic astatic epilepsy"
            }
        },
        {
            "context": "Color blindness defect and medical laboratory technologists: unnoticed problems and the care for screening. Color-blindness is the inability to perceive differences between some color that other people can distinguish. Using a literature search, the results indicate the prevalence of color vision deficiency in the medical profession and its on medical skills. Medical laboratory technicians and technologists employees should also screen for color blindness. This research aimed to study color blindness prevalence among Hospitals' Clinical Laboratories' Employees and Students in Tehran University of Medical Sciences (TUMS). A cross-sectional descriptive and analytical study was conducted among 633 TUMS Clinical Laboratory Sciences' Students and Hospitals' Clinical Laboratories' Employees to detect color-blindness problems by Ishihara Test. The tests were first screened with certain pictures, then compared to the Ishihara criteria to be possible color defective were tested further with other plates to determine color - blindness defects. The data was saved using with SPSS software and analyzed by statistical methods. This is the first study to determine the prevalence of color - blindness in Clinical Laboratory Sciences' Students and Employees. 2.4% of TUMS Medical Laboratory Sciences Students and Hospitals' Clinical Laboratories' Employees are color-blind. There is significant correlation between color-blindness and sex and age. But the results showed that there is not significant correlation between color-blindness defect and exposure to chemical agents, type of job, trauma and surgery history, history of familial defect and race. It would be a wide range of difficulties by color blinded students and employees in their practice of laboratory diagnosis and techniques with a potentially of errors. We suggest color blindness as a medical conditions should restrict employment choices for medical laboratory technicians and technologists job in Iran.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 834,
                "text": "Ishihara"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 601,
                "text": "SERCA2"
            }
        },
        {
            "context": "Unusual presentatıon of oropharyngeal tularemıa: a case report. Tularemia is a bacterial zoonotic disease that is caused by Francisella tularensis and among the infectious reasons that cause fever of unknown origin (FUO) in children. Typhoidal or pneumonic tularemia can manifest predominantly as FUO. However, presentation of oropharyngeal tularemia as FUO is uncommon. Here, we report a case of an 11-month-old infant with oropharyngeal tularemia presenting as FUO. To the best of our knowledge, this clinical presentation of oropharyngeal tularemia has not been previously reported in literature.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 124,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 1109,
                "text": "5p15.3"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1388,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting. The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 911,
                "text": "malaria"
            }
        },
        {
            "context": "Restless leg syndrome manifested by iron deficiency from chronic hemoptysis in cystic fibrosis. Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be a continuum of a neurological sleep disorder associated with abnormal iron metabolism or deficiency. I describe a case of RLS and PLMD in a cystic fibrosis patient with iron deficiency from chronic hemoptysis. This is the first case that reports RLS and PLMD manifesting from iron deficiency caused by chronic hemoptysis in advanced cystic fibrosis lung disease.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 464,
                "text": "iron"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 451,
                "text": "CaN"
            }
        },
        {
            "context": "TYK2 activity promotes ligand-induced IFNAR1 proteolysis. The type I IFNR (interferon receptor) is a heterodimer composed of two transmembrane chains, IFNAR1 (interferon-alpha receptor 1 subunit) and IFNAR2, which are associated with the tyrosine kinases Tyk2 and Jak1 (Janus kinase 1) respectively. Ligand-induced down-regulation of the type I IFNR is a major mechanism of negative regulation of cellular signalling and involves the internalization and lysosomal degradation of IFNAR1. IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. The non-catalytic role of Tyk2 in sustaining the steady-state IFNAR1 level at the plasma membrane is well documented; however, little is known about the function of Tyk2 in the steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to ligand binding. In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 598,
                "text": "beta-TrCP"
            }
        },
        {
            "context": "Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas. BACKGROUND: Facial nerve preservation surgery for large vestibular schwannomas is a novel strategy for maintaining normal nerve function by allowing residual tumor adherent to this nerve or root-entry zone. OBJECTIVE: To report, in a retrospective study, outcomes for large Koos grade 3 and 4 vestibular schwannomas. METHODS: After surgical treatment for vestibular schwannomas in 52 patients (2004-2013), outcomes included extent of resection, postoperative hearing, and facial nerve function. Extent of resection defined as gross total, near total, or subtotal were 7 (39%), 3 (17%), and 8 (44%) in 18 patients after retrosigmoid approaches, respectively, and 10 (29.5%), 9 (26.5%), and 15 (44%) for 34 patients after translabyrinthine approaches, respectively. RESULTS: Hearing was preserved in 1 (20%) of 5 gross total, 0 of 2 near-total, and 1 (33%) of 3 subtotal resections. Good long-term facial nerve function (House-Brackmann grades of I and II) was achieved in 16 of 17 gross total (94%), 11 of 12 near-total (92%), and 21 of 23 subtotal (91%) resections. Long-term tumor control was 100% for gross total, 92% for near-total, and 83% for subtotal resections. Postoperative radiation therapy was delivered to 9 subtotal resection patients and 1 near-total resection patient. Follow-up averaged 33 months. CONCLUSION: Our findings support facial nerve preservation surgery in becoming the new standard for acoustic neuroma treatment. Maximizing resection and close postoperative radiographic follow-up enable early identification of tumors that will progress to radiosurgical treatment. This sequential approach can lead to combined optimal facial nerve function and effective tumor control rates.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 57,
                "text": "vestibular schwannoma"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1738,
                "text": "MARS"
            }
        },
        {
            "context": "Mepolizumab treatment for asthma. INTRODUCTION: Five percent of asthmatics have severe symptoms despite high doses of inhaled (ICS) or additional oral corticosteroids (OCS): these patients have high morbidity, risk for asthma death, and account for half of asthma healthcare spending. A subgroup (20 - 40%) of these has persistent airway eosinophilia and frequent exacerbations. Mepolizumab is a humanized monoclonal antibody that blocks binding of the key cytokine implicated specifically in eosinophil maturation and survival, interleukin-5, to its receptor. AREAS COVERED: Pharmacology, Phase I/IIa and Phase II/III studies of mepolizumab for asthma. Mepolizumab depleted blood and sputum eosinophils and partially reduced airway and bone marrow eosinophils. It also reduced airway remodeling. In unselected patients with moderate/severe asthma there was no clinically significant effect on lung function, but a trend to reduced exacerbation rates. When patients were selected for persistent sputum eosinophilia despite high-dose ICS/OCS, and frequent exacerbations, mepolizumab reduced exacerbations by 50%. EXPERT OPINION: Mepolizumab can reduce exacerbation rates in the severe asthma cohort who have eosinophilic airway inflammation despite corticosteroid treatment. This may be 30% of severe asthmatics and represents a new and important treatment option. Further studies need to confirm efficacy and indications for asthma (and other eosinophilic airway disease), and to examine clinical consequences of reducing remodeling.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 529,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Cellular or Exosomal microRNAs Associated with CCN Gene Expression in Liver Fibrosis. Liver fibrosis occurs during chronic injury and represents, in large part, an exaggerated matrigenic output by hepatic stellate cells (HSCs) which become activated as a result of injury-induced signaling pathways in parenchymal and inflammatory cells (hepatocytes, macrophages, etc.). The molecular components in these pathways (e.g., CCN proteins) are modulated by transcription factors as well as by factors such as microRNAs (miRs) that act posttranscriptionally. MiRs are small (~23 nt) noncoding RNAs that regulate gene expression by specifically interacting with the 3' untranslated region (UTR) of target gene mRNA to repress translation or enhance mRNA cleavage. As well as acting in their cells of production, miRs (and other cellular constituents such as mRNAs and proteins) can be liberated from their cells of origin in nanovesicular membrane exosomes, which traverse the intercellular spaces, and can be delivered to neighboring cells into which they release their molecular payload, causing alterations in gene expression in the target cells. Here we summarize some of the experimental approaches for studying miR action and exosomal trafficking between hepatic cells. Insights into the mechanisms involved will yield new information about how hepatic fibrosis is regulated and, further, may identify new points of therapeutic intervention.",
            "question": "What is a miR?",
            "answers": {
                "answer_start": 553,
                "text": "MiRs are small (~23 nt) noncoding RNAs"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 405,
                "text": "Xa"
            }
        },
        {
            "context": "psygenet2r: a R/Bioconductor package for the analysis of psychiatric disease genes. Motivation: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. Results: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. Availability and implementation: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html). Contact: juanr.gonzalez@isglobal.org or laura.furlong@upf.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for the analysis of psychiatric disease genes?",
            "answers": {
                "answer_start": 850,
                "text": "Psygenet2r"
            }
        },
        {
            "context": "White matter damage is related to ataxia severity in SCA3. Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 265,
                "text": "ataxin-3"
            }
        },
        {
            "context": "A non-SUMOylated tax protein is still functional for NF-κB pathway activation. UNLABELLED: Whether NF-κB promoter transactivation by the human T-cell leukemia virus type 1 (HTLV-1) Tax protein requires Tax SUMOylation is still a matter of debate. In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme. We show that either a catalytically inactive form of Ubc9 (Ubc9-C93S) or Ubc9 small interfering RNA (siRNA) dramatically reduces Tax conjugation to endogenous SUMO-1 or SUMO-2/3, demonstrating that as expected, Tax SUMOylation is under the control of the catalytic activity of Ubc9. We further report that a non-SUMOylated Tax protein produced in 293T cells is still able to activate either a transfected or an integrated NF-κB reporter promoter and to induce expression of an NF-κB-regulated endogenous gene. Importantly, blocking Ubc9 activity in T cells also results in the production of a non-SUMOylated Tax that is still fully functional for the activation of a NF-κB promoter. These results provide the definitive evidence that Tax SUMOylation is not required for NF-κB-driven gene induction. IMPORTANCE: Human T-cell leukemia virus type 1 is able to transform CD4(+) T lymphocytes. The viral oncoprotein Tax plays a key role in this process by promoting cell proliferation and survival, mainly through permanent activation of the NF-κB pathway. Elucidating the molecular mechanisms involved in NF-κB pathway activation by Tax is therefore a key issue to understand HTLV-1-mediated transformation. Tax SUMOylation was initially proposed to be critical for Tax-induced NF-κB promoter activation, which was challenged by our later observation that a low-level-SUMOylated Tax mutant was still functional for activation of NF-κB promoters. To clarify the role of Tax SUMOylation, we set up a new approach based on the inhibition of the SUMOylation machinery in Tax-expressing cells. We show that blocking the SUMO-conjugating enzyme Ubc9 abolishes Tax SUMOylation and that a non-SUMOylated Tax still activates NF-κB promoters in either adherent cells or T cells.",
            "question": "What is the role of the UBC9 enzyme in the protein sumoylation pathway?",
            "answers": {
                "answer_start": 366,
                "text": "SUMO-conjugating enzyme"
            }
        },
        {
            "context": "Interdigital foot infections: Corynebacterium minutissimum and agents of superficial mycoses. Interdigital foot infections are mostly caused initially by dermatophytes, yeasts and less frequently by bacteria. Erythrasma caused by Corynebacterium minutissimum can be confused with superficial mycoses. The aim of the study was to determine the prevalence of the etiologic agents of superficial mycoses and the frequency of Corynebacterium minutissimum in interdigital foot infections. All the samples obtained from the 121 patients with interdigital foot infections were examined directly with the use of 20% potassium hydroxide mounts and Gram stain under the microscope and cultured on Sabouraud's dextrose agar plates. In identification of superficial mycoses, the rate was found to be 14% with the cultural method and 14% with direct microscopic examination. Using a combination of direct microscopic examination and culture, a 33.8% ratio was achieved. In the culture of these samples, the most isolated factor was Trichophyton rubrum (33.7%). In 24 of the patients (19.8%) Corynebacterium minutissimum was detected by Gram staining, in 6 of these patients Trichophyton rubrum was found, Trichophyton mentagrophytes was found in 2 and Trichosporon spp. was found in 1. The examination of interdigital foot lesions in the laboratory, the coexistence of erythrasma with dermatophytes and yeast should be considered.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 230,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1051,
                "text": "Xa"
            }
        },
        {
            "context": "Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila, many messenger RNAs involved in neuro-transmission are re-coded at the RNA level by the RNA-editing enzyme, dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto-regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto-editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviours. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re-coding events in fine-tuning brain function and organismal behaviour.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 409,
                "text": "ADAR"
            }
        },
        {
            "context": "Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes. AIMS: To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure-response (E-R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). METHODS: Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration < 12 weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin [HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E-R. RESULTS: The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation. CONCLUSIONS: E-R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 81,
                "text": "SGLT2"
            }
        },
        {
            "context": "Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. BACKGROUND: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (A beta) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce A beta formation may be of therapeutic benefit. OBJECTIVE: This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139). METHODS: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. RESULTS/CONCLUSIONS: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain A beta in a dose-dependent manner in animals and plasma and cerebrospinal fluid A beta in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 15,
                "text": "semagacestat"
            }
        },
        {
            "context": "Mowat-Wilson syndrome detected by using high resolution microarray. Individuals with Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene. This deletion or cytogenetic abnormality has been reported primarily from Europe, Australia and the United States, but not in Korea. Here we report a patient with characteristic facial features of MWS, developmental delay and spasticity. High resolution microarray analysis revealed 0.9 Mb deletion of 2q22.3 involving two genes: ZEB2 and GTDC1. This case shows the important role of high resolution microarray in patients with unexplained psychomotor retardation and/or facial dysmorphism. Knowledge about the most striking clinical signs and implementation of effective molecular tests like microarray could significantly increase the detection rate of new cases of MWS in Korea. This is the first reported case of MWS in Korea.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 291,
                "text": "ZEB2"
            }
        },
        {
            "context": "TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 424,
                "text": "7"
            }
        },
        {
            "context": "Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 112,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "CNS drug development: lessons from the development of ondansetron, aprepitant, ramelteon, varenicline, lorcaserin, and suvorexant. Part I. This column is the first in a two-part series exploring lessons for psychiatric drug development that can be learned from the development of six central nervous system drugs with novel mechanisms of action over the past 25 years. Part 1 presents a brief overview of the neuroscience that supported the development of each drug, including the rationale for selecting a) the target, which in each case was a receptor for a specific neurotransmitter system, and b) the indication, which was based on an understanding of the role that target played in a specific neural circuit in the brain. The neurotransmitter systems on which the development of these agents were based included serotonin for ondansetron and lorcaserin, dopamine for varenicline, substance P (or neurokinin) for aprepitant, melatonin for ramelteon, and orexin for suvorexant. The indications were chemotherapy-induced nausea and vomiting for ondansetron and aprepitant, smoking cessation for varenicline, weight loss for lorcaserin, and insomnia for suvorexant and ramelteon.",
            "question": "What molecule is targeted by suvorexant?",
            "answers": {
                "answer_start": 958,
                "text": "orexin"
            }
        },
        {
            "context": "Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 66,
                "text": "PD-L1"
            }
        },
        {
            "context": "Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. The tumorigenesis of sporadic endocrine tumors is still not fully understood. It is well known that patients with von Recklinghausen syndrome (NF-1) (OMIM 162200) carrying NF1 germline mutations are predisposed to endocrine tumors including pheochromocytomas and duodenal somatostatinomas. It is unclear, however, whether the rarely reported occurrence of pancreatic insulinomas in NF-1 patients represents a coincidental finding or whether insulinomas are a rare manifestation of the NF-1 syndrome. To determine the potential association between the NF-1 syndrome and pancreatic endocrine tumors, we analyzed a NF-1 patient with a well-differentiated pancreatic endocrine carcinoma for NF1 mutation, allelic loss of the NF1 gene and its expression in peripheral blood and tumor cells. The germline mutation c. 499 del TGTT known in the family was confirmed by polymerase chain reaction (PCR) and direct sequencing of exon 4 in DNA extracted from peripheral blood. Loss of heterozygosity (LOH) analysis of the NF1 gene was carried out using 3 intragenic microsatellite markers on 17q11.2. RNA expression was examined by reverse transcription and a consecutive PCR spanning intron 3 of the NF1 gene including the mutated site in exon 4. Immunohistochemistry was used to analyze NF-1 protein expression. Mutation analysis of peripheral blood leukocytes confirmed the 4 base pair deletion in exon 4 starting at codon 167 (499 del TGTT). LOH analysis of tumor tissue revealed retention of both NF1 alleles. While reverse transcriptase-PCR of peripheral blood showed bi-allelic expression of both the wild-type NF1 and the mutated form, reverse transcriptase-PCR of tumor extracts demonstrated expression of the mutated but not the wild-type NF1 allele. Additionally, neurofibromin, the NF1 gene product, was absent in the tumor tissue of the NF-1 patient. These results show that the wild-type NF1 transcrips and protein are reduced, in the reported insulinoma, supposedly by epigenetic mechanisms. This provides strong evidence that there is a relationship between von Recklinghausen disease and the patient's insulinoma. In this line, insulinomas may be viewed as a rare manifestation of the NF-1 syndrome. Furthermore, the NF1 gene must be considered as a candidate tumor suppressor gene for sporadic insulinomas and probably other pancreatic endocrine tumors.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 332,
                "text": "NF1"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 411,
                "text": "tyr"
            }
        },
        {
            "context": "Pregabalin: a review of its use in fibromyalgia. Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.",
            "question": "Which drug is considered as the first line treatment of fibromyalgia?",
            "answers": {
                "answer_start": 886,
                "text": "Pregabalin"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 935,
                "text": "Xa"
            }
        },
        {
            "context": "Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Progranulin (PGRN) is known to play a role in the pathogenesis of neurodegenerative diseases. Recently, it has been demonstrated that patients with the homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal function. In the present study, we investigated the possible role of PGRN in the lysosomes of activated microglia in the cerebral cortex after traumatic brain injury (TBI). We showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes. PGRN was colocalized with Lamp1, a lysosomal marker, and Lamp1-positive areas in GRN-deficient (KO) mice were significantly expanded compared with wild-type (WT) mice after TBI. Expression of all the lysosome-related genes examined in KO mice was significantly higher than that in WT mice. The number of activated microglia with TFEB localized to the nucleus was also significantly increased in KO as compared with WT mice. Since the TFEB translocation is regulated by the mammalian target of rapamycin complex 1 (mTORC1) activity in the lysosome, we compared ribosomal S6 kinase 1 (S6K1) phosphorylation that reflects mTORC1 activity. S6K1 phosphorylation in KO mice was significantly lower than that in WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive cells around the injury was significantly decreased and increased, respectively, in KO as compared with WT mice. These results suggest that PGRN localized in the lysosome is involved in the activation of mTORC1, and its deficiency leads to increased TFEB nuclear translocation with a resultant increase in lysosomal biogenesis in activated microglia and exacerbated neuronal damage in the cerebral cortex after TBI.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 746,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Latest concept of Lewy body disease. We proposed the term 'Lewy body disease' (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brainstem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. LBD has neuropathological characteristics whereby numerous Lewy bodies are present in the central and sympathetic nervous systems, and it is a type of alpha-synucleinopathy because the main component of Lewy body is alpha-synuclein. In this paper we explain the most recent concept of LBD from the historical viewpoint.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 679,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "mpMoRFsDB: a database of molecular recognition features in membrane proteins. SUMMARY: Molecular recognition features (MoRFs) are small, intrinsically disordered regions in proteins that undergo a disorder-to-order transition on binding to their partners. MoRFs are involved in protein-protein interactions and may function as the initial step in molecular recognition. The aim of this work was to collect, organize and store all membrane proteins that contain MoRFs. Membrane proteins constitute ∼30% of fully sequenced proteomes and are responsible for a wide variety of cellular functions. MoRFs were classified according to their secondary structure, after interacting with their partners. We identified MoRFs in transmembrane and peripheral membrane proteins. The position of transmembrane protein MoRFs was determined in relation to a protein's topology. All information was stored in a publicly available mySQL database with a user-friendly web interface. A Jmol applet is integrated for visualization of the structures. mpMoRFsDB provides valuable information related to disorder-based protein-protein interactions in membrane proteins. AVAILABILITY: http://bioinformatics.biol.uoa.gr/mpMoRFsDB",
            "question": "Which is the database of molecular recognition features in membrane proteins?",
            "answers": {
                "answer_start": 1028,
                "text": "mpMoRFsDB"
            }
        },
        {
            "context": "Is epineurectomy necessary in the surgical management of carpal tunnel syndrome? BACKGROUND: In this study, it was aimed to determine whether median nerve epineurectomy is beneficial in the surgical management of carpal tunnel syndrome (CTS). MATERIALS AND METHODS: The study enrolled 72 patients including 34 patients without epineurectomy (Group A) and 38 patients with epineurectomy (Group B). Surgery was performed in patients with severe electrodiagnostic CTS findings, CTS duration >1 year and flattening along with hypervascularization in median nerve. All patients were assessed by visual analog scale, two-point discrimination test as well as subjective and objective findings at baseline and on the months 1, 3, and 6 after surgery. RESULTS: The mean age was 58.3 years (42-75 years) in 38 patients who underwent an epineurectomy, whereas it was 61.5 years (41-82 years) in 34 patients who did not have an epineurectomy. The groups were similar with regard to age, gender, duration of symptoms, and preoperative physical findings. Mean visual analog scale (VAS) scores were 1.7 in Group A and 1.8 in Group B. Again, these differences were not significant, on physical examination, the average two-point discrimination in the distribution of the median nerve was 4.9 mm (range: 3-11 mm) in Group A and 5.3 mm (range: 3-10 mm) in Group B. In postoperative evaluations, there was a better improvement in visual analog scale scores, two-point discrimination test and subjective symptoms including dysesthesia, pain and nocturnal pain within first 3 months; however, there was no marked difference in objective and subjective findings on the 6th month. No complication or recurrence was observed. CONCLUSION: We believe that median nerve epineurectomy is unnecessary in the surgical management of primary CTS since it has no influence on the midterm outcomes.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 1730,
                "text": "median"
            }
        },
        {
            "context": "Negative regulation of the tumor suppressor p53 gene by microRNAs. The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 109,
                "text": "P53"
            }
        },
        {
            "context": "Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to αCGRP were performed in human isolated cerebral and middle meningeal arteries in the absence or presence of telcagepant. Arterial slices were stained for RAMP1, CLR and actin in a double immunofluorescence staining. RESULTS: In both arteries, we found that: (i) telcagepant was devoid of any contractile or relaxant effects per se; (ii) pretreatment with telcagepant antagonised the αCGRP-induced relaxation in a competitive manner; and (iii) immunohistochemistry revealed expression and co-localisation of CLR and RAMP1 in the smooth muscle cells in the media layer of both arteries. CONCLUSIONS: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of telcagepant in the treatment of migraine.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 14,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Is epineurectomy necessary in the surgical management of carpal tunnel syndrome? BACKGROUND: In this study, it was aimed to determine whether median nerve epineurectomy is beneficial in the surgical management of carpal tunnel syndrome (CTS). MATERIALS AND METHODS: The study enrolled 72 patients including 34 patients without epineurectomy (Group A) and 38 patients with epineurectomy (Group B). Surgery was performed in patients with severe electrodiagnostic CTS findings, CTS duration >1 year and flattening along with hypervascularization in median nerve. All patients were assessed by visual analog scale, two-point discrimination test as well as subjective and objective findings at baseline and on the months 1, 3, and 6 after surgery. RESULTS: The mean age was 58.3 years (42-75 years) in 38 patients who underwent an epineurectomy, whereas it was 61.5 years (41-82 years) in 34 patients who did not have an epineurectomy. The groups were similar with regard to age, gender, duration of symptoms, and preoperative physical findings. Mean visual analog scale (VAS) scores were 1.7 in Group A and 1.8 in Group B. Again, these differences were not significant, on physical examination, the average two-point discrimination in the distribution of the median nerve was 4.9 mm (range: 3-11 mm) in Group A and 5.3 mm (range: 3-10 mm) in Group B. In postoperative evaluations, there was a better improvement in visual analog scale scores, two-point discrimination test and subjective symptoms including dysesthesia, pain and nocturnal pain within first 3 months; however, there was no marked difference in objective and subjective findings on the 6th month. No complication or recurrence was observed. CONCLUSION: We believe that median nerve epineurectomy is unnecessary in the surgical management of primary CTS since it has no influence on the midterm outcomes.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 142,
                "text": "median"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 55,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 192,
                "text": "FBN1"
            }
        },
        {
            "context": "The status of fostamatinib in the treatment of rheumatoid arthritis. Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on oral administration. This (known as R406) is a potent inhibitor of spleen tyrosine kinase, required for the expression of a number of proinflammatory cytokines. Fostamatinib has shown significantly superior efficacy (when compared with placebo) in the control of patients with rheumatoid arthritis not responding to methotrexate in Phase II clinical trials. Treatment emergent adverse events with a higher frequency than in those on placebo included diarrhea, hypertension, urinary tract infections, neutropenia and elevated transaminases. The studied doses have shown a linear pharmacokinetic pattern and the administration of methotrexate does not affect it. Fostamatinib may have a role in the therapy of patients with rheumatoid arthritis with poor response to conventional therapy. If these results are confirmed once Phase III studies are completed, it may find a place in the evolving treatment algorithm for rheumatoid arthritis.",
            "question": "Which enzyme is inhibited by a drug fostamatinib?",
            "answers": {
                "answer_start": 215,
                "text": "spleen tyrosine kinase"
            }
        },
        {
            "context": "The stratum corneum: the rampart of the mammalian body. BACKGROUND: The stratum corneum (SC) is the outermost region of the epidermis and plays key roles in cutaneous barrier function in mammals. The SC is composed of 'bricks', represented by flattened, protein-enriched corneocytes, and 'mortar', represented by intercellular lipid-enriched layers. As a result of this 'bricks and mortar' structure, the SC can be considered as a 'rampart' that encloses water and solutes essential for physiological homeostasis and that protects mammals from physical, chemical and biological assaults. STRUCTURES AND FUNCTIONS: The corneocyte cytoskeleton contains tight bundles of keratin intermediate filaments aggregated with filaggrin monomers, which are subsequently degraded into natural moisturizing compounds by various proteases, including caspase 14. A cornified cell envelope is formed on the inner surface of the corneocyte plasma membrane by transglutaminase-catalysed cross-linking of involucrin and loricrin. Ceramides form a lipid envelope by covalently binding to the cornified cell envelope, and extracellular lamellar lipids play an important role in permeability barrier function. Corneodesmosomes are the main adhesive structures in the SC and are degraded by certain serine proteases, such as kallikreins, during desquamation. CLINICAL RELEVANCE: The roles of the different SC components, including the structural proteins in corneocytes, extracellular lipids and some proteins associated with lipid metabolism, have been investigated in genetically engineered mice and in naturally occurring hereditary skin diseases, such as ichthyosis, ichthyosis syndrome and atopic dermatitis in humans, cattle and dogs.",
            "question": "What are the structures formed when keratin molecules come together?",
            "answers": {
                "answer_start": 676,
                "text": "intermediate filaments"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1388,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 736,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Mutational analysis of copper binding by human tyrosinase. Tyrosinase (EC 1.14.18.1) is a copper-containing enzyme that catalyzes several reactions in the biosynthesis of melanin pigments and is deficient in patients with type I oculocutaneous albinism (OCA1). Tyrosinase is thought to bind two copper ions, one at each of two conserved sequence motifs, termed CuA and CuB, but to date this has been directly proved only for the Neurospora and mushroom enzyme. Here, we demonstrate that mammalian tyrosinase directly binds copper, and that the CuA and CuB sites are both required for copper binding and for catalytic activity. We show that in human tyrosinase, copper binding by the CuB site is most likely coordinated by residues His363, His367, and His389, and that copper binding may be cooperative, with copper binding at one site facilitating copper binding by the other site. Furthermore, correct folding of the tyrosinase polypeptide appears to be necessary for copper binding, and a number of human OCA1 mutations disrupt copper binding and thus catalytic function of tyrosinase.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 59,
                "text": "Tyr"
            }
        },
        {
            "context": "[French results of enzyme replacement therapy in Gaucher's disease]. Gaucher disease is an inborn recessive autosomal disease due to a partial deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient activity leads to accumulation of the lipid glucocerebroside in the liver, the spleen and bone marrow with concomitant anemia and thrombocytopenia. Patients with Gaucher disease have been classified in three types: type I is the more common, neurological manifestations occur in types II and III. Enzyme replacement therapy (ERT) with modified placental human glucocerebrosidase (ceredase) or recombinant glucocerebrosidase (cerezyme) is effective in most type I Gaucher disease and has become the current standard care administered to thousand of patients worldwide. ERT has obviated the need for bone marrow transplantation and virtually eliminated the need for splenectomy. We report here the French study including adults and children. ERT of 30 to 60 U/K every two weeks as starting dose was administrated to 108 patients with severe type I Gaucher disease. ERT fully reverse many of the manifestations of the disease. ERT regimen alleviated fatigue, and hematological and visceral signs and symptoms in nearly all severely-ill patients. Skeletal responses to treatment develop much more slowly than hematological or visceral responses. Studies in pediatrics show that the disease is more severe in children. These children should be treated early in the course of their disease to avoid irreparable damage. Hematological manifestation in type II cannot be reversed with enzyme replacement. In type III treatment can rarely reverse neurological deficit. Gaucher disease is also an excellent candidate for gene therapy.",
            "question": "Which enzyme is deficient in Gaucher's disease?",
            "answers": {
                "answer_start": 178,
                "text": "beta glucocerebrosidase"
            }
        },
        {
            "context": "Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance. The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK-RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1085,
                "text": "RANKL"
            }
        },
        {
            "context": "The Roles of Arabidopsis CDF2 in Transcriptional and Posttranscriptional Regulation of Primary MicroRNAs. The precise regulation of microRNA (miRNA) transcription and processing is important for eukaryotic development. Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1). We identified a cycling DOF transcription factor, CDF2, which interacts with DCL1 and regulates the accumulation of a population of miRNAs. CDF2 binds directly to the promoters of some miRNAs and works as a transcription activator or repressor for these miRNA genes. CDF2 binds preferentially to the pri-miRNAs regulated by itself and affects DCL1-mediated processing of these pri-miRNAs. Genetically, CDF2 works in the same pathway as miR156 or miR172 to control flowering. We conclude that CDF2 regulates a group of pri-miRNAs at both the transcriptional and posttranscriptional levels to maintain proper levels of their mature miRNAs to control plant development.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 298,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "SBP, SECIS binding protein, binds to the RNA fragment upstream of the Sec UGA codon in glutathione peroxidase mRNA. In mammals, most of the selenium contained in the body is present as an unusual amino acid, selenocysteine (Sec), whose codon is UGA. Because the UGA codon is typically recognized as a translation stop signal, it is intriguing how a cell recognizes and distinguishes a UGA Sec codon from a UGA stop codon. For eukaryotic selenoprotein mRNAs, it has been proposed that a conserved stem-loop structure designated the Sec insertion sequence (SECIS) in the 3'-untranslated (3'-UTR) region is required for recognition of UGA as a Sec codon. Some proteins which bind to SECIS (SBP) have been reported. However, it is not clear how the SECIS element in the 3'-UTR can mediate Sec insertion far at the in-frame UGA Sec codons. The idea that there must be a signal near the UGA Sec codon is still considered. Therefore, we searched for a protein which binds to an RNA sequence surrounding the UGA Sec codon on human glutathione peroxidase (GPx) mRNA. We found a protein which strongly bound to the RNA fragment upstream of the UGA Sec codon. However, this protein did not bind to the RNA sequence downstream of the UGA codon. This protein also bound to the SECIS sequence in the 3'-UTR of human GPx, and this binding to SECIS was competed with the RNA fragment upstream of the UGA Sec codon. Comparison of the RNA fragment with the SECIS fragment identified the conserved regions, which appeared in the region upstream of the in-frame UGA Sec codon of Se-protein mRNAs. Thus, this study proposes a novel model to understand the mechanisms of Sec incorporation at the UGA Sec codon, especially the regions upstream of the UGA codon of mRNAs of mammalian selenoproteins. This model explains that the stem-loop structure covering the UGA codon is recognized by SBP and how the UGA Sec codon escapes from attack by eRF of the peptide releasing factor.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 555,
                "text": "SECIS"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 606,
                "text": "webSDA"
            }
        },
        {
            "context": "Molecular cloning of cDNA encoding a bovine selenoprotein P-like protein containing 12 selenocysteines and a (His-Pro) rich domain insertion, and its regional expression. When cDNA containing proteins enriched in the bovine cerebellar cortex were cloned, a clone which seemed to encode a selenoprotein P-like protein was isolated. The coding nucleotide sequence of its cDNA insert displayed high homology to rat and human selenoprotein P cDNA but contained 12 rather than 10 TGAs (12 rather than 10 selenocysteines in deduced amino acids), a tandem repeat of one CACTCC (His-Ser) and seven CATCCCs (His-Pro), and a 3' untranslated region approximately 890 bases shorter than that of rat liver selenoprotein P. RT-PCR using a set of primers flanking to the repeat displayed the existence of mRNA without the repeat. The tandem repeat and its adjacent region consisted of a similar motif of CAC/TCC/AC/T. Thus, these proteins included a (His-Pro) rich domain with a slightly negative free energy change irrespective of having the tandem repeat or not. Such His-Pro repeats reportedly exist in the segmentation gene paired or homeobox protein Om(1D) of Drosophila. Moreover, both this selenoprotein P-like protein mRNA and selenoprotein P mRNA were expressed in all the areas of the brain but most prominently in the cerebellar cortex, hippocampus, and olfactory bulb. These findings suggest the possibility that these selenoproteins are major selenium carriers in the brain and play a role in the morphological response of nerve or glial cells.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 422,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "BPP: a sequence-based algorithm for branch point prediction. Motivation: Although high-throughput sequencing methods have been proposed to identify splicing branch points in the human genome, these methods can only detect a small fraction of the branch points subject to the sequencing depth, experimental cost and the expression level of the mRNA. An accurate computational model for branch point prediction is therefore an ongoing objective in human genome research. Results: We here propose a novel branch point prediction algorithm that utilizes information on the branch point sequence and the polypyrimidine tract. Using experimentally validated data, we demonstrate that our proposed method outperforms existing methods. Availability and implementation: https://github.com/zhqingit/BPP. Contact: djguo@cuhk.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which sequence-based algorithm for branch point prediction has been proposed?",
            "answers": {
                "answer_start": 0,
                "text": "BPP"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 523,
                "text": "TYR"
            }
        },
        {
            "context": "Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 665,
                "text": "flumazenil"
            }
        },
        {
            "context": "Reconstitution of an E box-binding Myc:Max complex with recombinant full-length proteins expressed in Escherichia coli. The c-Myc oncoprotein (Myc) is a DNA sequence-specific transcription factor that regulates transcription of a wide variety of genes involved in the control of cell growth, proliferation, differentiation, and apoptosis and its deregulated expression is implicated in many types of human cancer. Myc has an N-terminal transcription activation domain (TAD) that interacts with various coactivators and a C-terminal basic-helix-loop-helix-leucine zipper (bHLHZip) domain required for E box-specific DNA-binding and heterodimerization with its obligatory bHLHZip protein partner Max. The analysis of the mechanisms by which the Myc:Max complex regulates transcription at the molecular level in vitro has been hampered by the difficulty in obtaining highly pure recombinant Myc:Max heterodimers that contain full-length Myc with its complete TAD domain and that have sequence-specific DNA-binding activity. Here, we describe a simple method to reconstitute recombinant Myc:Max complexes from highly purified full-length proteins expressed in Escherichia coli that are soluble and highly active in E box-specific DNA-binding in vitro. The reconstituted Myc:Max complexes are stable and lack Max:Max homodimers. This procedure should facilitate the characterization of the DNA-binding and transcription activation functions of full-length Myc:Max complexes in vitro and in particular the role of Myc TAD-interacting cofactors and Myc:Max post-translational modifications.",
            "question": "What is the role of TAD protein domain?",
            "answers": {
                "answer_start": 436,
                "text": "transcription activation domain"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 678,
                "text": "7"
            }
        },
        {
            "context": "Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 101,
                "text": "Thyroid transcription factor 1"
            }
        },
        {
            "context": "A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. BACKGROUND: Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase. METHODS: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions. RESULTS: A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P=0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P=0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P=0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%). CONCLUSIONS: Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression. (Funded by Geron; ClinicalTrials.gov number, NCT01731951.).",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 21,
                "text": "Telomerase"
            }
        },
        {
            "context": "Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. p53 is a sequence specific transcription factor that is activated in response to various forms of genotoxic stress to induce cell cycle arrest and apoptosis. Induction of p53 is subjected to complex and strict control through several pathways, as it will often determine cellular fate. The p73 protein shares strong structural and functional similarities with p53 such as the potential to activate p53 responsive genes and the ability to induce apoptosis. In addition to alternative splicing at the carboxyl terminus which yields several p73 isoforms, a p73 variant lacking the N-terminal transactivation domain (Delta Np73) was described in mice. In this study, we report the cloning and characterisation of the human Delta Np73 isoforms, their regulation by p53 and their possible role in carcinogenesis. As in mice, human Delta Np73 lacks the transactivation domain and starts with an alternative exon (exon 3'). Its expression is driven by a second promoter located in a genomic region upstream of this exon, supporting the idea of two independently regulated proteins, derived from the same gene. As anticipated, Delta Np73 is capable of regulating TAp73 and p53 function since it is able to block their transactivation activity and their ability to induce apoptosis. Interestingly, expression of the Delta Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. The regulation of Delta Np73 is exerted through a p53 responsive element located on the Delta N promoter. Expression of Delta Np73 not only regulates the function of p53 and TAp73 but also shuts off its own expression, once again finely regulating the whole system. Our data also suggest that increased expression of Delta Np73, functionally inactivating p53, could be involved in tumorogenesis. An extensive analysis of the expression pattern of Delta Np73 in primary tumours would clarify this issue.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1479,
                "text": "7"
            }
        },
        {
            "context": "Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 923,
                "text": "L-dopa"
            }
        },
        {
            "context": "Defining the phenotype of restless legs syndrome/Willis-Ekbom disease (RLS/WED): a clinical and polysomnographic study. Clinical features variability between familial and sporadic restless legs syndrome/Willis-Ekbom disease (RLS/WED) has been previously reported. With this retrospective cohort study, we aimed to determine the clinical and polysomnographic characteristics of 400 RLS/WED patients. Patients with familial RLS/WED were significantly younger than sporadic RLS/WED, while clinical and polysomnographic characteristics were similar in both groups. No difference was found for the age-at-onset between idiopathic and secondary RLS/WED. Periodic limb movements (PLM) index and REM sleep time were higher in idiopathic RLS/WED. Time of onset of symptoms was in the evening or at bedtime in 28.04 and 37.80% of patients, respectively, while in 21.34% of patients onset was more than 1 h after sleep onset. Impulse control and compulsive behaviours (ICBs) were found in 13.29% patients on dopamine agonist therapy. Our analyses support the hypothesis that patients with a familial history of RLS/WED may have a genetic component. Nevertheless, the dichotomy between early and late onset disease seems to be less sharp than previously reported. A large proportion of RLS/WED patients can have atypical features, therefore making the diagnosis challenging. Some cases can be missed even when the patient refers to a sleep specialist, as revealed by the partial absence of daytime symptoms, the high comorbidity with insomnia and other sleep complaints and the high percentage of symptoms beginning after sleep onset. This draws attention on the importance of a careful evaluation of the patient, to recognize potentially treatable secondary forms of RLS/WED.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 26,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "The COMPASS family of H3K4 methylases in Drosophila. Methylation of histone H3 lysine 4 (H3K4) in Saccharomyces cerevisiae is implemented by Set1/COMPASS, which was originally purified based on the similarity of yeast Set1 to human MLL1 and Drosophila melanogaster Trithorax (Trx). While humans have six COMPASS family members, Drosophila possesses a representative of the three subclasses within COMPASS-like complexes: dSet1 (human SET1A/SET1B), Trx (human MLL1/2), and Trr (human MLL3/4). Here, we report the biochemical purification and molecular characterization of the Drosophila COMPASS family. We observed a one-to-one similarity in subunit composition with their mammalian counterparts, with the exception of LPT (lost plant homeodomains [PHDs] of Trr), which copurifies with the Trr complex. LPT is a previously uncharacterized protein that is homologous to the multiple PHD fingers found in the N-terminal regions of mammalian MLL3/4 but not Drosophila Trr, indicating that Trr and LPT constitute a split gene of an MLL3/4 ancestor. Our study demonstrates that all three complexes in Drosophila are H3K4 methyltransferases; however, dSet1/COMPASS is the major monoubiquitination-dependent H3K4 di- and trimethylase in Drosophila. Taken together, this study provides a springboard for the functional dissection of the COMPASS family members and their role in the regulation of histone H3K4 methylation throughout development in Drosophila.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 89,
                "text": "H3K4"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 1409,
                "text": "LARVA"
            }
        },
        {
            "context": "Mis-sesnse mutations in Tafazzin (TAZ) that escort to mild clinical symptoms of Barth syndrome is owed to the minimal inhibitory effect of the mutations on the enzyme function: In-silico evidence. Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic Location: Xq28) in human. Its mutations cause Barth syndrome (MIM ID: #302060)/3-Methyl Glutaconyl Aciduria Type II, an inborn error of metabolism often leading to foetal or infantile fatality. Nevertheless, some mis-sense mutations result in mild clinical symptoms. To evaluate the rationale of mild symptoms and for an insight of Tafazzin active site, sequence based and structure based ramifications of wild and mutant Tafazzins were compared in-silico. Sequence based domain predictions, surface accessibilities on substitution & conserved catalytic sites with statistical drifts, as well as thermal stability changes for the mutations and the interaction analysis of Tafazzin were performed. Crystal structure of Tafazzin is not yet resolved experimentally, therefore 3D coordinates of Tafazzin and its mutants were spawned through homology modeling. Energetically minimized and structurally validated models were used for comparative docking simulations. We analyzed active site geometry of the models in addition to calculating overall substrate binding efficiencies for each of the enzyme-ligand complex deduced from binding energies instead of comparing only the docking scores. Also, individual binding energies of catalytic residues on conserved HX4D motif of Acyltransferase superfamily present in Tafazzins were estimated. This work elucidates the basis of mild symptoms in patients with mis-sense mutations, identifies the most pathogenic mutant among others in the study and also divulges the critical role of HX4D domain towards successful transacylation by Taffazin. The in-silico observations are in complete agreement with clinical findings reported for the patients with mutations.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 357,
                "text": "Xq28"
            }
        },
        {
            "context": "From tall to short: the role of TGFβ signaling in growth and its disorders. The acromelic dysplasia group is characterized by short stature, short hands and feet, stiff joint, and \"muscular\" build. Four disorders can now be ascribed to this group, namely Weill-Marchesani syndrome (WMS), geleophysic dysplasia (GD), acromicric dysplasia (AD), and Myhre syndrome (MS). Although closely similar, they can be distinguished by subtle clinical features and their pattern inheritance. WMS is characterized by the presence of dislocation of microspherophakia and has autosomal dominant or recessive mode of inheritance. GD is the more severe one, with a progressive cardiac valvular thickening, tracheal stenosis, bronchopulmonary insufficiency, often leading to an early death. AD has an autosomal dominant mode of inheritance, distinct facial and skeleton features (a hoarse voice and internal notch of the femoral head). Finally, MS is sporadic, characterized by prognathism, deafness, developmental delay, thickened calvarium, and large vertebrae with short and large pedicles. We first identified mutations in Fibrillin-1 (FBN1) in the dominant form of WMS and then mutations in A Disintegrin-like And Metalloproteinase domain with ThromboSpondin type 1 repeats 10 (ADAMTS10) in the recessive form of WMS. The function of ADAMTS10 is unknown but these findings support a direct interaction between ADAMTS10 and FBN1. We then identified mutations in ADAMTSL2 in the recessive form of GD and a hotspot of mutations in FBN1 in the dominant form of GD and in AD (exon 41-42, encoding TGFβ binding protein-like domain 5 (TB5) of FBN1). The function of ADAMTSL2 is unknown. Using a yeast double hybrid screen, we identified latent transforming growth factor-β (TGFβ) binding protein 1 as a partner of ADAMTSL2. We found an increased level of active TGFβ in the fibroblast medium from patients with FBN1 or ADAMTSL2 mutations and an enhanced phosphorylated SMAD2 level, allowing us to conclude at an enhanced TGFβ signaling in GD and AD. Finally, a direct interaction between ADAMTSL2 and FBN1 was demonstrated suggesting a dysregulation of FBN1/ADAMTSL2 interrelationship as the underlying mechanism of the short stature phenotypes. Using exome sequencing in MS probands, we identified de novo SMAD4 missense mutations, all involving isoleucine residue at position 500, in the MH2 domain. In MS fibroblasts, we found decreased ubiquitination level of SMAD4 and increased level of SMAD4 supporting a stabilization of SMAD4 protein. Functional SMAD4 is required for canonical signal transduction through the oligomerization with phosphorylated SMAD2/3 and SMAD1/5/8. We therefore studied the nuclear localization of mutant SMAD complexes and found that the complexes translocate to the nucleus. We finally observed a decreased expression of downstream TGFβ target genes supporting impaired TGFβ driven transcriptional control in MS. Our findings support a direct link between the short stature phenotypes and the TGFβ signaling. However, the finding of enhanced TGFβ signaling in Marfan phenotypes supports the existence of yet unknown mechanisms regulating TGFβ action.",
            "question": "What is the mode of inheritance of Acromicric dysplasia?",
            "answers": {
                "answer_start": 782,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1345,
                "text": "factor Xa"
            }
        },
        {
            "context": "[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 120,
                "text": "xa"
            }
        },
        {
            "context": "APOBEC3B is an enzymatic source of mutation in breast cancer. Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 788,
                "text": " nuclear"
            }
        },
        {
            "context": "Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 458,
                "text": "dabigatran"
            }
        },
        {
            "context": "In vivo analysis of Cajal body movement, separation, and joining in live human cells. Cajal bodies (also known as coiled bodies) are subnuclear organelles that contain specific nuclear antigens, including splicing small nuclear ribonucleoproteins (snRNPs) and a subset of nucleolar proteins. Cajal bodies are localized in the nucleoplasm and are often found at the nucleolar periphery. We have constructed a stable HeLa cell line, HeLa(GFP-coilin), that expresses the Cajal body marker protein, p80 coilin, fused to the green fluorescent protein (GFP-coilin). The localization pattern and biochemical properties of the GFP-coilin fusion protein are identical to the endogenous p80 coilin. Time-lapse recordings on 63 nuclei of HeLa(GFP-coilin) cells showed that all Cajal bodies move within the nucleoplasm. Movements included translocations through the nucleoplasm, joining of bodies to form larger structures, and separation of smaller bodies from larger Cajal bodies. Also, we observed Cajal bodies moving to and from nucleoli. The data suggest that there may be at least two classes of Cajal bodies that differ in their size, antigen composition, and dynamic behavior. The smaller size class shows more frequent and faster rates of movement, up to 0.9 microm/min. The GFP-coilin protein is dynamically associated with Cajal bodies as shown by changes in their fluorescence intensity over time. This study reveals an unexpectedly high level of movement and interactions of nuclear bodies in human cells and suggests that these movements may be driven, at least in part, by regulated mechanisms.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 499,
                "text": "coilin"
            }
        },
        {
            "context": "chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.",
            "question": "Which R package is used for visualization of linear and circular karyotypes?",
            "answers": {
                "answer_start": 0,
                "text": "chromDraw"
            }
        },
        {
            "context": "Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 192,
                "text": "FBN1"
            }
        },
        {
            "context": "Enhancer evolution across 20 mammalian species. The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.",
            "question": "Are human enhancers or promoters evolving faster?",
            "answers": {
                "answer_start": 790,
                "text": "enhancers"
            }
        },
        {
            "context": "SECIS-binding protein 2, a key player in selenoprotein synthesis, is an intrinsically disordered protein. Selenocysteine (Sec) is co-translationally incorporated into selenoproteins at a reprogrammed UGA codon. In mammals, this requires a dedicated machinery comprising a stem-loop structure in the 3' UTR RNA (the SECIS element) and the specific SECIS Binding Protein 2. In this report, disorder-prediction methods and several biophysical techniques showed that ca. 70% of the SBP2 sequence is disordered, whereas the RNA binding domain appears to be folded and functional. These results are consistent with a recent report on the role of the Hsp90 chaperone for the folding of SBP2 and other functionally unrelated proteins bearing an RNA binding domain homologous to SBP2.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 315,
                "text": "SECIS"
            }
        },
        {
            "context": "Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective. Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 470,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Chemical and biological evaluation of dipeptidyl boronic acid proteasome inhibitors for use in prodrugs and pro-soft drugs targeting solid tumors. Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from \"on target\" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 261,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Thyroid function and morphology in patients affected by Williams syndrome. OBJECTIVE: To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of patients with Williams syndrome (WS). METHODS: Serum concentrations of free-T3, free-T4, TSH, thyroperoxidase antibodies (TPOA) and thyroglobulin antibodies (TgA), as well as ultrasonographic data, of 20 patients with WS (12 females and eight males), aged 1.7-34.9 years, were evaluated. RESULTS: Three cases (15%) of subclinical hypothyroidism were identified. Overt hypothyroidism was diagnosed in two cases (10%). Thyroid antibodies were negative in all patients. Fourteen patients (70%) showed thyroid hypoplasia involving the entire gland. In these patients, the left thyroid lobe appeared usually, but not significantly, reduced compared with the right thyroid lobe. One patient (5%) showed thyroid hemiagenesis. Only five patients (25%) showed a thyroid with normal volume, and of these five, one patient showed marked thyroid hypoplasia of the left lobe. In all WS patients with diagnosis of subclinical or overt hypothyroidism, thyroid hypoplasia was detected. No cases of subclinical or overt hypothyroidism were found in WS with normal thyroid volume. CONCLUSIONS: This study confirms the presence of alterations of thyroid function in WS and also suggests the frequent occurrence of abnormalities of thyroid morphology in these patients. Patients with WS should be monitored for thyroid function and a thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1392,
                "text": "thyroid"
            }
        },
        {
            "context": "Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene. Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 177,
                "text": "insulin receptor"
            }
        },
        {
            "context": "The Roles of Arabidopsis CDF2 in Transcriptional and Posttranscriptional Regulation of Primary MicroRNAs. The precise regulation of microRNA (miRNA) transcription and processing is important for eukaryotic development. Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1). We identified a cycling DOF transcription factor, CDF2, which interacts with DCL1 and regulates the accumulation of a population of miRNAs. CDF2 binds directly to the promoters of some miRNAs and works as a transcription activator or repressor for these miRNA genes. CDF2 binds preferentially to the pri-miRNAs regulated by itself and affects DCL1-mediated processing of these pri-miRNAs. Genetically, CDF2 works in the same pathway as miR156 or miR172 to control flowering. We conclude that CDF2 regulates a group of pri-miRNAs at both the transcriptional and posttranscriptional levels to maintain proper levels of their mature miRNAs to control plant development.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 298,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Restless legs syndrome. Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterised by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. The pathophysiology is only partially known and a genetic component together with dopaminergic and brain iron dysregulation plays an important role. Secondary causes for RLS need to be excluded. Treatment depends on the severity and frequency of RLS symptoms, comprises non-pharmacological (eg lifestyle changes) and pharmacological interventions (eg dopaminergic medication, alpha-2-delta calcium channel ligands, opioids) and relieves symptoms only. Augmentation is the main complication of long-term dopaminergic treatment of RLS. This article will provide a clinically useful overview of RLS with provision of diagnostic criteria, differential diagnoses, possible investigations and different treatment strategies with their associated complications.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 24,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men. AIMS: To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODS: Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTS: The aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONS: Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 11,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 307,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Leptin secretion by white adipose tissue and gastric mucosa. Leptin is a hormone that plays a central role in the regulation of food intake and energy expenditure. Originally discovered in mature white adipocytes, it was subsequently isolated from the gastric mucosa. This tissue contains a large number of epithelial endocrine and exocrine cells secreting leptin in the blood stream and in the gastric lumen, respectively. Light and electron microscopy have shown that adipocytes and gastric epithelial cells contain leptin along their rough endoplasmic reticulum-Golgi-granules secretory pathway. Both tissues synthesize a soluble form of the leptin receptor that is secreted bound to leptin in the blood and into the gastric juice. This soluble receptor protect leptin and enhances its half-life. Despite the similarities in the mechanisms of leptin secretion by adipocytes and gastric epithelial cells, they are in fact radically different. In gastric cells leptin follows a rapid regulated secretion pathway whereas adipocytes secrete leptin in a constitutive slow fashion. These differences can be explained by the specific roles play by leptin originating from these two different tissues. Gastric leptin is involved in the short-term regulation of digestion, including delay of gastric emptying, absorption of nutrients by the intestinal wall and secretion of gastric, intestinal and pancreatic hormones. On the other hand, leptin secreted by white adipocytes acts primarily on the hypothalamus for the long-term regulation of food intake. Therefore, the coordination of adipose and gastric leptins ensures the proper management of food processing and energy storage.",
            "question": "From which cell type is leptin secreted?",
            "answers": {
                "answer_start": 1021,
                "text": "adipocytes"
            }
        },
        {
            "context": "In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. METHODS: Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. RESULTS: Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. CONCLUSIONS: Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 143,
                "text": "Poly(ADP-ribose) polymerase"
            }
        },
        {
            "context": "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.",
            "question": "Which SWI/SNF protein complex subunit has been demonstrated to interact with the FANCA gene product?",
            "answers": {
                "answer_start": 47,
                "text": "BRG1"
            }
        },
        {
            "context": "Evidence for a complex of transcription factor IIB with poly(A) polymerase and cleavage factor 1 subunits required for gene looping. Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB). We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner (El Kaderi, B., Medler, S., Raghunayakula, S., and Ansari, A. (2009) J. Biol. Chem. 284, 25015-25025). The presence of TFIIB at the 3' end of a gene required its interaction with cleavage factor 1 (CF1) 3' end processing complex subunit Rna15. Here, employing affinity chromatography and glycerol gradient centrifugation, we show that TFIIB associates with poly(A) polymerase and the entire CF1 complex in yeast cells. The factors required for general transcription such as TATA-binding protein, RNA polymerase II, and TFIIH are not a component of the TFIIB complex. This holo-TFIIB complex was resistant to MNase digestion. The complex was observed only in the looping-competent strains, but not in the looping-defective sua7-1 strain. The requirement of Rna15 in gene looping has been demonstrated earlier. Here we provide evidence that poly(A) polymerase (Pap1) as well as CF1 subunits Rna14 and Pcf11 are also required for loop formation of MET16 and INO1 genes. Accordingly, cross-linking of TFIIB to the 3' end of genes was abolished in the mutants of Pap1, Rna14, and Pcf11. We further show that in sua7-1 cells, where holo-TFIIB complex is not formed, the kinetics of activated transcription is altered. These results suggest that a complex of TFIIB, CF1 subunits, and Pap1 exists in yeast cells. Furthermore, TFIIB interaction with the CF1 complex and Pap1 is crucial for gene looping and transcriptional regulation.",
            "question": "Which protein mediates gene loop formation in the yeast S. cerevisiae?",
            "answers": {
                "answer_start": 336,
                "text": "TFIIB"
            }
        },
        {
            "context": "Nucleosomes are preferentially positioned at exons in somatic and sperm cells. Nucleosome positioning is constrained at eukaryotic transcription start sites and implicated in transcriptional regulation. Moreover, recent observations indicate that chromatin structure, transcription and splicing are functionally intertwined, and that modified nucleosomes with trimethylation of lysine 36 in histone subunit 3 (H3K36me3) are enriched at internal exons and the downstream flanking intronic regions of highly expressed genes. However, the position of nucleosomes in the interior of genes has been thought to be largely random. Here we show, by analysis of data sets from human sperm and T cells and medaka (Japanese killifish, Oryzias latipes) blastulae, that internal exons of genes are characterized by sharply elevated average nucleosome occupancy in comparison to flanking intronic sequences. We also show that the preferential positioning of nucleosomes at internal exons is independent of their modification status, and of the GC content, conservation or the expression level of the exon. These findings show that the location of exons is recorded in the chromatin structure and may be inherited across generations. Such embedded information may underpin transcriptionally coupled exon recognition and splice site selection.",
            "question": "What histone trimethylation has been associated to RNA splicing?",
            "answers": {
                "answer_start": 410,
                "text": "H3K36me3"
            }
        },
        {
            "context": "Clinical and pathologic manifestations of necrobiosis lipoidica-like skin involvement in sarcoidosis. Necrobiosis lipoidica dibeticum (NLD) is a granulomatous skin disease mostly associated with diabetes mellitus. NLD has been reported in patients with other systemic disease. Also, the lesions of NLD may be clinically, and sometimes even histologically indistinguishable from other inflammatory skin lesions. We described three patients with established diagnosis of sarcoidosis that developed skin lesions consistent with NLD. The association of NLD-like skin lesion in sarcoidosis is not widely appreciated. The subject of NLD and sarcoidosis is reviewed.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 195,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 158,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "[Antileukemic drug--a selective inhibitor of BCR-ABL tyrosine kynase, imatinib(STI571)]. Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by Philadelphia chromosome and resultant production of the constitutively activated BCR-ABL tyrosine kinase. Imatinib (STI571), selective inhibitor of the ABL-tyrosine kinase, inhibits the activity of BCR-ABL tyrosine kinase. A phase I and II study of STI571 showed remarkable cytogenetic effect in patients with interferon-refractory CML, offering new hope for therapy for CML. It will, however, require long-term follow-up data from phase II and III clinical studies to validate the effect of STI571 on survival. As therapy for CML improves, monitoring minimal residual disease will be important.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 263,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Origin and evolution of the long non-coding genes in the X-inactivation center. Random X chromosome inactivation (XCI), the eutherian mechanism of X-linked gene dosage compensation, is controlled by a cis-acting locus termed the X-inactivation center (Xic). One of the striking features that characterize the Xic landscape is the abundance of loci transcribing non-coding RNAs (ncRNAs), including Xist, the master regulator of the inactivation process. Recent comparative genomic analyses have depicted the evolutionary scenario behind the origin of the X-inactivation center, revealing that this locus evolved from a region harboring protein-coding genes. During mammalian radiation, this ancestral protein-coding region was disrupted in the marsupial group, whilst it provided in eutherian lineage the starting material for the non-translated RNAs of the X-inactivation center. The emergence of non-coding genes occurred by a dual mechanism involving loss of protein-coding function of the pre-existing genes and integration of different classes of mobile elements, some of which modeled the structure and sequence of the non-coding genes in a species-specific manner. The rising genes started to produce transcripts that acquired function in regulating the epigenetic status of the X chromosome, as shown for Xist, its antisense Tsix, Jpx, and recently suggested for Ftx. Thus, the appearance of the Xic, which occurred after the divergence between eutherians and marsupials, was the basis for the evolution of random X inactivation as a strategy to achieve dosage compensation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 397,
                "text": "Xist"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1338,
                "text": "53BP1"
            }
        },
        {
            "context": "Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome. The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 36,
                "text": "Mitf"
            }
        },
        {
            "context": "Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 140,
                "text": "tyr"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 547,
                "text": "Teriflunomide"
            }
        },
        {
            "context": "[Regulation of melanogenesis: the role of cAMP and MITF]. The article presents the melanogenesis pathway and the role of cyclic adenosine monophosphate (cAMP) and microphthalmia transcription factor (MITF) in regulation of this process. Products of melanogenesis are eu- and/or pheomelanins synthesized in a multistage process of tyrosine oxidation and polymerization. The conversions require the presence of tyrosinase (TYR, key enzyme), tyrosine hydroxylase isoform I (THI) and tyrosinase related proteins (TRP1 and TRP2). Many types of signal molecules and transcription factors participate in regulation of melanin synthesis, but the most important are cAMP and MITF. cAMP is the second messenger in the intracellular signal cascade, which is synthesized from adenosine triphosphate (ATP) by adenylyl cyclase, activated among others by the melanocortin receptor and the αS subunit of G protein. The signal molecule cAMP regulates MITF, TYR, THI, GTP-cyclohydroxylase I (GTP-CHI) transcription and phenylalanine hydroxylase (PAH) phosphorylation at Ser16 by protein kinase A (PKA). Mutations of genes encoding proteins belonging to the cAMP signal cascade may lead to McCune-Albright and Carney syndromes. MITF is one of the most important nuclear transcription factors regulating melanogenesis. Currently 10 isoforms of human MITF are known, but in melanocytes only MITF-M, MITF-Mdel, MITF-A and MITF-H occur. MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. It also affects expression of other factors regulating melanosome maturation, biogenesis and transport. Moreover, it regulates melanocyte proliferation and protection against apoptosis. Mutations of the MITF gene may lead to hereditary diseases: Waardenburg type II and Tietz syndromes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 1725,
                "text": "MITF"
            }
        },
        {
            "context": "Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. Empagliflozin (Jardiance): a novel SGLT2 inhibitor for the treatment of type-2 diabetes.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 35,
                "text": "SGLT2"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 411,
                "text": "tyr"
            }
        },
        {
            "context": "Cranial Nerve I: The Olfactory Nerve. Hyperosmia is increased olfactory acuity, and hypoosmia is diminished olfactory acuity. Anosmia, the inability to recognize odors, may be unilateral or bilateral. Dysosmia is an abnormal sense of smell.",
            "question": "What is hyperosmia",
            "answers": {
                "answer_start": 52,
                "text": "increased olfactory acuity"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 0,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys. Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses > 3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2252,
                "text": "CYP17A1"
            }
        },
        {
            "context": "Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Methylation of cytosine in DNA plays a crucial role in development through inheritable gene silencing. The DNA methyltransferase Dnmt1 is responsible for the propagation of methylation patterns to the next generation via its preferential methylation of hemimethylated CpG sites in the genome; however, how Dnmt1 maintains methylation patterns is not fully understood. Here we report the crystal structure of the large fragment (291-1620) of mouse Dnmt1 and its complexes with cofactor S-adenosyl-L-methionine and its product S-adenosyl-L-homocystein. Notably, in the absence of DNA, the N-terminal domain responsible for targeting Dnmt1 to replication foci is inserted into the DNA-binding pocket, indicating that this domain must be removed for methylation to occur. Upon binding of S-adenosyl-L-methionine, the catalytic cysteine residue undergoes a conformation transition to a catalytically competent position. For the recognition of hemimethylated DNA, Dnmt1 is expected to utilize a target recognition domain that overhangs the putative DNA-binding pocket. Taking into considerations the recent report of a shorter fragment structure of Dnmt1 that the CXXC motif positions itself in the catalytic pocket and prevents aberrant de novo methylation, we propose that maintenance methylation is a multistep process accompanied by structural changes.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 219,
                "text": "Dnmt1"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 488,
                "text": "Hsp90"
            }
        },
        {
            "context": "Antibodies to watch in 2014. Since 2010, mAbs has documented the biopharmaceutical industry's progress in transitioning antibody therapeutics to first Phase 3 clinical studies and regulatory review, and its success at gaining first marketing approvals for antibody-based products. This installment of the \"Antibodies to watch\" series outlines events anticipated to occur between December 2013 and the end of 2014, including first regulatory actions on marketing applications for vedolizumab, siltuximab, and ramucirumab, as well as the Fc fusion proteins Factor IX-Fc and Factor VIII-Fc; and the submission of first marketing applications for up to five therapeutics (secukinumab, ch14.18, onartuzumab, necitumumab, gevokizumab). Antibody therapeutics in Phase 3 studies are described, with an emphasis on those with study completion dates in 2014, including antibodies targeting interleukin-17a or the interleukin-17a receptor (secukinumab, ixekizumab, brodalumab), proprotein convertase subtilisin/kexin type 9 (alirocumab, evolocumab, bococizumab), and programmed death 1 receptor (lambrolizumab, nivolumab). Five antibodies with US Food and Drug Administration's Breakthrough Therapy designation (obinutuzumab, ofatumumab, lambrolizumab, bimagrumab, daratumumab) are also discussed.",
            "question": "Which enzyme is targeted by Evolocumab?",
            "answers": {
                "answer_start": 967,
                "text": "proprotein convertase subtilisin/kexin type 9"
            }
        },
        {
            "context": "Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts. RATIONALE: The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiac myocyte-specific interruption of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. OBJECTIVE: To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission-defective adult mouse hearts. METHODS AND RESULTS: Parkin mRNA and protein were present at low levels in normal mouse hearts, but were upregulated after cardiac myocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiac myocyte-specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission-defective hearts, also increasing 6-week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/sequestosome 1 (SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiac myocytes. CONCLUSIONS: Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not only interrupts mitochondrial fission, but also markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 443,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Tomatinase from Fusarium oxysporum f. sp. lycopersici is required for full virulence on tomato plants. Saponin detoxification enzymes from pathogenic fungi are involved in the infection process of their host plants. Fusarium oxysporum f. sp lycopersici, a tomato pathogen, produces the tomatinase enzyme Tom1, which degrades alpha-tomatine to less toxic derivates. To study the role of the tom1 gene in the virulence of F. oxysporum, we performed targeted disruption and overexpression of the gene. The infection process of tomato plants inoculated with transformants constitutively producing Tom1 resulted in an increase of symptom development. By contrast, tomato plants infected with the knockout mutants showed a delay in the disease process, indicating that Tom1, although not essential for pathogenicity, is required for the full virulence of F. oxysporum. Total tomatinase activity in the disrupted strains was reduced only 25%, leading to beta(2)-tomatine as the main hydrolysis product of the saponin in vitro. In silico analysis of the F. oxysporum genome revealed the existence of four additional putative tomatinase genes with identities to tomatinases from family 3 of glycosyl hydrolases. These might be responsible for the remaining tomatinase activity in the Deltatom1 mutants. Our results indicate that detoxification of alpha-tomatine in F. oxysporum is carried out by several tomatinase activities, suggesting the importance of these enzymes during the infection process.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 256,
                "text": "tomato"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1924,
                "text": "fungi"
            }
        },
        {
            "context": "G-protein-coupled receptor-2-interacting protein-1 is required for endothelial cell directional migration and tumor angiogenesis via cortactin-dependent lamellipodia formation. OBJECTIVE: Recent evidence suggests G-protein-coupled receptor-2-interacting protein-1 (GIT1) overexpression in several human metastatic tumors, including breast, lung, and prostate. Tumor metastasis is associated with an increase in angiogenesis. We have showed previously that GIT1 is required for postnatal angiogenesis during lung development. However, the functional role of GIT1 in pathological angiogenesis during tumor growth is unknown. APPROACH AND RESULTS: In the present study, we show inhibition of angiogenesis in matrigel implants as well as reduced tumor angiogenesis and melanoma tumor growth in GIT1-knockout mice. We demonstrate that this is a result of impaired directional migration of GIT1-depleted endothelial cells toward a vascular endothelial growth factor gradient. Cortactin-mediated lamellipodia formation in the leading edge is critical for directional migration. We observed a significant reduction in cortactin localization and lamellipodia formation in the leading edge of GIT1-depleted endothelial cells. We specifically identified that the Spa homology domain (aa 250-420) of GIT1 is required for GIT1-cortactin complex localization to the leading edge. The mechanisms involved extracellular signal-regulated kinases 1 and 2-mediated Cortactin-S405 phosphorylation and activation of Rac1/Cdc42. Finally, using gain of function studies, we show that a constitutively active mutant of cortactin restored directional migration of GIT1-depleted cells. CONCLUSION: Our data demonstrated that a GIT1-cortactin association through GIT1-Spa homology domain is required for cortactin localization to the leading edge and is essential for endothelial cell directional migration and tumor angiogenesis.",
            "question": "Which G protein is essential in the formation and function of lamellipodia?",
            "answers": {
                "answer_start": 1495,
                "text": "Rac1"
            }
        },
        {
            "context": "Expression of the aromatic L-amino acid decarboxylase mRNA in human tumour cell lines of neuroendocrine and neuroectodermal origin. Neuroendocrine differentiation of lung tumours is characterised by the expression of several neuroendocrine markers and is confined mostly to specific histological subtypes, i.e. small cell carcinomas and carcinoids. One of the markers seen in neuroendocrine tumours, high activity of the aromatic L-amino acid decarboxylase (AADC), is helpful in distinguishing the classic and variant small cell lung tumour subtypes. Here, we have analysed the expression and quantified the level of mRNA coding for AADC in human tumour cell lines by use of the reverse transcription and polymerase chain reaction (RT-PCR). High amounts of mRNA were detected in classic small cell lung carcinomas and a neuroblastoma cell line. Other cell lines (melanomas, non-small cell lung carcinomas and osteosarcoma) also showed AADC expression, but the levels were 2-3 orders lower. Also, the tissue-specific (neuronal versus liver-specific) mRNA type has been estimated. Small cell lung carcinomas, neuroblastoma and melanoma expressed messenger RNA specific for neuronal tissues. Importantly, the non-small cell lung carcinoma cell lines expressed either liver-specific (non-neuronal) mRNA (cell line A549) or predominantly the neuronal (cell line NCI-H520) AADC message. These data indicate that a range of tumour cell lines transcribe the AADC gene and that two distinct types of AADC mRNA which reflect the embryonal (neuronal or non-neuronal) origin of the tumour may be produced in non-small cell lung cancer cells.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 1221,
                "text": "lung"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 439,
                "text": "IL-1β"
            }
        },
        {
            "context": "Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions. Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 318,
                "text": "cancer"
            }
        },
        {
            "context": "The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 60,
                "text": "orally"
            }
        },
        {
            "context": "The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 138,
                "text": "NCX"
            }
        },
        {
            "context": "Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. To investigate the effect of global cerebral ischemia on brain cell proliferation in young adult macaques, we infused 5-bromo-2'-deoxyuridine (BrdU), a DNA replication indicator, into monkeys subjected to ischemia or sham-operated. Subsequent quantification by BrdU immunohistochemistry revealed a significant postischemic increase in the number of BrdU-labeled cells in the hippocampal dentate gyrus, subventricular zone of the temporal horn of the lateral ventricle, and temporal neocortex. In all animals, 20-40% of the newly generated cells in the dentate gyrus and subventricular zone expressed the neural progenitor cell markers Musashi1 or Nestin. A few BrdU-positive cells in postischemic monkeys were double-stained for markers of neuronal progenitors (class III beta-tubulin, TUC4, doublecortin, or Hu), neurons (NeuN), or glia (S100beta or GFAP). Our results suggest that ischemia activates endogenous neuronal and glial precursors residing in diverse locations of the adult primate central nervous system.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 756,
                "text": "Nestin"
            }
        },
        {
            "context": "Primary cilia and signaling pathways in mammalian development, health and disease. Although first described as early as 1898 and long considered a vestigial organelle of little functional importance, the primary cilium has become one of the hottest research topics in modern cell biology and physiology. Primary cilia are nonmotile sensory organelles present in a single copy on the surface of most growth-arrested or differentiated mammalian cells, and defects in their assembly or function are tightly coupled to many developmental defects, diseases and disorders. In normal tissues, the primary cilium coordinates a series of signal transduction pathways, including Hedgehog, Wnt, PDGFRalpha and integrin signaling. In the kidney, the primary cilium may function as a mechano-, chemo- and osmosensing unit that probes the extracellular environment and transmits signals to the cell via, e.g., polycystins, which depend on ciliary localization for appropriate function. Indeed, hypomorphic mutations in the mouse ift88 (previously called Tg737) gene, which encodes a ciliogenic intraflagellar transport protein, result in malformation of primary cilia, and in the collecting ducts of kidney tubules this is accompanied by development of autosomal recessive polycystic kidney disease (PKD). While PKD was one of the first diseases to be linked to dysfunctional primary cilia, defects in this organelle have subsequently been associated with many other phenotypes, including cancer, obesity, diabetes as well as a number of developmental defects. Collectively, these disorders of the cilium are now referred to as the ciliopathies. In this review, we provide a brief overview of the structure and function of primary cilia and some of their roles in coordinating signal transduction pathways in mammalian development, health and disease.",
            "question": "Which is the most common disease attributed to malfunction or absence of primary cilia?",
            "answers": {
                "answer_start": 1259,
                "text": "polycystic kidney disease (PKD)"
            }
        },
        {
            "context": "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 18,
                "text": "xa"
            }
        },
        {
            "context": "Replication-biased genome organisation in the crenarchaeon Sulfolobus. BACKGROUND: Species of the crenarchaeon Sulfolobus harbour three replication origins in their single circular chromosome that are synchronously initiated during replication. RESULTS: We demonstrate that global gene expression in two Sulfolobus species is highly biased, such that early replicating genome regions are more highly expressed at all three origins. The bias by far exceeds what would be anticipated by gene dosage effects alone. In addition, early replicating regions are denser in archaeal core genes (enriched in essential functions), display lower intergenic distances, and are devoid of mobile genetic elements. CONCLUSION: The strong replication-biased structuring of the Sulfolobus chromosome implies that the multiple replication origins serve purposes other than simply shortening the time required for replication. The higher-level chromosomal organisation could be of importance for minimizing the impact of DNA damage, and may also be linked to transcriptional regulation.",
            "question": "Do archaeal genomes contain one or multiple origins of replication?",
            "answers": {
                "answer_start": 799,
                "text": "multiple"
            }
        },
        {
            "context": "Differential regulation of M3/6 (DUSP8) signaling complexes in response to arsenite-induced oxidative stress. Mitogen-activated protein kinase (MAPK) cascades are involved in the regulation of cellular proliferation, differentiation, survival, apoptosis, as well as in inflammatory responses. Signal intensity and duration have been recognized as crucial parameters determining MAPK signaling output. Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. The JNK family consists of three genes, giving rise to at least ten different splice variants. Some functional differences between these gene products have been demonstrated, but the underlying molecular mechanisms and the roles of individual splice variants are still incompletely understood. We have investigated the interaction of M3/6 with JNK isoforms, as well as scaffold proteins of the JNK interacting protein (JIP) family, in order to elucidate the contribution of M3/6 to the regulation of distinct JNK signaling modules. M3/6 exhibited stronger binding towards JNK1β and JNK2α isoforms and this was reflected in higher enzymatic activity towards JNK2α2 when compared to JNK1α1 in vitro. After activation of the pathway by exposure of cells to arsenite, the interaction of M3/6 with JNK1α and JNK3 was enhanced, whereas that with JNK1β or JNK2α decreased. The modulation of binding affinities was found to be independent of JNK-mediated M3/6 phosphorylation. Furthermore, arsenite treatment resulted in an inducible recruitment of M3/6 to JNK-interacting protein 3 (JIP3) scaffold complexes, while its interaction with JIP1 or JIP2 was constitutive. The presented data suggest an isoform-specific role for the M3/6 phosphatase and the dynamic targeting of M3/6 towards distinct JNK-containing signaling complexes.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 629,
                "text": "JNK"
            }
        },
        {
            "context": "Cellular mechanisms of beta-amyloid production and secretion. The major constituent of senile plaques in Alzheimer's disease is a 42-aa peptide, referred to as beta-amyloid (Abeta). Abeta is generated from a family of differentially spliced, type-1 transmembrane domain (TM)-containing proteins, called APP, by endoproteolytic processing. The major, relatively ubiquitous pathway of APP metabolism in cell culture involves cleavage by alpha-secretase, which cleaves within the Abeta sequence, thus precluding Abeta formation and deposition. An alternate secretory pathway, enriched in neurons and brain, leads to cleavage of APP at the N terminus of the Abeta peptide by beta-secretase, thus generating a cell-associated beta-C-terminal fragment (beta-CTF). A pathogenic mutation at codons 670/671 in APP (APP \"Swedish\") leads to enhanced cleavage at the beta-secretase scissile bond and increased Abeta formation. An inhibitor of vacuolar ATPases, bafilomycin, selectively inhibits the action of beta-secretase in cell culture, suggesting a requirement for an acidic intracellular compartment for effective beta-secretase cleavage of APP. beta-CTF is cleaved in the TM domain by gamma-secretase(s), generating both Abeta 1-40 (90%) and Abeta 1-42 (10%). Pathogenic mutations in APP at codon 717 (APP \"London\") lead to an increased proportion of Abeta 1-42 being produced and secreted. Missense mutations in PS-1, localized to chromosome 14, are pathogenic in the majority of familial Alzheimer's pedigrees. These mutations also lead to increased production of Abeta 1-42 over Abeta 1-40. Knockout of PS-1 in transgenic animals leads to significant inhibition of production of both Abeta 1-40 and Abeta 1-42 in primary cultures, indicating that PS-1 expression is important for gamma-secretase cleavages. Peptide aldehyde inhibitors that block Abeta production by inhibiting gamma-secretase cleavage of beta-CTF have been discovered.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 1313,
                "text": "ad"
            }
        },
        {
            "context": "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 1441,
                "text": "ZEB2"
            }
        },
        {
            "context": "Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. BACKGROUND: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (A beta) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce A beta formation may be of therapeutic benefit. OBJECTIVE: This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139). METHODS: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. RESULTS/CONCLUSIONS: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain A beta in a dose-dependent manner in animals and plasma and cerebrospinal fluid A beta in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 489,
                "text": "semagacestat"
            }
        },
        {
            "context": "PPADS, a P2X receptor antagonist, as a novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger in guinea pig airway smooth muscle. The Na(+)/Ca(2+)exchanger (NCX) principal function is taking 1 Ca(2+) out of the cytoplasm and introducing 3 Na(+). The increase of cytoplasmic Na(+) concentration induces the NCX reverse mode (NCX(REV)), favoring Ca(2+) influx. NCX(REV) can be inhibited by: KB-R7943 a non-specific compound that blocks voltage-dependent and store-operated Ca(2+) channels; SEA0400 that appears to be selective for NCX(REV), but difficult to obtain and SN-6, which efficacy has been shown only in cardiomyocytes. We found that PPADS, a P2X receptor antagonist, acts as a NCX(REV) inhibitor in guinea pig tracheal myocytes. In these cells, we characterized the NCX(REV) by substituting NaCl and NaHCO(3) with LiCl, resulting in the increase of the intracellular Ca(2+) concentration ([Ca(2+)]i) using fura 2-AM. We analyzed 5 consecutive responses of the NCX(REV) every 10 min, finding no differences among them. To evaluate the effect of different NCX(REV) blockers, concentration response curves to KB-R7943 (1, 3.2 and 10 μM), and SN-6 (3.2, 10 and 30 μM) were constructed, whereas PPADS effect was characterized as time- and concentration-dependent (1, 3.2, 10 and 30 μM). PPADS had similar potency and efficacy as KB-R7943, whereas SN-6 was the least effective. Furthermore, KCl-induced contraction, sensitive to D600 and nifedipine, was blocked by KB-R7943, but not by PPADS. KCl-induced [Ca(2+)]i increment in myocytes was also significantly decreased by KBR-7943 (10 μM). Our results demonstrate that PPADS can be used as a reliable pharmacological tool to inhibit NCX(REV), with the advantage that it is more specific than KB-R7943 because it does not affect L-type Ca(2+) channels.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 536,
                "text": "NCX"
            }
        },
        {
            "context": "The clinical presentation of Ehlers-Danlos syndrome. Ehlers-Danlos syndrome (EDS), a heterogeneous group of inheritable connective tissue disorders, is attributed to mutations in connective tissue genes. These mutations cause defects in collagen. Collagen, a connective tissue protein that acts like glue, gives strength to the body and provides support and elasticity for movement. Thus, the altered gene affects the mechanical properties of skin, joints, ligaments, and blood vessels. Ehlers-Danlos syndrome is transmitted through autosomal dominant, autosomal recessive, or x-linked patterns of inheritance. The life expectancy of an affected infant varies with the type of EDS. This article provides an overview of the 6 major classifications of EDS, their unique clinical presentations, a focused physical assessment guide, considerations for nursing care, and resources for parents. Ehlers-Danlos syndrome can be a potentially debilitating syndrome. It requires preventative and protective measures starting at birth to preserve joint function to improve infant outcomes. Caring for patients with EDS requires an understanding of the potential associated complications to help minimize the physical and emotional impact of the syndrome and improve the quality of life for affected individuals.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 120,
                "text": "connective tissue"
            }
        },
        {
            "context": "Posttraumatic stress disorder in victims of the March 11 attacks in Madrid admitted to a hospital emergency room: 6-month follow-up. PURPOSE: To determine the change in prevalence of posttraumatic stress disorder (PTSD) symptoms in victims of the March 11 attacks and their relatives, 1 and 6 months after the attacks. SUBJECTS AND METHODS: Evaluation of PTSD symptoms using the Davidson Trauma Scale (DTS) and General Health Questionnaire (GHQ) in a sample of 56 patients admitted to an emergency room of a general hospital, and assessment of PTSD symptoms in relatives of the patients. RESULTS: At Month 1, 41.1% of patients (31.3% of males and 54.2% of females) presented with PTSD. At Month 6, this figure was 40.9% (30.4% of males and 52.4% of females). There was a significant improvement in perception of health among females between Month 1 and Month 6. Relatives presented similar DTS scores at baseline and at 6 months. DISCUSSION: We verified that rates of PTSD did not vary substantively between the two evaluations. PTSD symptoms positively correlated with psychological health involvement. This correlation points out that both PTSD symptoms and subjective general health involvement are part of the psychological response to trauma. CONCLUSION: The prevalence of PTSD symptoms was high and remained stable between Month 1 and Month 6, while subjective perception of health improved significantly.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 544,
                "text": "PTSD"
            }
        },
        {
            "context": "Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). PURPOSE: To investigate refractive, topometric, pachymetric, and visual rehabilitation changes induced by anterior surface normalization for keratoconus by partial topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking. METHODS: Two hundred thirty-one keratoconic cases subjected to the Athens Protocol procedure were studied for visual acuity, keratometry, pachymetry, and anterior surface irregularity indices up to 3 years postoperatively by Scheimpflug imaging (Oculus Optikgeräte GmbH, Wetzlar, Germany). RESULTS: Mean visual acuity changes at 3 years postoperatively were +0.38 ± 0.31 (range: -0.34 to +1.10) for uncorrected distance visual acuity and +0.20 ± 0.21 (range: -0.32 to +0.90) for corrected distance visual acuity. Mean K1 (flat meridian) keratometric values were 46.56 ± 3.83 diopters (D) (range: 39.75 to 58.30 D) preoperatively, 44.44 ± 3.97 D (range: 36.10 to 55.50 D) 1 month postoperatively, and 43.22 ± 3.80 D (range: 36.00 to 53.70 D) up to 3 years postoperatively. The average Index of Surface Variance was 98.48 ± 43.47 (range: 17 to 208) pre-operatively and 76.80 ± 38.41 (range: 7 to 190) up to 3 years postoperatively. The average Index of Height Decentration was 0.091 ± 0.053 μm (range: 0.006 to 0.275 μm) preoperatively and 0.057 ± 0.040 μm (range: 0.001 to 0.208 μm) up to 3 years postoperatively. Mean thinnest corneal thickness was 451.91 ± 40.02 μm (range: 297 to 547 μm) preoperatively, 353.95 ± 53.90 μm (range: 196 to 480 μm) 1 month postoperatively, and 370.52 ± 58.21 μm (range: 218 to 500 μm) up to 3 years postoperatively. CONCLUSIONS: The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. Progressive potential for long-term flattening validates using caution in the surface normalization to avoid overcorrection.",
            "question": "Which eye condition is managed by the athens protocol?",
            "answers": {
                "answer_start": 1905,
                "text": "keratoconus"
            }
        },
        {
            "context": "EFFECT OF THE APOE ε4 ALLELE AND COMBAT EXPOSURE ON PTSD AMONG IRAQ/AFGHANISTAN-ERA VETERANS. BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans. METHOD: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report. RESULTS: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5). CONCLUSIONS: Although preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 1303,
                "text": "PTSD"
            }
        },
        {
            "context": "Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells. Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non-small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G(0)-G(1) and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I-dependent Akt phosphorylation and epidermal growth factor-dependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 773,
                "text": "lung"
            }
        },
        {
            "context": "TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules. Summary: The molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton. Contact: luis.sanchez-pulido@igmm.ed.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "What is the function of the TMEM132 genes?",
            "answers": {
                "answer_start": 864,
                "text": "cellular adhesion function"
            }
        },
        {
            "context": "Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 18,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Atrial fibrillation in the 21st century: a current understanding of risk factors and primary prevention strategies. Atrial fibrillation (AF) is the most common arrhythmia worldwide, and it has a significant effect on morbidity and mortality. It is a significant risk factor for stroke and peripheral embolization, and it has an effect on cardiac function. Despite widespread interest and extensive research on this topic, our understanding of the etiology and pathogenesis of this disease process is still incomplete. As a result, there are no set primary preventive strategies in place apart from general cardiology risk factor prevention goals. It seems intuitive that a better understanding of the risk factors for AF would better prepare medical professionals to initially prevent or subsequently treat these patients. In this article, we discuss widely established risk factors for AF and explore newer risk factors currently being investigated that may have implications in the primary prevention of AF. For this review, we conducted a search of PubMed and used the following search terms (or a combination of terms): atrial fibrillation, metabolic syndrome, obesity, dyslipidemia, hypertension, type 2 diabetes mellitus, omega-3 fatty acids, vitamin D, exercise toxicity, alcohol abuse, and treatment. We also used additional articles that were identified from the bibliographies of the retrieved articles to examine the published evidence for the risk factors of AF.",
            "question": "Which is the most prevalent form of arrhythmia worldwide?",
            "answers": {
                "answer_start": 137,
                "text": "AF"
            }
        },
        {
            "context": "Postictal generalized EEG suppression and SUDEP: a review. Sudden unexpected death in epilepsy (SUDEP) remains a leading cause of epilepsy-related death, and yet, its pathogenic mechanisms remain ill-defined. Although epidemiological studies of SUDEP in heterogenous populations have established a number of clinical associations, evaluation and stratification of individual risk remains difficult. Thus, potential markers as predictors of risk of SUDEP are important not only clinically but also for research on SUDEP prevention. Recordings from rare monitored cases of SUDEP demonstrate postictal generalized EEG suppression after terminal seizures, raising expectations that postictal generalized EEG suppression may identify individuals at higher risk. In this review, we consider the literature on postictal generalized EEG suppression and evaluate its relevance and utility as a possible marker of SUDEP.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 59,
                "text": "Sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration. Disturbance of intracellular trafficking plays a major role in several neurodegenerative disorders including Alzheimer or Parkinson's disease. The Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and increased susceptibility to infection with various degrees of involvement of the nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) mutagenesis screen, we identified the first murine missense mutation in the lysosomal trafficking regulator gene (Lyst(Ing3618)) located at a highly conserved position in the WD40 protein domain. Nearly all described human Lyst alleles lead to protein truncation and fatal childhood CHS. Only four different missense mutations have been reported in patients with adolescent or adult forms of CHS involving the nervous system. Interestingly, the Lyst(Ing3618) model presents with a predominant neurodegenerative phenotype with progressive degeneration and loss of Purkinje cells and lacks severe impairment of the immune system. Therefore, the Lyst(Ing3618 )allele could represent a new model for adult CHS with neurological impairment. It could also provide an important tool to elucidate the role of neuronal lysosomal trafficking in the pathophysiology of neurodegeneration.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 261,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) and Fatal Pneumonia with Pediatric Deaths in Krasnoyarsk, Siberian Russia: Unique MRSA's Multiple Virulence Factors, Genome, and Stepwise Evolution. Methicillin-resistant Staphylococcus aureus (MRSA) is a common multidrug-resistant (MDR) pathogen. We herein discussed MRSA and its infections in Krasnoyarsk, Siberian Russia between 2007 and 2011. The incidence of MRSA in 3,662 subjects was 22.0% and 2.9% for healthcare- and community-associated MRSA (HA- and CA-MRSA), respectively. The 15-day mortality rates for MRSA hospital- and community-acquired pneumonia (HAP and CAP) were 6.5% and 50%, respectively. MRSA CAP cases included pediatric deaths; of the MRSA pneumonia episodes available, > 27.3% were associated with bacteremia. Most cases of HA-MRSA examined exhibited ST239/spa3(t037)/SCCmecIII.1.1.2 (designated as ST239Kras), while all CA-MRSA cases examined were ST8/spa1(t008)/SCCmecIV.3.1.1(IVc) (designated as ST8Kras). ST239Kras and ST8Kras strongly expressed cytolytic peptide (phenol-soluble modulin α, PSMα; and δ-hemolysin, Hld) genes, similar to CA-MRSA. ST239Kras pneumonia may have been attributed to a unique set of multiple virulence factors (MVFs): toxic shock syndrome toxin-1 (TSST-1), elevated PSMα/Hld expression, α-hemolysin, the staphylococcal enterotoxin SEK/SEQ, the immune evasion factor SCIN/SAK, and collagen adhesin. Regarding ST8Kras, SEA was included in MVFs, some of which were common to ST239Kras. The ST239Kras (strain OC3) genome contained: a completely unique phage, φSa7-like (W), with no att repetition; S. aureus pathogenicity island SaPI2R, the first TSST-1 gene-positive (tst+) SaPI in the ST239 lineage; and a super copy of IS256 ( > 22 copies/genome). ST239Kras carried the Brazilian SCCmecIII.1.1.2 and United Kingdom-type tst. ST239Kras and ST8Kras were MDR, with the same levofloxacin resistance mutations; small, but transmissible chloramphenicol resistance plasmids spread widely enough to not be ignored. These results suggest that novel MDR and MVF+ HA- and CA-MRSA (ST239Kras and ST8Kras) emerged in Siberian Russia (Krasnoyarsk) associated with fatal pneumonia, and also with ST239Kras, a new (Siberian Russian) clade of the ST239 lineage, which was created through stepwise evolution during its potential transmission route of Brazil-Europe-Russia/Krasnoyarsk, thereby selective advantages from unique MVFs and the MDR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 82,
                "text": "MRSA"
            }
        },
        {
            "context": "Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait. We report a case of fulminant liver failure resulting in emergent liver transplantation following 3 weeks of nausea, vomiting, and malaise from Jamaican Vomiting Sickness. Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks. It is characterized by acute gastrointestinal illness and hypoglycemia. In severe cases, central nervous system depression can occur. In previous studies, histologic sections taken from patients with Jamaican Vomiting Sickness have shown hepatotoxicity similar to that seen in Reye syndrome and/or acetaminophen toxicity. We highlight macroscopic and microscopic changes in the liver secondary to hepatoxicity of Ackee fruit versus those caused by a previously unknown sickle cell trait. We discuss the clinical variables and the synergistic hepatotoxic effect of Ackee fruit and ischemic injury from sickled red blood cells, causing massive hepatic necrosis in this patient.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 348,
                "text": "Ackee fruit"
            }
        },
        {
            "context": "Carboxyl terminus of hsc70-interacting protein (CHIP) can remodel mature aryl hydrocarbon receptor (AhR) complexes and mediate ubiquitination of both the AhR and the 90 kDa heat-shock protein (hsp90) in vitro. The regulation of the aryl hydrocarbon receptor (AhR) protein levels has been an area of keen interest, given its important role in mediating the cellular adaptation and toxic response to several environmental pollutants. The carboxyl terminus of hsc70-interacting protein (CHIP) ubiquitin ligase was previously associated with the regulation of the aryl hydrocarbon receptor, although the mechanisms were not directly demonstrated. In this study, we established that CHIP could associate with the AhR at cellular levels of these two proteins, suggesting a potential role for CHIP in the regulation of the AhR complex. The analysis of the sucrose-gradient-fractionated in vitro translated AhR complexes revealed that CHIP can mediate hsp90 ubiquitination while cooperating with unidentified factors to promote the ubiquitination of mature unliganded AhR complexes. In addition, the immunophilin-like protein XAP2 was able to partially protect the AhR from CHIP-mediated ubiquitination in vitro. This protection required the direct interaction of the XAP2 with the AhR complex. Surprisingly, CHIP silencing in Hepa-1c1c7 cells by siRNA methods did not reveal the function of CHIP in the AhR complex, because it did not affect well-characterized activities of the AhR nor affect its steady-state protein levels. However, the presence of potential compensatory mechanisms may be confounding this particular observation. Our results suggest a model where the E3 ubiquitin ligase CHIP cooperates with other ubiquitination factors to remodel native AhR-hsp90 complexes and where co-chaperones such as the XAP2 may affect the ability of CHIP to target AhR complexes for ubiquitination.",
            "question": "Which is the E3 ubiquitin ligase of Hsp90?",
            "answers": {
                "answer_start": 0,
                "text": "Carboxyl terminus of hsc70-interacting protein (CHIP)"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 997,
                "text": "xa"
            }
        },
        {
            "context": "Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 380,
                "text": "5-HT2A"
            }
        },
        {
            "context": "The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. The Sotos syndrome gene product, NSD1, is a SET domain histone methyltransferase that primarily dimethylates nucleosomal histone H3 lysine 36 (H3K36). To date, the intrinsic properties of NSD1 that determine its nucleosomal substrate selectivity and dimethyl H3K36 product specificity remain unknown. The 1.7 Å structure of the catalytic domain of NSD1 presented here shows that a regulatory loop adopts a conformation that prevents free access of H3K36 to the bound S-adenosyl-L-methionine. Molecular dynamics simulation and computational docking revealed that this normally inhibitory loop can adopt an active conformation, allowing H3K36 access to the active site, and that the nucleosome may stabilize the active conformation of the regulatory loop. Hence, our study reveals an autoregulatory mechanism of NSD1 and provides insight into the molecular mechanism of the nucleosomal substrate selectivity of this disease-related H3K36 methyltransferase.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 140,
                "text": "SET domain"
            }
        },
        {
            "context": "Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review. Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 110,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Community-acquired methicillin-resistant Staphylococcus aureus in southern New England children. OBJECTIVE: This study was performed to understand the epidemiology of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in southern New England children. METHODS: A retrospective review was conducted of the medical records of children 0 to 18 years old with MRSA isolated by the Rhode Island Hospital microbiology laboratory (Providence, RI) between 1997 and 2001. A case was classified as either health care-associated MRSA (HCA-MRSA) or CA-MRSA based on time of culture and other strict criteria. The spectrum of illness of the HCA-MRSA and CA-MRSA cases was compared, as were the antibiotic-susceptibility patterns of their isolates. Risk factors for CA-MRSA acquisition were identified, and molecular subtyping of selected isolates was performed. RESULTS: Between 1997 and 2001, S aureus was isolated from 1063 children. Of these children, 57 had MRSA. During this period, both the absolute number of MRSA cases and the proportion of S aureus cases due to MRSA rose more than threefold due to increases in both CA-MRSA and HCA-MRSA infections. Of the 57 MRSA cases, 23 (40%) were CA-MRSA. CA-MRSA patients were more likely to have skin/soft-tissue infections than HCA-MRSA patients (83% vs 38%). Risk factors for acquisition of MRSA including intrafamilial spread, frequent antibiotic exposure, and child-care attendance were identified in 8 of the 23 (35%) CA-MRSA patients. CA-MRSA isolates were more likely to be susceptible to non-beta-lactam antibiotics than HCA-MRSA isolates. All isolates were vancomycin susceptible. CONCLUSIONS: MRSA accounts for an increasing proportion of all pediatric S aureus infections in southern New England. A significant percentage of these cases are due to CA-MRSA. Pediatricians should have heightened suspicion for CA-MRSA in children with presumed S aureus infections, especially if they have skin/soft-tissue infections or risk factors for MRSA acquisition.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 234,
                "text": "MRSA"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome manifested by seizure in late childhood: a case report. The patient was a 19-year-old woman who presented with hemiatrophy and diminished superficial sensation on the left side of her body including her face. She had a past history of tonic-clonic seizures accompanied by left hemiparesis in late childhood. Brain CT demonstrated dilatation of the frontal sinus, calvarial thickening, cerebral hemiatrophy and dilatation of the lateral ventricle on the right side. Brain MRI showed atrophy of the right cerebrum and midbrain and dilatation of the lateral ventricle on T1-weighted images, as well as a high signal intensity area from the parietal to the occipital lobe on T2-weighted images. These findings are suggestive of an episode that may have caused a transient ischemia through the right cerebral hemisphere after the intrauterine period.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 415,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 511,
                "text": "xa"
            }
        },
        {
            "context": "Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1407,
                "text": "FSHD"
            }
        },
        {
            "context": "Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 195,
                "text": "ALS"
            }
        },
        {
            "context": "Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. A single cell has the potential to kill an entire human being. Efforts to cure cancer are limited by survival of individual cancer cells despite immune surveillance and toxic therapies. Understanding the intricate network of pathways that maintain cellular homeostasis and mediate stress response or default into cell death is critical to the development of strategies to eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein response (UPR) are cellular pathways that degrade and recycle excess or damaged proteins to maintain cellular homeostasis and survival. This review will discuss autophagy and how it is integrated with proteasomal degradation and UPR to govern cell fate through restoration of cellular homeostasis or default into the apoptotic cell death pathway. The first response of autophagy is macroautophagy, which sequesters cytoplasm including organelles inside double-membraned autophagosome vesicles that fuse with lysosomes to degrade and recycle the contents. Ubiquitination patterns on proteins targeted for degradation determine whether adapter proteins will bring them to developing autophagosomes or to proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. These two processes and the lesser understood microautophagy, which involves direct engulfment of proteins into lysosomes, occur at basal and induced levels. Insufficient proteasome function or ER stress induction of UPR can induce autophagy, which can mitigate damage and stress. If this network is incapable of repairing the damage or overcoming continued stress, the default pathway of apoptosis is engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics has led to clinical trials investigating combinations of HCQ (hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. Further study of the complex integration of autophagy, proteasomal degradation, UPR and apoptosis is likely to provide additional targets for our fight against cancer. This article is part of a Special Issue entitled \"Apoptosis: Four Decades Later\".",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 1287,
                "text": "chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "[STI571 (Glivec)--a new drug for the treatment of chronic myeloid leukemia]. Chronic myeloid leukaemia (CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase. In the chronic phase of the disease, normal peripheral blood values are achieved within the first month of treatment in the large majority of patients and in many patients also a cytogenic response within the following months. The results in the advanced phase are far less favourable, which is explained by the development of resistance owing to reactivation of the BCR-ABL signal transduction. Side effects are primarily nausea, vomiting, various rashes, oedema, most often in the periorbital region, and musculoskeletal symptoms, including muscle cramps. Perspectives for treatment with STI571 are described, as are combinations with alpha-interferon and other cytostatics with a synergistic profile.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 551,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children's Oncology Group Phase I Consortium Study (ADVL1112). PURPOSE: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors. EXPERIMENTAL DESIGN: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle. RESULTS: Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. CONCLUSIONS: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 283,
                "text": "telomerase"
            }
        },
        {
            "context": "Molecular interaction of NADPH oxidase 1 with betaPix and Nox Organizer 1. It is well established that growth-factor-induced reactive oxygen species (ROS) act as second messengers in cell signaling. We have previously reported that betaPix, a guanine nucleotide exchange factor for Rac, interacts with NADPH oxidase 1 (Nox1) leading to EGF-induced ROS generation. Here, we report the identification of the domains of Nox1 and betaPix responsible for the interaction between the two proteins. GST pull-down assays show that the PH domain of betaPix binds to the FAD-binding region of Nox1. We also show that overexpression of the PH domain of betaPix results in inhibition of superoxide anion generation in response to EGF. Additionally, NADPH oxidase Organizer 1 (NoxO1) is shown to interact with the NADPH-binding region of Nox1. These results suggest that the formation of the complex consisting of Nox1, betaPix, and NoxO1 is likely to be a critical step in EGF-induced ROS generation.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 825,
                "text": "Nox1"
            }
        },
        {
            "context": "Ackee (Blighia sapida) hypoglycin A toxicity: dose response assessment in laboratory rats. Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome. Hypoglycin A toxicity in this study was determined by feeding male and female Sprague-Dawley rats a control diet and ackee diets that contained 4-3840 ppm of hypoglycin. The fixed dose method was used to quantify the acute toxic dose of hypoglycin A and was determined by feeding a diet consisting of the lowest hypoglycin A concentration; this was increased to the next highest dose after 24h until toxicity was observed. The maximum tolerated dose (MTD) of hypoglycin A was determined by feeding rats the ackee and control diets over a 30-day period. The acute toxic dose for male and female rats was 231.19+/-62.5 5mg hypoglycinA/kgBW and 215.99+/-63.33 mg hypoglycinA/kgBW, respectively. This was considerably greater than the dose of 100 mg hypoglycin/kgBW reported in a previous study when aqueous hypoglycin was administered orally. The MTD of hypoglycin A in both male and female rats was 1.50+/-0.07 mg hypoglycinA/kgBW/day. These findings suggest that the form in which hypoglycin in ackee is administered could affect the toxicological properties it exhibits. Therefore, for the purpose of a hazard assessment, it may be best administered within the matrix of the fruit, which is the form that humans consume it.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 128,
                "text": "ackee fruit"
            }
        },
        {
            "context": "Studies of complex Ph translocations in cases with chronic myelogenous leukemia and one with acute lymphoblastic leukemia. The BCR/ABL gene fusion, the hallmark of chronic myelogenous leukemia (CML) is generated in 2-10% of patients by a variant Ph translocation involving 9q34, 22q11.2, and one or more additional genomic regions. The objective of this study was the characterization by conventional and molecular cytogenetics of complex variant Ph translocations present at diagnosis. FISH studies were performed in 7 cases using the LSI BCR/ABL ES probe allowing the detection of the fusion BCR/ABL gene on the Ph chromosome in all of them and 9q34 deletions in 2 cases. Three cryptic complex rearrangements were detected by FISH studies. The third and the fourth chromosome regions involved in the 8 complex variant translocations were: 1q21, 1p36, 5q31, 11q13, 12q13, 12p13, and 20q12. In conclusion, FISH studies have been useful in the detection of the BCR/ABL rearrangements and 9q34 deletions, and to identify complex rearrangements that differ from the ones previously established by conventional cytogenetics.",
            "question": "Which gene fusion is the result of the \"philadelphia translocation\" or the \"philadelphia chromosome\" mutation?",
            "answers": {
                "answer_start": 123,
                "text": "The BCR/ABL gene fusion"
            }
        },
        {
            "context": "Protrusio acetabuli in Marfan's syndrome. Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems. Revised criteria for the clinical diagnosis of Marfan's syndrome regard skeletal involvement as a major criterion if at least four of eight typical skeletal manifestations are present, one of which is protrusio acetabuli. Using Kulman's method to determine the presence of protrusio, we analysed the pelvic X-rays of 15 patients with Marfan's syndrome and 15 controls. Protrusio was present in 47% (7/15) of Marfan patients, compared with 7% (1/15) of controls (P = 0.035). Using the revised criteria, the presence of protrusio would have affected the final diagnosis of Marfan's syndrome in only one patient out of 15. Therefore, we recommend that a pelvic X-ray is reserved for those cases in which the presence of protrusio will alter the final diagnosis. With regard to the radiological assessment of protrusio, in our opinion this can be performed simply and reliably using the position of the acetabular line alone.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 97,
                "text": "connective tissue"
            }
        },
        {
            "context": "The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.",
            "question": "Which peptide plays a pivotal role in human cystatin C fibrillization?",
            "answers": {
                "answer_start": 767,
                "text": "LQVVR"
            }
        },
        {
            "context": "Allan-Herndon-Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels. Allan-Herndon-Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels. Mutation was also detected, although in the heterozygous state, in three females showing thyroid hormone levels in the normal range. Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 913,
                "text": "thyroid"
            }
        },
        {
            "context": "Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis. The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 157,
                "text": "MC1R"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 1153,
                "text": "chromosome XII"
            }
        },
        {
            "context": "A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 488,
                "text": "LPIN2"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 1090,
                "text": "coilin"
            }
        },
        {
            "context": "Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay. BACKGROUND: Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index. METHODS: We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsy-proven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14). RESULTS: Of thirty deregulated proteins between SLE and the healthy controls (P  < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (P  < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (P  < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (P  < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease. CONCLUSIONS: This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.",
            "question": "Which method is Proseek based on?",
            "answers": {
                "answer_start": 564,
                "text": "proximity extension immunoassay"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 1487,
                "text": "miR-7"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 47,
                "text": "XK"
            }
        },
        {
            "context": "McLeod syndrome resulting from a novel XK mutation. McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1216,
                "text": "XK"
            }
        },
        {
            "context": "Defining the phenotype of restless legs syndrome/Willis-Ekbom disease (RLS/WED): a clinical and polysomnographic study. Clinical features variability between familial and sporadic restless legs syndrome/Willis-Ekbom disease (RLS/WED) has been previously reported. With this retrospective cohort study, we aimed to determine the clinical and polysomnographic characteristics of 400 RLS/WED patients. Patients with familial RLS/WED were significantly younger than sporadic RLS/WED, while clinical and polysomnographic characteristics were similar in both groups. No difference was found for the age-at-onset between idiopathic and secondary RLS/WED. Periodic limb movements (PLM) index and REM sleep time were higher in idiopathic RLS/WED. Time of onset of symptoms was in the evening or at bedtime in 28.04 and 37.80% of patients, respectively, while in 21.34% of patients onset was more than 1 h after sleep onset. Impulse control and compulsive behaviours (ICBs) were found in 13.29% patients on dopamine agonist therapy. Our analyses support the hypothesis that patients with a familial history of RLS/WED may have a genetic component. Nevertheless, the dichotomy between early and late onset disease seems to be less sharp than previously reported. A large proportion of RLS/WED patients can have atypical features, therefore making the diagnosis challenging. Some cases can be missed even when the patient refers to a sleep specialist, as revealed by the partial absence of daytime symptoms, the high comorbidity with insomnia and other sleep complaints and the high percentage of symptoms beginning after sleep onset. This draws attention on the importance of a careful evaluation of the patient, to recognize potentially treatable secondary forms of RLS/WED.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 180,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Random aneuploidy in CML patients at diagnosis and under imatinib treatment. Chronic myeloid leukemia (CML) is characterized by the presence of a BCR-ABL fusion gene, which is the result of a reciprocal translocation between chromosomes 9 and 22, and is cytogenetically visible as a shortened chromosome 22 (Philadelphia). Research during the past two decades has established that BCR-ABL is probably the pathogenetic pathway leading to CML, and that constitutive tyrosine kinase activity is central to BCR-ABL capacity to transform hematopoietic cells in vitro and in vivo. The tyrosine kinase inhibitor imatinib mesylate was introduced into the treatment regimen for CML in 1998. During the last few years, reports on chromosomal changes during imatinib treatment have been described. In this study, we evaluated the random aneuploidy rate with chromosomes 9 and 18 in bone marrow from treated and untreated patients. We found higher aneuploidy rates in both treated and untreated patients compared to the control group. In three patients who were treated with imatinib mesylate for more than 1.5 years, triploidy also appeared in some nuclei. To our knowledge, this is the first report on new chromosomal changes such as random aneuploidy and triploidy under imatinib treatment, but more studies are needed to investigate the long-term effect of the imatinib treatment on genetic instability.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 146,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Neuroimaging and clinical characterization of Sotos syndrome. Sotos syndrome is a well-known overgrowth syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial appearance and learning disability. This disorder is caused by mutations or deletions in NSD1 gene. The aim of this study is to examine the relationship between the neuroimaging and clinical features of children with Sotos syndrome. Six Turkish children with Sotos syndrome were followed up about 3-7 years. The diagnosis was confirmed with molecular genetic analysis. We identified the pathogenic NSD1 mutation including three novel in all patients. All the patients had a characteristic facial gestalt of Sotos syndrome consisting of triangular face with prominent forehead, frontoparietal sparseness of hair and small nose. However, the degree of psychomotor and intellectual development was variable. Severe learning defect and speech delay were remarkable in two patients. The neuroimaging analysis showed abnormalities in four of six patients including bilateral large ventricles, thinning of the corpus callosum and persistent cavum septum pellucidum et vergae. Typical craniofacial appearance is the primary finding for the diagnosis of the disease even in the infantile period. However, the degree of psychomotor and intellectual development is very variable and does not correlate with the neuroimaging findings.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 287,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 240,
                "text": "IgG4"
            }
        },
        {
            "context": "Delayed cell cycle progression from SEPW1 depletion is p53- and p21-dependent in MCF-7 breast cancer cells. Selenium (Se) is an essential redox-active trace element with close connections to cancer. Most of Se's biological functions have been attributed to the antioxidant properties of Se-containing proteins. However, the relative contribution of selenoproteins and small Se compounds in cancer protection is still a matter of debate. The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the \"guardian of the genome\". In response to genomic stresses, p53 causes cell cycle arrest to allow time for genomic damage to be repaired before cell division or induces apoptosis to eliminate irreparably damaged cells. Selenoprotein W (SEPW1) is a highly conserved small thioredoxin-like protein required for cell cycle progression. The present work shows that SEPW1 facilitates the G1 to S-phase transition by down-regulating expression of the cyclin-dependent kinase inhibitor p21. SEPW1 controls p21 by modulating levels of the p53 transcription factor, and this is associated with changes in phosphorylation of Ser-33 in p53. More work is needed to identify the mechanism by which SEPW1 regulates phosphorylation of Ser-33 and the kinase or phosphatase enzymes involved.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 458,
                "text": "p53"
            }
        },
        {
            "context": "Left hemisphere and male sex dominance of cerebral hemiatrophy (Dyke-Davidoff-Masson Syndrome). Although radiological findings of cerebral hemiatrophy (Dyke-Davidoff-Masson Syndrome) are well known, there is no systematic study about the gender and the affected side in this syndrome. Brain images in 26 patients (mean aged 11) with cerebral hemiatrophy were retrospectively reviewed. Nineteen patients (73.5%) were male and seven patients (26.5%) were female. Left hemisphere involvement was seen in 18 patients (69.2%) and right hemisphere involvement was seen in eight patients (30.8%). We conclude that male gender and left side involvement are frequent in cerebral hemiatrophy disease.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 130,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Critical assessment of proteome-wide label-free absolute abundance estimation strategies. There is a great interest in reliable ways to obtain absolute protein abundances at a proteome-wide scale. To this end, label-free LC-MS/MS quantification methods have been proposed where all identified proteins are assigned an estimated abundance. Several variants of this quantification approach have been presented, based on either the number of spectral counts per protein or MS1 peak intensities. Equipped with several datasets representing real biological environments, containing a high number of accurately quantified reference proteins, we evaluate five popular low-cost and easily implemented quantification methods (Absolute Protein Expression, Exponentially Modified Protein Abundance Index, Intensity-Based Absolute Quantification Index, Top3, and MeanInt). Our results demonstrate considerably improved abundance estimates upon implementing accurately quantified reference proteins; that is, using spiked in stable isotope labeled standard peptides or a standard protein mix, to generate a properly calibrated quantification model. We show that only the Top3 method is directly proportional to protein abundance over the full quantification range and is the preferred method in the absence of reference protein measurements. Additionally, we demonstrate that spectral count based quantification methods are associated with higher errors than MS1 peak intensity based methods. Furthermore, we investigate the impact of miscleaved, modified, and shared peptides as well as protein size and the number of employed reference proteins on quantification accuracy.",
            "question": "What does iBAQ stand for in proteomic analysis?",
            "answers": {
                "answer_start": 794,
                "text": "Intensity-Based Absolute Quantification"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 3384,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Transcription-associated mutation in Bacillus subtilis cells under stress. Adaptive (stationary phase) mutagenesis is a phenomenon by which nondividing cells acquire beneficial mutations as a response to stress. Although the generation of adaptive mutations is essentially stochastic, genetic factors are involved in this phenomenon. We examined how defects in a transcriptional factor, previously reported to alter the acquisition of adaptive mutations, affected mutation levels in a gene under selection. The acquisition of mutations was directly correlated to the level of transcription of a defective leuC allele placed under selection. To further examine the correlation between transcription and adaptive mutation, we placed a point-mutated allele, leuC427, under the control of an inducible promoter and assayed the level of reversion to leucine prototrophy under conditions of leucine starvation. Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels. This mutagenic response was not observed under conditions of exponential growth. Since transcription is a ubiquitous biological process, transcription-associated mutagenesis may influence evolutionary processes in all organisms.",
            "question": "In which phase of cell cycle does  stress-induced transcription-associated mutagenesis (TAM) occur?",
            "answers": {
                "answer_start": 85,
                "text": "stationary phase"
            }
        },
        {
            "context": "Excellent tolerability but relatively low initial clinical efficacy of telcagepant in migraine. In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. Telcagepant, thus, has excellent tolerability in migraine. Only a quarter (26%) (334/1307) of patients were, however, pain free after 2 hours, while 56% (729/1297) of patients had pain relief at 2 hours. Telcagepant 300 mg in one randomized clinical trial was equipotent to zolmitriptan 5 mg. Based on results from a meta-analysis, rizatriptan 10 mg (41%) and almotriptan (35%) seem superior to telcagepant (26%) for pain free at 2 hours whereas rizatriptan 10 mg (25%) showed no difference from telcagepant 300 mg (19 %) for sustained pain free (2-24 hours). The introduction of calcitonin gene-related peptide receptor antagonism in the acute treatment of migraine is a major step forward but so far mostly because of its specific mode of action and excellent tolerability.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 143,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers. OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0-∞) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-∞ and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope β of the regression lines being slightly less than 1 (slope β for AUC0-∞: 0.94, 95% CI: 0.90 - 0.97; slope β for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 91,
                "text": "SGLT2"
            }
        },
        {
            "context": "Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Jervell and Lange-Nielsen syndrome (MIM 220400; JLNS), is a rare form of profound congenital deafness combined with syncopal attacks and sudden death due to prolonged QTc; it is an autosomal recessive trait. After its first description in Norway in 1957, later reports from many other countries have confirmed its occurrence. Nowhere is the prevalence so high as in Norway, where we estimate a prevalence of at least 1:200,000. The KCNQ1 and KCNE1 proteins coassemble in a potassium channel, and mutations in either the KCNQ1 gene or the KCNE1 gene disrupt endolymph production in the stria vascularis in the cochlea, causing deafness. KCNQ1 seems to be the major gene in JLNS. Long QT syndrome (LQTS) is a separate disorder of either autosomal dominant or recessive inheritance caused by mutations in four different ion channel genes; KCNQ1 is the one most frequently involved. Some heterozygous carriers of JLNS mutations in either gene may suffer from prolonged QTc and be symptomatic LQTS patients with a need for appropriate medical treatment to prevent life-threatening cardiac arrhythmia. In general, frameshift/stop mutations cause JLNS, and missense/splice site mutations cause LQTS, but a precise genotype-phenotype correlation in LQTS and JLNS is not established, which complicates both genetic counseling and clinical risk evaluation in carriers. We review JLNS from a Norwegian perspective because of the unusually high prevalence, the genetic homogeneity associated with considerable mutational heterogeneity, and some evidence for recurrent mutational events as well as one founder mutation. We outline the clinical implications for investigation of deaf children and cases of sudden infant death syndrome as well as careful electrocardiographic monitoring of identified mutation carriers to prevent sudden death. Am. J. Med. Genet. (Semin. Med. Genet.) 89:137-146, 1999.",
            "question": "What is the mode of inheritance of  long QT  Jervell and Lange-Nielsen syndrome?",
            "answers": {
                "answer_start": 242,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "Tyr"
            }
        },
        {
            "context": "Experience with a gluten free diet in the treatment of linear IgA disease. A study was undertaken to determine whether the skin eruption of linear IgA disease (LAD) was gluten dependent. Six patients with LAD were treated with a gluten free diet (GFD) for an average period of 33 months (range 19-48). Although one patient with LAD had an enteropathy which was clearly gluten sensitive, there was no convincing evidence that the rash of any of the patients responded to a GFD. Four of the six patients showed no significant alteration in their drug requirements. The remaining 2 patients showed a fall in minimum drug requirement but there was no increase after gluten challenge indicating that they were entering spontaneous remission. This contrasts to the situation in dermatitis herpetiformis, where both the rash and the enteropathy are gluten dependent. These data add further to the evidence that LAD and dermatitis herpetiformis are separate entities.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 772,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Management of cutaneous erythrasma. Corynebacterium minutissimum is the bacteria that leads to cutaneous eruptions of erythrasma and is the most common cause of interdigital foot infections. It is found mostly in occluded intertriginous areas such as the axillae, inframammary areas, interspaces of the toes, intergluteal and crural folds, and is more common in individuals with diabetes mellitus than other clinical patients. This organism can be isolated from a cutaneous site along with a concurrent dermatophyte or Candida albicans infection. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis and intertrigo, and methods for differentiating include Wood's light examination and bacterial and mycological cultures. Erythromycin 250mg four times daily for 14 days is the treatment of choice and other antibacterials include tetracycline and chloramphenicol; however, the use of chloramphenicol is limited by bone marrow suppression potentially leading to neutropenia, agranulocytosis and aplastic anaemia. Further studies are needed but clarithromycin may be an additional drug for use in the future. Where there is therapeutic failure or intertriginous involvement, topical solutions such as clindamycin, Whitfield's ointment, sodium fusidate ointment and antibacterial soaps may be required for both treatment and prophylaxis. Limited studies on the efficacy of these medications exist, however, systemic erythromycin demonstrates cure rates as high as 100%. Compared with tetracyclines, systemic erythromycin has greater efficacy in patients with involvement of the axillae and groin, and similar efficacy for interdigital infections. Whitfield's ointment has equal efficacy to systemic erythromycin in the axillae and groin, but shows greater efficacy in the interdigital areas and is comparable with 2% sodium fusidate ointment for treatment of all areas. Adverse drug effects and potential drug interactions need to be considered. No cost-effectiveness data are available but there are limited data on cost-related treatment issues. A guideline is proposed for the detection, evaluation, treatment and prophylaxis of this cutaneous eruption.",
            "question": "Which bacteria causes erythrasma?",
            "answers": {
                "answer_start": 36,
                "text": "Corynebacterium minutissimum"
            }
        },
        {
            "context": "3-[2-[4-(4-[18F]Fluorobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3H-quinazolin-4-one . Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiologic roles as a neurotransmitter in the central nervous system (1). It is involved in regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which include several subtypes (4). There are three receptor subtypes within the G protein-coupled 5-HT2 receptor family: 5-HT2A, 5-HT2B, and 5-HT2C. 5-HT2A receptors are abundantly present in the cerebral cortex, basal forebrain, hippocampus, amygdala, dorsal thalamus, hypothalamus, superior colliculus, substantia nigra, pedunculopontine nucleus, legmental area, and myelencephalon (5). 5-HT2A receptors are involved in mediation of normal and psychotic states, working memory, regulation of GABAergic and cholinergic neuronal cells, sleep, peripheral pain, and cardiovascular functions. 5-HT2B receptors are found mainly in several peripheral tissues, such as the stomach, intestine, and pulmonary smooth muscle, and in the myocardium. In the brain, 5-HT2B receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT2C receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT2A receptors are implicated in several psychiatric disorders, such as schizophrenia, depression, and obsessive-compulsive disorder. Thus, there is a need for selective ligands to investigate the pharmacologic role of 5-HT2A receptors. There have been several studies to develop specific 5-HT2A radioligands, such as [11C]ketanserin (6), [18F]spiperone (7), [11C]methylspiperone ([11C]NMSP), and [18F]setoperone [PubMed], for positron emission tomography (PET) imaging. However, none has proven specific for 5-HT2A receptors because these compounds also bind to other receptors, such as dopamine receptors and 5-HT1 receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent inhibitor of 5-HT2A receptors with >100-fold selectivity over D2/3 receptors, 5-HT1A, 5-HT6, and 5-HT7 (8, 9). This led to the development of 3-[2-[4-(4-[18F]fluorobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3H-quinazolin-4-one ([18F]altanserin) as a useful tool for 5-HT2A receptor PET imaging in vivo (10).",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2416,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS: An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 254,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "PI3K-δ inhibitor produces long-lasting responses. In a phase I study, Gilead Sciences' PI3K-δ inhibitor idelalisib produced rapid tumor shrinkage-a response that lasted for 17 months on average-in about half of the 54 patients with chronic lymphocytic leukemia who participated.",
            "question": "What is the target protein of the drug Idelalisib?",
            "answers": {
                "answer_start": 87,
                "text": "PI3K-δ"
            }
        },
        {
            "context": "Rapamycin inhibits the growth of glioblastoma. The molecular target of rapamycin (mTOR) is up-regulated in glioblastoma (GBM) and this is associated with the rate of cell growth, stem cell proliferation and disease relapse. Rapamycin is a powerful mTOR inhibitor and strong autophagy inducer. Previous studies analyzed the effects of rapamycin in GBM cell lines. However, to our knowledge, no experiment was carried out to evaluate the effects of rapamycin neither in primary cells derived from GBM patients nor in vivo in brain GBM xenograft. These data are critical to get a deeper insight into the effects of such adjuvant therapy in GBM patients. In the present study, various doses of rapamycin were tested in primary cell cultures from GBM patients. These effects were compared with that obtained by the same doses of rapamycin in GBM cell lines (U87Mg). The effects of rapamycin were also evaluated in vivo, in brain tumors developed from mouse xenografts. Rapamycin, starting at the dose of 10nm inhibited cell growth both in U87Mg cell line and primary cell cultures derived from various GBM patients. When administered in vivo to brain xenografts in nude mice rapamycin almost doubled the survival time of mice and inhibited by more than 95% of tumor volume.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 82,
                "text": "mTOR"
            }
        },
        {
            "context": "Red hair is the null phenotype of MC1R. The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible for production of the darker eumelanin pigment and the tanning response. The MC1R gene has many polymorphisms, some of which have been linked to variation in pigmentation phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and p.D294 H alleles have been strongly associated with red hair, fair skin and increased skin cancer risk. These red hair colour (RHC) variants are relatively well described and are thought to result in altered receptor function, while still retaining varying levels of signaling ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W and p.D294 H alleles were able to partially rescue this phenotype, leading to the question of what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null alleles in human populations, they have only been found in the heterozygous state until now. We report here the first case of a homozygous MC1R null individual, phenotypic analysis indicates that red hair and fair skin is found in the absence of MC1R function.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 206,
                "text": "MC1R"
            }
        },
        {
            "context": "Designing calcium release channel inhibitors with enhanced electron donor properties: stabilizing the closed state of ryanodine receptor type 1. New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 452,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells. Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non-small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G(0)-G(1) and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I-dependent Akt phosphorylation and epidermal growth factor-dependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 758,
                "text": "non-small cell lung cancer"
            }
        },
        {
            "context": "The effects of gender and sex hormones on outcome in rheumatoid arthritis. Disease patterns in RA vary between the sexes; the condition is more commonly seen in women, who exhibit a more aggressive disease and a poorer long-term outcome. Men, however, are more likely than women to die from extra-articular complications of rheumatoid disease. This chapter discusses the outcome and mortality studies that substantiate these conclusions and then examines the possible mechanisms that may account for them, including the HLA system, seropositivity, compliance, response to therapy and pain threshold. In particular, sex and sex hormones emerge as independent risk factors in rheumatoid disease. The epidemiological evidence points towards a peak age of onset of RA at the time of the menopause in women and towards later in life in men. Premenopausal women may fare better than postmenopausal women with RA. The possible protective effects of the oral contraceptive pill and the dramatic amelioration with pregnancy are well documented. In vivo and in vitro studies have demonstrated that sex hormones interfere with a number of the putative processes involved in the pathogenesis of RA, including immunoregulation, interaction with inflammatory mediators and the cytokine system, and direct effects on cartilage itself. All these observations point towards the importance of gonadal hormones. However, trials on the potential therapeutic use of sex hormones in RA are limited and, as yet, disappointing. Further work is necessary to determine whether the roles of sex hormones are as central protagonists or just supporting cast in the complex arena of rheumatoid disease.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 161,
                "text": "women"
            }
        },
        {
            "context": "Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys. (S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the \"ON\" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 1025,
                "text": "L-DOPA"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 495,
                "text": "xa"
            }
        },
        {
            "context": "Differential involvement of COX1 and COX2 in the vasculopathy associated with the alpha-galactosidase A-knockout mouse. The lysosomal storage disorder Fabry disease is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal alpha-galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Endothelial dysfunction is associated with Fabry disease and excessive cellular Gb3. We previously demonstrated that excessive vascular Gb3 in a mouse model of Fabry disease, the Gla-knockout (Gla(-/0)) mouse, results in abnormal vascular function, which includes abnormal endothelium-dependent contractions, a vascular phenomenon known to involve cyclooxygenase (COX). Therefore, we hypothesized that the vasculopathy in the Gla knockout mouse may be due to a vasoactive COX-derived product. To test this hypothesis, vascular reactivity experiments were performed in aortic rings from wild-type (Gla(+/0)) and Gla(-/0) mice in the presence and absence of specific and nonspecific COX inhibitors. Specific inhibition of COX1 or COX2 in endothelium-intact rings from Gla(-/0) mice decreased overall phenylephrine contractility compared with untreated Gla(-/0) rings, whereas COX inhibitors had no effect on contractility in endothelium-denuded rings. Nonspecific inhibition of COX with indomethacin (10 micromol/l) or COX1 inhibition with valeryl salicylate (3 mmol/l) improved endothelial function in rings from Gla(-/0) mice, but COX2 inhibition with NS-398 (1 micromol/l) further increased endothelial dysfunction in rings from Gla(-/0) mice. These results suggest that, in the Gla(-/0) mice, COX1 and COX2 activity are increased and localized in the endothelium, producing vasopressor and vasorelaxant products, which contribute to the Fabry-related vasculopathy.",
            "question": "Which is the defective protein causing the lysosomal storage disease Fabry?",
            "answers": {
                "answer_start": 302,
                "text": "alpha-galactosidase A"
            }
        },
        {
            "context": "[Immune regulatory effect of citalopram on microglial cells]. OBJECTIVE: To investigate the effects of antidepressant citalopram on the gene expressions of tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β), and to discuss the impacts of citalopram on p38 and c-jun N-terminal kinase (JNK) of mitogen-activated protein kinase (MAPK) family in microglial cells. METHODS: BV2 cells were induced by lipopolysaccharide (LPS) to produce TNF-α and IL-1β. After pretreatment with citalopram (20 μmol/L) for 4 h, the mRNA levels of TNF-α and IL-1β were measured by quantitative real-time PCR (qRT-PCR); after pretreatment for 24 h, the protein levels of TNF-α and IL-1β were analyzed by ELISA; the effects of citalopram on the phosphorylation of p38MAPK and JNK were observed after pretreatment for 30 min. RESULTS: Citalopram significantly inhibited the mRNA and protein expressions of TNF-α and IL-1β, and the phosphorylation of p38MAPK and JNK. CONCLUSION: Citalopram may play the anti-inflammatory role by inhibiting MAPK pathway in microglial cells.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 301,
                "text": "JNK"
            }
        },
        {
            "context": "Congenital short QT syndrome. A review. Sudden cardiac death in individuals with structurally normal hearts accounts for approximately 20% of sudden cardiac death cases. Patients in this subgroup suffer from what has been named \"electrical diseases\" which are gradually coming into focus as inherited ion channelopathies, diseases of anchoring proteins or of intracellular calcium regulating proteins. From 1993, the Short QT Syndrome (SQTS) came to our attention, as a new inherited \"electrical disease\" associated with increased risk of sudden cardiac death and atrial fibrillation. Mutations of Ikr, Iks, Ikl channels cause dysfunctional Iks, Ikr, Ikl channels with an increase in the net outward K current leading to shortening of repolarization. This in turn leads to a shorter QT interval on the ECG and shorter atrial and ventricular refractory periods with increased susceptibility to VF and AF. There seems to be an autosomal dominant mode of inheritance. The clinical profile of SQTS consists of: family history of sudden cardiac death, personal history of palpitations, syncope, dizziness, resuscitated SCD, history of AF and documented VF. It is important to emphasize that SQTS is symptomatic from early age (new-born) to old age. Therefore, it is possible that SQTS accounts for some of the sudden infant death syndrome cases and for some cases of AF, especially lone AF. The only efficient treatment for ventricular arrhythmias is ICD, associated with drugs (Quinidine or Propaphenone) for AF prophylaxis and for reducing the number of ventricular arrhythmic events (and ICD discharges).",
            "question": "What is the mode of inheritance of short QT syndrome?",
            "answers": {
                "answer_start": 925,
                "text": "autosomal dominant mode of inheritance"
            }
        },
        {
            "context": "Whole-genome sequencing for high-resolution investigation of methicillin-resistant Staphylococcus aureus epidemiology and genome plasticity. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a major challenge in health care, yet the limited heterogeneity within this group hinders molecular investigations of related outbreaks. Pulsed-field gel electrophoresis (PFGE) has been the gold standard approach but is impractical for many clinical laboratories and is often replaced with PCR-based methods. Regardless, both approaches can prove problematic for identifying subclonal outbreaks. Here, we explore the use of whole-genome sequencing for clinical laboratory investigations of MRSA molecular epidemiology. We examine the relationships of 44 MRSA isolates collected over a period of 3 years by using whole-genome sequencing and two PCR-based methods, multilocus variable-number tandem-repeat analysis (MLVA) and spa typing. We find that MLVA offers higher resolution than spa typing, as it resolved 17 versus 12 discrete isolate groups, respectively. In contrast, whole-genome sequencing reproducibly cataloged genomic variants (131,424 different single nucleotide polymorphisms and indels across the strain collection) that uniquely identified each MRSA clone, recapitulating those groups but enabling higher-resolution phylogenetic inferences of the epidemiological relationships. Importantly, whole-genome sequencing detected a significant number of variants, thereby distinguishing between groups that were considered identical by both spa typing (minimum, 1,124 polymorphisms) and MLVA (minimum, 193 polymorphisms); this suggests that these more conventional approaches can lead to false-positive identification of outbreaks due to inappropriate grouping of genetically distinct strains. An analysis of the distribution of variants across the MRSA genome reveals 47 mutational hot spots (comprising ∼ 2.5% of the genome) that account for 23.5% of the observed polymorphisms, and the use of this selected data set successfully recapitulates most epidemiological relationships in this pathogen group.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 186,
                "text": "MRSA"
            }
        },
        {
            "context": "Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 156,
                "text": "7"
            }
        },
        {
            "context": "Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies. Drug-drug interactions are a major practical concern for physicians treating human immunodeficiency virus (HIV) because of the many medications that HIV-positive patients must take. Pharmacokinetic drug interactions can occur at different levels (absorption, distribution, metabolism, excretion) and are difficult to predict. Of all the processes that give rise to drug interactions, metabolism by cytochrome P450 (CYP3A) is the most frequent. Moreover, medications prescribed to HIV-positive patients may also be CYP3A inhibitors and inducers: Tipranavir, in the absence of ritonavir, is a CYP3A inducer, and ritonavir is a CYP3A inhibitor. Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized. This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral-treatment-related conditions such as hyperlipidemia, and side effects such as diarrhea.",
            "question": "Cytochrome p450 CYP3A is induced by rifampicin  and compounds used to treat what virus?",
            "answers": {
                "answer_start": 613,
                "text": "HIV"
            }
        },
        {
            "context": "Flumazenil: a benzodiazepine antagonist. The mechanism of action, pharmacokinetics, and use of flumazenil in benzodiazepine overdose, as well as in the management of other disease states, are reviewed. Flumazenil interacts at the central benzodiazepine receptor to antagonize or reverse the behavioral, neurologic, and electrophysiologic effects of benzodiazepine agonists and inverse agonists. Flumazenil has been studied for a variety of indications, including as an antidote to benzodiazepine overdose and for awakening of comatose patients, reversal of sedation after surgery and in critically ill patients, and management of hepatic encephalopathy. It improves the level of consciousness in patients with benzodiazepine overdose; however, resedation may occur within one to two hours after administration, so repeated doses or a continuous infusion may be required to maintain therapeutic efficacy. It appears to be effective in reversing sedation induced by midazolam or diazepam, and case reports suggest that it is useful in awakening comatose patients, although its clinical utility is questionable. Flumazenil has proved useful in reversing conscious sedation in critically ill patients, although response may be dose dependent. Animal models indicate that flumazenil is of some benefit in hepatic encephalopathy, but until well-designed clinical trials are conducted, hepatic encephalopathy must be considered an investigational indication for flumazenil. Adverse reactions include CNS manifestations, resedation, cardiovascular effects, seizures, and alterations in intracranial pressure and cerebral perfusion pressure. Hepatic dysfunction results in a substantial change in the pharmacokinetic profile of flumazenil; therefore, dosage adjustment may be necessary in patients with hepatic dysfunction or in those receiving medications that alter flumazenil metabolism. Flumazenil has been shown to reverse sedation caused by intoxication with benzodiazepines alone or benzodiazepines in combination with other agents, but it should not be used when cyclic antidepressant intoxication is suspected. It may be beneficial after surgery when benzodiazepines have been used as part of anesthesia and after a diagnostic or surgical procedure when assessment of CNS function is necessary.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1882,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Transcriptional regulation by MAP kinases. Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 2082,
                "text": "Jnk"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 554,
                "text": "Aurora A"
            }
        },
        {
            "context": "p53: a guide to apoptosis. Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 gene locus, while germ line mutations confer a high familial risk and are associated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein is often referred to as the \"guardian of the genome\" since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses. One of the most important functions of p53 is its ability to induce apoptosis, while disruption of this route can promote tumor progression and chemo resistance. Besides its ability to promote apoptosis through transcription dependent mechanisms, p53 may also be able to activate apoptosis independent of transcriptional regulation. Therefore, to ensure normal cell growth, p53 levels and activity are tightly regulated. Upon diverse forms of cellular stress the steady state levels and transcriptional activity of p53 are considerably increased. The stabilization and activation of p53 are a result of hindered inhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, while on the other hand activators such as HIPK2 and DYRK2 enhance the p53 response. The continually increasing understanding of the mechanisms of regulation of p53 may provide the basis for new drug designs that could eventually lead to therapeutics to reactivate p53 in cancers.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 231,
                "text": "p53"
            }
        },
        {
            "context": "Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 570,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "In silico analysis of DosR regulon proteins of Mycobacterium tuberculosis. One of the challenges faced by Mycobacterium tuberculosis (M. tuberculosis) in dormancy is hypoxia. DosR/DevR of M. tuberculosis is a two component dormancy survival response regulator which induces the expression of 48 genes. In this study, we have used DosR regulon proteins of M. tuberculosis H37Rv as the query set and performed a comprehensive homology search against the non-redundant database. Homologs were found in environmental mycobacteria, environmental bacteria and archaebacteria. Analysis of genomic context of DosR regulon revealed that they are distributed as nine blocks in the genome of M. tuberculosis with many transposases and integrases in their vicinity. Further, we classified DosR regulon proteins into eight functional categories. One of the hypothetical proteins Rv1998c could probably be a methylisocitrate lyase or a phosphonomutase. Another hypothetical protein, Rv0572 was found only in mycobacteria. Insights gained in this study can potentially aid in the development of novel therapeutic interventions.",
            "question": "How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?",
            "answers": {
                "answer_start": 292,
                "text": "48 genes"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1433,
                "text": "CD38"
            }
        },
        {
            "context": "Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. In cells of the immune system that are stimulated by antigen or antigen-antibody complexes, Ca(2+) entry from the extracellular medium is driven by depletion of endoplasmic reticulum Ca(2+) stores and occurs through specialized store-operated Ca(2+) channels known as Ca(2+)-release-activated Ca(2+) (CRAC) channels. The process of store-operated Ca(2+) influx is essential for short-term as well as long-term responses by immune-system cells. Short-term responses include mast cell degranulation and killing of target cells by effector cytolytic T cells, whereas long-term responses typically involve changes in gene transcription and include T and B cell proliferation and differentiation. Transcription downstream of Ca(2+) influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin. The importance of the Ca(2+)/calcineurin/NFAT signalling pathway for lymphocyte activation is underscored by the finding that the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca(2+) entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defence. We recently used a two-pronged genetic approach to identify Orai1 as the pore subunit of the CRAC channel. On the one hand, we initiated a positional cloning approach in which we utilised genome-wide single nucleotide polymorphism (SNP) mapping to identify the genomic region linked to the mutant gene in the SCID family described above. In parallel, we used a genome-wide RNAi screen in Drosophila to identify critical regulators of NFAT nuclear translocation and store-operated Ca(2+) entry. These approaches, together with subsequent mutational and electrophysiological analyses, converged to identify human Orai1 as a pore subunit of the CRAC channel and as the gene product mutated in the SCID patients.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 1106,
                "text": "calcineurin"
            }
        },
        {
            "context": "Friedreich's ataxia: clinical aspects and pathogenesis. Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 389,
                "text": "frataxin"
            }
        },
        {
            "context": "Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 156,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Multicenter evaluation of the Cepheid Xpert methicillin-resistant Staphylococcus aureus (MRSA) test as a rapid screening method for detection of MRSA in nares. The first U.S. multicenter clinical trial to assess the performance of the Cepheid Xpert MRSA assay (Xpert MRSA) was conducted. The assay is a qualitative test designed for the rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) directly from nares swabs. This novel test combines integrated nucleic acid extraction and automated real-time PCR for the detection of a MRSA-specific signature sequence. A total of 1,077 nares specimens were collected from seven geographically distinct health care sites across the United States with prevalence rates ranging from 5.2% to 44%. Nares specimens were tested by (i) the Xpert MRSA assay, (ii) direct culture on CHROMagar MRSA medium (direct CM culture), and (iii) broth-enriched culture (Trypticase soy broth with 6.5% sodium chloride) followed by plating onto CHROMagar MRSA medium (broth-enriched CM culture). When direct CM culture was designated the reference method, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA assay were 94.3%, 93.2%, 73.0%, and 98.8%, respectively. When broth-enriched CM culture was used as the reference method, the clinical sensitivity, specificity, PPV, and NPV of the Xpert MRSA assay were 86.3%, 94.9%, 80.5%, and 96.6%, respectively. The BD GeneOhm MRSA (BDGO) assay was performed as a comparative molecular method. No statistical performance differences were observed between the Xpert MRSA and BDGO assays when they were compared to culture methods. From this large-scale, multicenter clinical comparison, we conclude that the Xpert MRSA assay is a simple, rapid, and accurate method for performing active surveillance for MRSA in a variety of health care populations.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 145,
                "text": "MRSA"
            }
        },
        {
            "context": "The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals. DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron-sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 32,
                "text": "frataxin"
            }
        },
        {
            "context": "Pharmacokinetics, Safety, and Tolerability of Glecaprevir and Pibrentasvir in Healthy White, Chinese, and Japanese Adult Subjects. Glecaprevir and pibrentasvir are direct-acting antiviral agents being developed as combination therapy for the treatment of chronic hepatitis C virus infection. The aim of the present studies was to assess the effect of race and ethnicity (white, Han Chinese, Japanese) on the pharmacokinetics and safety of multiple oral doses of glecaprevir and pibrentasvir given alone and in combination. Two multiple-dose, single-center, phase 1 studies were conducted in healthy adult male and female subjects (n = 170) of respective Asian and white race/ethnicity. Glecaprevir (100, 200, 300, or 700 mg once daily) and pibrentasvir (80, 120, or 160 mg once daily) were administered alone for 7 days followed by the combination of both direct-acting antiviral agents for another 7 days. Intensive blood sampling was performed, and pharmacokinetic parameters were estimated by noncompartmental analyses. ANOVA was employed to evaluate for differences of steady-state glecaprevir and pibrentasvir exposures between Asian (Japanese or Han Chinese) and white subjects. Glecaprevir and pibrentasvir exposures in Han Chinese and Japanese were similar to those in whites across dose levels. The nonlinear dose-exposure relationships for glecaprevir and pibrentasvir were similar across Japanese, Han Chinese, and white subjects, and the safety profiles of the agents were comparable across these groups. The results of these studies demonstrate that race/ethnicity has no clinically meaningful impact on direct-acting antiviral agent exposures, safety, or tolerability of the glecaprevir and pibrentasvir combination. This is supported in part by the large global registration program of the pangenotypic, coformulated fixed-dose glecaprevir/pibrentasvir regimen and allows for inclusion of diverse ethnic populations.",
            "question": "Glecaprevir and Pibrentasvir are used for tratment of which disease?",
            "answers": {
                "answer_start": 263,
                "text": "hepatitis C virus infection"
            }
        },
        {
            "context": "Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. OBJECTIVE: In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). METHODS: The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED. RESULTS: Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions. CONCLUSIONS: These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 221,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1784,
                "text": "IL-1β"
            }
        },
        {
            "context": "Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; < 12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ∼25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 232,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 2123,
                "text": "fungi"
            }
        },
        {
            "context": "Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease. One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 144,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Sleepiness, fatigue, and risk of obstructive sleep apnea using the STOP-BANG questionnaire in multiple sclerosis: a pilot study. PURPOSE: This study aims: (1) to identify patients with multiple sclerosis (MS) who are at high risk for obstructive sleep apnea (OSA) by utilizing the STOP-BANG questionnaire and (2) to evaluate the relationship between OSA risk as determined by the STOP-BANG questionnaire and self-reported sleepiness and fatigue using the Epworth Sleepiness Scale (ESS) and the Fatigue Severity Scale (FSS), respectively. METHODS: A total of 120 consecutive patients presenting to the UC Davis Neurology MS Clinic were invited to participate in an anonymous survey. The exclusion criteria were: age <18 years, indefinite MS diagnosis, or incomplete survey. RESULTS: There were 103 subjects included in our study: 42% of subjects (n = 43) met the criteria for high-risk OSA, 69% of subjects (n = 71) screened high for fatigue (FSS > 4), but only 24 subjects (23%) screened high for excessive daytime sleepiness (ESS > 10). In males, 44% of the variation in ESS scores and 63% in FSS scores were explained by the STOP-BANG components. However, only 17% of the variation in ESS scores and 15% of the variation in FSS scores was explained by the STOP-BANG components in females. CONCLUSIONS: Over 40% of MS patients were identified as high risk for OSA based on the STOP-BANG questionnaire. The STOP-BANG questionnaire offers clinicians an efficient and objective tool for improving detection of OSA risk in MS patients.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 234,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "In vitro characterization of mutant yeast RNA polymerase II with reduced binding for elongation factor TFIIS. We have reported previously the isolation and genetic characterization of mutations in the gene encoding the largest subunit of yeast RNA polymerase II (RNAPII), which lead to 6-azauracil (6AU)-sensitive growth. It was suggested that these mutations affect the functional interaction between RNAPII and transcription-elongation factor TFIIS because the 6AU-sensitive phenotype of the mutant strains was similar to that of a strain defective in the production of TFIIS and can be suppressed by increasing the dosage of the yeast TFIIS-encoding gene, PPR2, RNAPIIs were purified and characterized from two independent 6AU-sensitive yeast mutants and from wild-type (wt) cells. In vitro, in the absence of TFIIS, the purified wt polymerase and the two mutant polymerases showed similar specific activity in polymerization, readthrough at intrinsic transcriptional arrest sites and nascent RNA cleavage. In contrast to the wt polymerase, both mutant polymerases were not stimulated by the addition of a 3-fold molar excess of TFIIS in assays of promoter-independent transcription, readthrough or cleavage. However, stimulation of the ability of the mutant RNAPIIs to cleave nascent RNA and to read through intrinsic arrest sites was observed at TFIIS:RNAPII molar ratios greater than 600:1. Consistent with these findings, the binding affinity of the mutant polymerases for TFIIS was found to be reduced by more than 50-fold compared with that of the wt enzyme. These studies demonstrate that TFIIS has an important role in the regulation of transcription by yeast RNAPII and identify a possible binding site for TFIIS on RNAPII.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 1132,
                "text": "TFIIS"
            }
        },
        {
            "context": "Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 185,
                "text": "obesity"
            }
        },
        {
            "context": "Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. BACKGROUND: Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. These three mutations are valuable companion diagnostic biomarkers for guiding personalized treatment. Quantitative polymerase chain reaction (qPCR)-based methods have been widely used in the clinic by physicians to guide treatment decisions. The aim of this study was to evaluate the technical and clinical sensitivity and specificity of the droplet digital polymerase chain reaction (ddPCR) method in detecting the three EGFR mutations in patients with lung cancer. METHODS: Genomic DNA from H1975 and PC-9 cells, as well as 92 normal human blood specimens, was used to determine the technical sensitivity and specificity of the ddPCR assays. Genomic DNA of formalin-fixed, paraffin-embedded specimens from 78 Chinese patients with lung adenocarcinoma were assayed using both qPCR and ddPCR. RESULTS: The three ddPCR assays had a limit of detection of 0.02% and a wide dynamic range from 1 to 20,000 copies measurement. The L858R and ex19del assays had a 0% background level in the technical and clinical settings. The T790M assay appeared to have a 0.03% technical background. The ddPCR assays were robust for correct determination of EGFR mutation status in patients, and the dynamic range appeared to be better than qPCR methods. The ddPCR assay for T790M could detect patient samples that the qPCR method failed to detect. About 49% of this patient cohort had EGFR mutations (L858R, 15.4%; ex19del, 29.5%; T790M, 6.4%). Two patients with the ex19del mutation also had a naïve T790M mutation. CONCLUSION: These data suggest that the ddPCR method could be useful in the personalized treatment of patients with lung cancer.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 175,
                "text": "EGFR"
            }
        },
        {
            "context": "Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH. Alpha-synuclein (alphaS) is the primary component of Lewy bodies, the pathological hallmark of Parkinson's Disease. Aggregation of alphaS is thought to proceed from a primarily disordered state with nascent secondary structure through intermediate conformations to oligomeric forms and finally to mature amyloid fibrils. Low pH conditions lead to conformational changes associated with increased alphaS fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary chemical shifts, relaxation parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of alphaS and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-beta component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a role in the increased aggregation of alphaS at low pH, which we instead attribute to the increased hydrophobicity of the protein.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 88,
                "text": "Alpha-synuclein"
            }
        },
        {
            "context": "Finkelstein's test: a biomechanical analysis. PURPOSE: Finkelstein's test is the classic diagnostic test for de Quervain's disease. Finkelstein hypothesized that the entry of the muscle bellies of the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons into the first extensor compartment was responsible for the findings observed in his now eponymous test. We agree with Finkelstein's hypothesis and further hypothesize that this position would induce measurable bulk (muscle mass within the retinaculum) and tethering (stretching of synovial tissue) effects within the compartment. To test this latter hypothesis we measured the excursion and gliding resistance of the EPB and APL tendons within the first compartment. METHODS: Fifteen fresh-frozen cadavers were used. Gliding resistance and excursion were measured in 4 different wrist positions, including the wrist position of Finkelstein's test (30 degrees ulnar deviation). The bulk and tethering effect was calculated based on the mean gliding resistance over the tendon proximal/distal excursion cycle and the gliding resistance at the terminal distal excursion. RESULTS: The EPB tendon excursion was significantly more distal in 30 degrees ulnar deviation than in 60 degrees extension. Additionally the bulk and tethering resistance was significantly greater in 30 degrees ulnar deviation compared with 60 degrees extension. For the APL tendon there was no significant difference in either the tendon excursion or the bulk and tethering resistance between 30 degrees ulnar deviation and 60 degrees extension. CONCLUSIONS: We showed that in the position of Finkelstein's test the EPB tendon is significantly more distal and has significantly greater bulk and tethering effect compared with the other EPB positions. This is not the case for the APL tendon in the position of Finkelstein's test. These results suggest that an abnormal Finkelstein's test reflects differences of the EPB more than it does the APL.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 109,
                "text": "de Quervain's disease"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 1005,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS: In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight < 100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS: At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS: Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).",
            "question": "What molecule is targeted by brodalumab?",
            "answers": {
                "answer_start": 127,
                "text": "interleukin-17"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 42,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Epigenetic modifications of histones regulate gene expression and chromatin structure. Here we show that Meisetz (meiosis-induced factor containing a PR/SET domain and zinc-finger motif) is a histone methyltransferase that is important for the progression of early meiotic prophase. Meisetz transcripts are detected only in germ cells entering meiotic prophase in female fetal gonads and in postnatal testis. Notably, Meisetz has catalytic activity for trimethylation, but not mono- or dimethylation, of lysine 4 of histone H3, and a transactivation activity that depends on its methylation activity. Mice in which the Meisetz gene is disrupted show sterility in both sexes due to severe impairment of the double-stranded break repair pathway, deficient pairing of homologous chromosomes and impaired sex body formation. In Meisetz-deficient testis, trimethylation of lysine 4 of histone H3 is attenuated and meiotic gene transcription is altered. These findings indicate that meiosis-specific epigenetic events in mammals are crucial for proper meiotic progression.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 242,
                "text": "SET domain"
            }
        },
        {
            "context": "New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 104,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Alternative scoring models of STOP-bang questionnaire improve specificity to detect undiagnosed obstructive sleep apnea. BACKGROUND: Obstructive sleep apnea (OSA) is common among surgical patients. The STOP-Bang questionnaire is a validated screening tool with a high sensitivity. However, its moderate specificity may yield fairly high false positive rate. We hypothesized that the specific combinations of predicting factors in the STOP-Bang questionnaire would improve its specificity. METHODS: After research ethics approval, consented patients were asked to complete the STOP-Bang questionnaire and then underwent sleep studies. The predictive performance of the STOP-Bang alternative scoring models was evaluated. Five hundred sixteen patients with complete data on the STOP-Bang questionnaire and polysomnography were reported. RESULTS: When the STOP-Bang score was > 3 (any 3 positive items), the sensitivity and specificity for identifying moderate-severe OSA was 87% and 31%, respectively. The specificity for any 2 positive items from the 4 STOP questions plus BMI > 35 kg/m(2), male gender, or neck circumference > 40 cm for identifying moderate-severe OSA was 85%, 77%, and 79%, respectively. Compared with STOP-Bang score > 3, the predicted probability for severe OSA of the specific combinations of STOP score > 2 + male and STOP score > 2 + BMI increased by 36% and 42%, respectively. For severe OSA, the specific combination of STOP score > 2 + BMI + male demonstrated a specificity of 97% and 86% increase in predicted probability versus any 4 positive items of STOP-Bang questionnaire. CONCLUSIONS: The specific constellations of predictive factors improved the specificity of STOP-Bang questionnaire. For patients with STOP score > 2, male gender, and BMI > 35 kg/m(2) were more predictive than age > 50 and neck circumference > 40 cm.",
            "question": "Which disease risk can be estimated with the Stop-Bang questionnaire?",
            "answers": {
                "answer_start": 96,
                "text": "obstructive sleep apnea"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 201,
                "text": "CD38"
            }
        },
        {
            "context": "Effect of the mutant microphthalmia-associated transcription factor found in Tietz syndrome on the in vitro development of mast cells. Mutations in microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome type 2 (WS2), a dominantly inherited disorder involving hearing loss and pigment disturbances caused by a lack of melanocytes. On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. The MITF gene is the human homolog of the mouse microphthalmia (mi) gene in some families. Mi/mi mice show decreased numbers and an abnormal phenotype of mast cells (MC). In contrast, the number and phenotype of MC in WS2/TS patients who also have an alteration in their MITF gene are unclear. In this study, we identified a mutation in the MITF gene, delR217, which was equivalent to that found in mi/mi mice, in a case of TS. None of the MITF isoforms with the mutation were able to transactivate the tyrosinase gene promoter. In addition, mutant MITF-M showed dominant negative activity toward wild-type MITF-M, inhibiting its transactivation of the tyrosinase gene promoter. The patient's peripheral blood CD34 cells showed no differences with respect to total cell number or their expression levels of tryptase mRNA in a serum-deprived liquid culture system for 6 weeks when compared with normal control cells. These findings suggest that MITF does not play a critical role in MC development in humans.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 196,
                "text": "MITF"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 826,
                "text": "dabigatran"
            }
        },
        {
            "context": "Genomic context analysis reveals dense interaction network between vertebrate ultraconserved non-coding elements. MOTIVATION: Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic. RESULTS: In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online and at http://ccg.vital-it.ch/ucne/",
            "question": "How are ultraconserved elements called when they form clusters?",
            "answers": {
                "answer_start": 488,
                "text": "gene regulatory blocks (GRBs)"
            }
        },
        {
            "context": "[Screening of FBN1 gene mutations in a family with Marfan syndrome]. OBJECTIVE: To identify FBN1 gene mutations in a Chinese family with Marfan syndrome. METHODS: Four affected and two unaffected individuals in the family were recruited after informed consent. Five ml blood samples were drawn from each family member and genomic DNA was extracted. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of FBN1 gene. Polyphen program was used to predict the functional and structural changes of the mutant protein. RESULTS: We found all four affected individuals carried FBN1gene mutations, c.2261A > G (p.Y754C), in exon18 by sequence analysis, while two unaffected family members and 100 normal controls did not have this mutation. A PSIC score of 2.6 was acquired by Polyphen program analysis. CONCLUSION: Our study supports that FBN1 gene mutation, c.2261A > G (p.Y754C), is the underlying molecular pathogenesis of this family with Marfan syndrome. This mutation is identified for the first time in Chinese population.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 92,
                "text": "FBN1"
            }
        },
        {
            "context": "Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems in computational biology is how to effectively formulate the sequence of a biological sample (such as DNA, RNA or protein) with a discrete model or a vector that can effectively reflect its sequence pattern information or capture its key features concerned. Although several web servers and stand-alone tools were developed to address this problem, all these tools, however, can only handle one type of samples. Furthermore, the number of their built-in properties is limited, and hence it is often difficult for users to formulate the biological sequences according to their desired features or properties. In this article, with a much larger number of built-in properties, we are to propose a much more flexible web server called Pse-in-One (http://bioinformatics.hitsz.edu.cn/Pse-in-One/), which can, through its 28 different modes, generate nearly all the possible feature vectors for DNA, RNA and protein sequences. Particularly, it can also generate those feature vectors with the properties defined by users themselves. These feature vectors can be easily combined with machine-learning algorithms to develop computational predictors and analysis methods for various tasks in bioinformatics and system biology. It is anticipated that the Pse-in-One web server will become a very useful tool in computational proteomics, genomics, as well as biological sequence analysis. Moreover, to maximize users' convenience, its stand-alone version can also be downloaded from http://bioinformatics.hitsz.edu.cn/Pse-in-One/download/, and directly run on Windows, Linux, Unix and Mac OS.",
            "question": "Which server is used for generating modes of pseudo components of DNA, RNA and protein sequences?",
            "answers": {
                "answer_start": 0,
                "text": "Pse-in-One"
            }
        },
        {
            "context": "MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 1066,
                "text": "MC1R"
            }
        },
        {
            "context": "In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. BACKGROUND: Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML. METHODS: The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software. RESULTS: STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures. CONCLUSIONS: In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 232,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Selenoprotein P expression, purification, and immunochemical characterization. Most selenoproteins contain a single selenocysteine residue per polypeptide chain, encoded by an in-frame UGA codon. Selenoprotein P is unique in that its mRNA encodes 10-12 selenocysteine residues, depending on species. In addition to the high number of selenocysteines, the protein is cysteine- and histidine-rich. The function of selenoprotein P has remained elusive, in part due to the inability to express the recombinant protein. This has been attributed to presumed inefficient translation through the selenocysteine/stop codons. Herein, we report for the first time the expression of recombinant rat selenoprotein P in a transiently transfected human epithelial kidney cell line, as well as the endogenously expressed protein from HepG2 and Chinese hamster ovary cells. The majority of the expressed protein migrates with the predicted 57-kDa size of full-length glycosylated selenoprotein P. Based on the histidine-rich nature of selenoprotein P, we have purified the recombinant and endogenously expressed proteins using nickel-agarose affinity chromatography. We show that the recombinant rat and endogenous human proteins react in Western blotting and immunoprecipitation assays with commercial anti-histidine antibodies. The ability to express, purify, and immunochemically detect the recombinant protein provides a foundation for investigating the functions and efficiency of expression of this intriguing protein.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 196,
                "text": "Selenoprotein P"
            }
        },
        {
            "context": "PTEN: a new guardian of the genome. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT signaling pathway and suppresses cell survival as well as cell proliferation. PTEN is the second most frequently mutated gene in human cancer after p53. Germline mutations of PTEN have been found in cancer susceptibility syndromes, such as Cowden syndrome, in which over 80% of patients have mutations of PTEN. Homozygous deletion of Pten causes embryonic lethality, suggesting that PTEN is essential for embryonic development. Mice heterozygous for Pten develop spontaneous tumors in a variety of organs comparable with the spectrum of its mutations in human cancer. The mechanisms of PTEN functions in tumor suppression are currently under intense investigation. Recent studies demonstrate that PTEN plays an essential role in the maintenance of chromosomal stability and that loss of PTEN leads to massive alterations of chromosomes. The tumor suppressor p53 is known as a guardian of the genome that mediates the cellular response to environmental stress, leading to cell cycle arrest or cell death. Through completely different mechanisms, PTEN also protects the genome from instability. Thus, we propose that PTEN is a new guardian of the genome. In this review, we will discuss new discoveries on the role of PTEN in tumor suppression and explore mechanisms by which PTEN maintains genomic stability.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 1045,
                "text": "p53"
            }
        },
        {
            "context": "Effect of gefitinib on the survival of patients with recurrence of lung adenocarcinoma after surgery: a retrospective case-matching cohort study. BACKGROUND: Patients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. However, the effect of EGFR-TKI treatment on the prolongation of overall survival (OS) of these patients remains uncertain, although several recent studies have shown prolongation of progression free survival compared with cytotoxic chemotherapy. METHODS: A total of 304 patients with lung adenocarcinoma who had postoperative recurrent disease were studied. To eliminate potential biases as possible, the matching of four potential predictive factors of responsiveness to EGFR-TKI led to the identification of 81 pairs of patients (those who were treated with gefitinib and those who were not). A deletion mutation in exon 19 and a point mutation (L858R) in exon 21 of the EGFR gene were also analyzed. We compared the OS between the two groups. RESULTS: OS in the gefitinib group was significantly longer than in the control group (median, 63 vs. 41 months; p = 0.015). EGFR mutations were detected in 65 out of 129 patients (50%) in the whole sample. EGFR mutational status was not an independent prognostic factor of gefitinib benefit; rather, it was a predictive factor. CONCLUSIONS: This study strongly suggested that gefitinib treatment improved OS of lung adenocarcinoma patients who had postoperative recurrence, especially those carrying EGFR mutations.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 202,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Determination of cis/trans phase of variations in the MC1R gene with allele-specific PCR and single base extension. The MC1R gene encodes a protein with key regulatory functions in the melanin synthesis. A multiplex PCR and a multiplex single base extension protocol were established for genotyping six exonic MC1R variations highly penetrant for red hair (R), four exonic MC1R variations weakly penetrant for red hair (r), two frameshift variations highly penetrant for red hair (R) and three variations in the promoter region. We genotyped 600 individuals from Denmark using either CE or MALDI-TOF MS as the detection platform. A total of 62 individuals were genotyped R/R and among the 62 individuals, 57 had red hair and five had blond hair colour. Two different R alleles may be located in cis (RR/-) position or trans (R/R) position, and the phenotype associated with RR/- and R/R may be different. Two allele-specific PCRs were established with primers targeting the -G445A variation in the MC1R promoter and the allele-specific PCR products were used in the multiplex single base extension assay. In all 62 individuals, the MC1R variants were situated in trans position. Another 18 individuals with red hair colour were either genotyped R/- or R/r, suggesting that other genes influence hair colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 310,
                "text": "MC1R"
            }
        },
        {
            "context": "SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. The pre-synaptic protein alpha-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Mutations in the alpha-synuclein gene cause familial forms of Parkinson's disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human alpha-synuclein(1-120) that develops alpha-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinson's disease. We now show that in the striatum of these mice, as in Parkinson's disease, synaptic accumulation of alpha-synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length alpha-synuclein(1-140) or truncated alpha-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of alpha-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson's disease.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 127,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 56,
                "text": "programmed death-ligand 1"
            }
        },
        {
            "context": "Secukinumab in plaque psoriasis--results of two phase 3 trials. BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 199,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "The poisoned patient with altered consciousness. Controversies in the use of a 'coma cocktail'. OBJECTIVE: In the assessment and management of the potentially poisoned patient with altered consciousness, the most consequential and controversial interventions occur during the first 5 minutes of care. In this review article, the risks and benefits of standard diagnostic and therapeutic interventions are presented to guide clinicians through this critical period of decision making. DATA SOURCES: Data for discussion were obtained from a search of English-language publications referenced on MEDLINE for the years 1966 to 1994. Older literature was included when pertinent. Search terms included poisoning, overdose, toxicity, naloxone, glucose, thiamine, and flumazenil. STUDY SELECTION: Only large trials were used for determinations of diagnostic utility and efficacy. Small trials, case series, and case reports were reviewed extensively for adverse effects. DATA EXTRACTION AND SYNTHESIS: Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcome. CONCLUSION: Analysis favors empirical administration of hypertonic dextrose and thiamine hydrochloride to patients with altered consciousness. Although rapid reagent test strips can be used to guide this therapy, they are not infallible, and they fail to recognize clinical hypoglycemia that may occur without numerical hypoglycemia. Administration of naloxone hydrochloride should be reserved for patients with signs and symptoms of opioid intoxication. Flumazenil is best left for reversal of therapeutic conscious sedation and rare select cases of benzodiazepine overdose.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1560,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks. Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 464,
                "text": "telomerase"
            }
        },
        {
            "context": "A modified SILCS contraceptive diaphragm for long-term controlled release of the HIV microbicide dapivirine. BACKGROUND: There is considerable interest in developing new multipurpose prevention technologies to address women's reproductive health needs. This study describes an innovative barrier contraceptive device--based on the SILCS diaphragm--that also provides long-term controlled release of the lead candidate anti-HIV microbicide dapivirine. STUDY DESIGN: Diaphragm devices comprising various dapivirine-loaded polymer spring cores overmolded with a nonmedicated silicone elastomer sheath were fabricated by injection molding processes. In vitro release testing, thermal analysis and mechanical characterization were performed on the devices. RESULTS: A diaphragm device containing a polyoxymethylene spring core loaded with 10% w/w dapivirine provided continuous and controlled release of dapivirine over a 6-month period, with a mean in vitro daily release rate of 174 mcg/day. The mechanical properties of the new diaphragm were closely matched to the SILCS diaphragm. CONCLUSIONS: The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. In discontinuous clinical use, release of dapivirine may be readily extended over 1 or more years.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 1235,
                "text": "HIV"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 132,
                "text": "OikoBase"
            }
        },
        {
            "context": "[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 503,
                "text": "Xa"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 606,
                "text": "webSDA"
            }
        },
        {
            "context": "Clinical perspective of afatinib in non-small cell lung cancer. Reversible ATP-competitive inhibitors targeting the epidermal growth factor receptor (EGFR) have been established as the most effective treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring \"activating\" mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment. The mechanisms for acquired resistance include selection of the EGFR T790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms. Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. Here we review the current status of clinical application of afatinib in NSCLC. We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention.",
            "question": "Which type of lung cancer is afatinib used for?",
            "answers": {
                "answer_start": 1203,
                "text": "EGFR-mutant NSCLC"
            }
        },
        {
            "context": "Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules. Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.",
            "question": "Which kinase is inhibited by Tripolin A?",
            "answers": {
                "answer_start": 467,
                "text": "Aurora A"
            }
        },
        {
            "context": "ConteXt of change--X inactivation and disease. Epigenetic regulation is important for stable maintenance of cell identity. For continued function of organs and tissues, illegitimate changes in cell identity must be avoided. Failure to do so can trigger tumour development and disease. How epigenetic patterns are established during cell differentiation has been explored by studying model systems such as X inactivation. Mammals balance the X-linked gene dosage between the sexes by silencing of one of the two X chromosomes in females. This is initiated by expression of the non-coding X-inactive specific transcript (Xist) RNA and depends on specific cellular contexts, in which essential silencing factors are expressed. Normally X inactivation is initiated in early embryogenesis, but recent reports identified instances where Xist is expressed and can initiate gene repression. Here we describe the features that characterize the cellular permissivity to initiation of X inactivation and note that these can also occur in cancer cells and in specific haematopoietic progenitors. We propose that embryonic pathways for epigenetic regulation are re-established in adult progenitor cells and tumour cells. Understanding their reactivation will deepen our understanding of tumourigenesis and may be exploited for cancer therapy.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 619,
                "text": "Xist"
            }
        },
        {
            "context": "Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 207,
                "text": "NF1"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 456,
                "text": "CD38"
            }
        },
        {
            "context": "Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). METHODS: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). RESULTS: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. CONCLUSIONS: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.",
            "question": "Which molecule is targeted by a monoclonal antibody Secukinumab?",
            "answers": {
                "answer_start": 55,
                "text": "interleukin-17A"
            }
        },
        {
            "context": "Retroviral-mediated transfer of the galactocerebrosidase gene in neural progenitor cells. Globoid cell leukodystrophy (GCL or Krabbe disease) is a recessive disease caused by mutations of the lysosomal enzyme galactocerebrosidase (GALC) and twitcher is the murine model of GCL. We have prepared retroviral packaging cell lines to transduce the GALC gene. Retroviral transduction restored GALC activity in GCL fibroblasts and increased such activity to very high levels in immortalized neural progenitor cells (ST14A cells). GALC activity was also normalized in twitcher fibroblasts co-cultured with ST14A cells over-expressing GALC, demonstrating that this enzyme is secreted and can be imported efficiently by GALC-deficient cells. These results give the necessary background to evaluate the therapeutic effect in twitcher of brain grafting of neural progenitor cells engineered to release high levels of GALC.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 209,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called \"neurofibromin.\" It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the \"two hit\" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 283,
                "text": "NF1"
            }
        },
        {
            "context": "Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism. BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2 concentrations, with increased expression of virulence factors that include the anthrax toxins and extracellular capsular layer. This response requires the presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To better understand the genetic basis of this response, we utilized a controlled in vitro system and Next Generation sequencing to determine and compare RNA expression profiles of the parental strain and an isogenic AtxA-deficient strain in a 2 × 2 factorial design with growth environments containing or lacking carbon dioxide. RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were strongly regulated by the separate or synergistic actions of AtxA and carbon dioxide. The majority of the regulated genes responded to both AtxA and carbon dioxide rather than to just one of these factors. Interestingly, we identified two previously unrecognized small RNAs that are highly expressed under physiological carbon dioxide concentrations in an AtxA-dependent manner. Expression levels of the two small RNAs were found to be higher than that of any other gene differentially expressed in response to these conditions. Secondary structure and small RNA-mRNA binding predictions for the two small RNAs suggest that they may perform important functions in regulating B. anthracis virulence. CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are regulated by the presence of either CO2 or AtxA separately are also regulated synergistically in the presence of both. These results also elucidate novel pXO1-encoded small RNAs that are associated with virulence conditions.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 258,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the \"hybrid\" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 243,
                "text": "FBN1"
            }
        },
        {
            "context": "Defective Proteasome Delivery of Polyubiquitinated Proteins by Ubiquilin-2 Proteins Containing ALS Mutations. Ubiquilin proteins facilitate delivery of ubiquitinated proteins to the proteasome for degradation. Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which the mutations cause ALS are not known. Here we report on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations in affecting proteasome-mediated degradation. We found that overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations slow degradation of Myc, a prototypic proteasome substrate. Examination of coprecipitating proteins indicated that the mutant proteins are generally capable of binding polyubiquitinated proteins, but defective in binding the proteasome. GST-pulldown studies revealed that many of the mutants bind weaker to the S5a subunit of the proteasome, compared with wild type (WT) ubiquilin-2 protein. The results suggest the mutant proteins are unable to deliver their captured cargo to the proteasome for degradation, which presumably leads to toxicity. Quantification of cell death is consistent with this idea. Measurement of protein turnover further indicated the mutant proteins have longer half-lives than WT ubiquilin-2. Our studies provide novel insight into the mechanism by which ALS-linked mutations in UBQLN2 interfere with protein degradation.",
            "question": "Which human disease is associated with mutated UBQLN2",
            "answers": {
                "answer_start": 363,
                "text": "ALS"
            }
        },
        {
            "context": "In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 284,
                "text": "HIV"
            }
        },
        {
            "context": "[SENSITIVITY OF THE NEW SKIN TEST DIASKINTEST® FOR THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN CHILDREN AND ADOLESCENTS]. In Russia, an intradermal Diaskintest® drug has been designed, which is a recombinant tuberculosis allergen based on M. tuberculosis-- specific proteins: ESAT-6 and CFP-10 produced by a genetically modified Escherichia coli culture. Diaskintest® test and Mantoux test with 2TE PPD-L were concurrently carried out in 300 children and adolescents with tuberculosis and followed up in risk groups at a tuberculosis dispensary to determine the sensitivity of the new skin test in active tuberculosis infection. Diaskintest® showed a high sensitivity not only in active tuberculosis, but also in occult, the so-called latent, tuberculosis infection. This is suggested by the following evidence. The high percentage (83.8%) of positive responses to Diaskintest® is noted in children and adolescents with tuberculosis, receiving an intensive course of chemotherapy. Negative tests were observed only in minor forms at the resolution stage. In the children who had completed treatment, positive tests were seen in 78.3%, moreover in those with prior tuberculosis of intrathoracic lymph nodes; negative tests were observed not earlier than 18 months after start of treatment. The highest sensitivity of Diaskintest® was shown in children with early primary tuberculosis infection and through family contact with bacteria-excreting subjects (91.7%). These children may be judged with the highest assurance to have latent tuberculosis infection, the population of which is in an active state at the moment of the study. The children with early primary tuberculosis infection, but in no family contact with bacteria-excreting individuals, showed a lower percentage of positive responses to Diaskintest® both before (37.5%) and after (10%) treatment, which suggests that there must be a lower bacterial burden in the child. A high percentage of positive responses to Diaskintest® (76.2%) were found in subjects with hyperergic reactions to tuberculin. These were in only 16.7% in the group of patients receiving preventive therapy. In children and adolescents with a persistent positive Mantoux test (for more than 3 years), the response to Diaskintest® was negative in most cases since in early infection when mycobacteria propagated, the reaction to the drug was positive, but as 3 years pass the probability of the infection transition to the persistence stage is high--at that time the response to Diaskintest® becomes negative. Diaskintest® induces no delayed hypersensitivity associated with BCG vaccination, suggesting its high specificity. There were no positive reactions in patients with nonspecific lung diseases.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 471,
                "text": "tuberculosis"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 0,
                "text": "RADAR"
            }
        },
        {
            "context": "Pancreatic Islet APJ Deletion Reduces Islet Density and Glucose Tolerance in Mice. Protection and replenishment of a functional pancreatic β-cell mass (BCM) are key goals of all diabetes therapies. Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor. The apelin-APJ signaling system is expressed in rodent and human islet cells. Apelin exposure has been shown to inhibit and to stimulate insulin secretion. Our aim was to assess the influence of a selective APJ deletion in pancreatic islet cells on islet homeostasis and glucose tolerance in mice. Cre-LoxP strategy was utilized to mediate islet APJ deletion. APJ deletion in islet cells (APJ(Δislet)) resulted in a significantly reduced islet size, density and BCM. An ip glucose tolerance test showed significantly impaired glucose clearance in APJ(Δislet) mice. APJ(Δislet) mice were not insulin resistant and in vivo glucose-stimulated insulin secretion was reduced modestly. In vitro glucose-stimulated insulin secretion showed a significantly reduced insulin secretion by islets from APJ(Δislet) mice. Glucose clearance in response to ip glucose tolerance test in obese APJ(Δislet) mice fed a chronic high-fat (HF) diet, but not pregnant APJ(Δislet) mice, was impaired significantly. In addition, the obesity-induced adaptive elevations in mean islet size and fractional islet area were reduced significantly in obese APJ(Δislet) mice when compared with wild-type mice. Together, these findings demonstrate a stimulatory role for the islet cell apelin-APJ signaling axis in regulation of pancreatic islet homeostasis and in metabolic induced β-cell hyperplasia. The results indicate the apelin-APJ system can be exploited for replenishment of BCM.",
            "question": "What is apelin?",
            "answers": {
                "answer_start": 198,
                "text": "Apelin, a small regulatory peptide, is the endogenous ligand for the apelin receptor (APJ) receptor."
            }
        },
        {
            "context": "Targeting kinases: a new approach to treating inflammatory rheumatic diseases. After two decades of research and development activity focussed on orally active kinase inhibitors, the first such drug (the JAK inhibitor Xeljanz, tofacitinib) was approved by the FDA in November 2012 for the treatment of rheumatoid arthritis (RA). There is an intense activity in many companies both on expanding the utility of JAK inhibitors in other auto-immune indications and in discovering inhibitors of the JAK family with different and more selective profiles. Progress is also being made with orally active Syk inhibitors. One such inhibitor (fostamatinib) is currently in large-scale phase 3 trials, and there are others in clinical development. The last two to three years have been transformative for kinase inhibitors in auto-immune diseases, as several inhibitors have finally progressed beyond phase 2 trials after so many failures on other targets. Thus, there are new treatment options for RA patients beyond existing oral DMARDs and parenteral biologics.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 227,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 2110,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 786,
                "text": "l-DOPA"
            }
        },
        {
            "context": "Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair. Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma. The association of MC1R gene variants with nonmelanoma skin cancer is largely unknown. A total of 838 subjects were included in the present study: 453 patients with nonmelanoma skin cancer and 385 subjects with no skin cancer. The coding sequence of the human MC1R gene was tested using single-stranded conformation polymorphism analysis followed by sequencing of unknown variants. Risk of skin cancer dependent on the various MC1R gene variants was estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair skin and red hair. A total of 27 MC1R gene variants were found. The number of carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (24.8%), and 7 (0.9%), respectively. A strong association between MC1R gene variants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P < .0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds ratio 3.77; 95% confidence interval [CI] 2.11-6.78), nodular basal cell carcinoma (odds ratio 2.26; 95% CI 1.45-3.52), and superficial multifocal basal cell carcinoma (odds ratio 3.43; 95% CI 1.92-6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. The highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk was only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp variant alleles. When subjects were stratified by skin type and hair color, analysis showed that these factors did not materially change the relative risks. These findings indicate that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 150,
                "text": "MC1R"
            }
        },
        {
            "context": "Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the \"Mowat-Wilson\" syndrome. ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway. ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 38,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "A genome-wide study on the perception of the odorants androstenone and galaxolide. Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h (2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.",
            "question": "Which olfactory gene senses androsterone?",
            "answers": {
                "answer_start": 669,
                "text": "OR7D4"
            }
        },
        {
            "context": "Chediak-Higashi syndrome: novel mutation of the CHS1/LYST gene in 3 Omani patients. BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare, autosomal, recessive lysosomal disorder with hematological and immunologic abnormalities; however, stem-cell transplantation from a matched or related donor may be curative. Many mutations of the CHS1/LYST gene have been reported to date. We report a novel nonsense mutation of the CHS1/LYST gene in 3 Omani patients. METHODS AND RESULTS: Three patients from 2 different families presented with clinical and laboratory features of CHS and a history of death of a previous sibling because of a severe illness, suggestive of the accelerated phase of CHS. Giant granules were present in the myeloid cell lines. Before the stem-cell transplant, the first patient underwent gene sequencing of all exons of the lysosome trafficking regulator (CHS1/LYST) gene and revealed a nonsense mutation in exon 5 (c.925C>T, p.R309X). Subsequently, upon presentation, the second and third patients' direct gene sequencing of exon 5 revealed the same mutation. CONCLUSIONS: We report a nonsense mutation in exon 5 (c.925C>T, p.R309X). This supports the allelic heterogeneity of CHS and is in line with most reported mutation types that lead to a truncated protein. Identification of the mutation type will facilitate timely diagnosis, management, and family counseling for those with affected children in Oman.",
            "question": "Which syndrome is associated with mutations in the LYST gene?",
            "answers": {
                "answer_start": 0,
                "text": "Chediak-Higashi syndrome"
            }
        },
        {
            "context": "High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. BACKGROUND AND OBJECTIVES: Iron depletion is common in regular blood donors. The objective of the study was to investigate the frequency and severity of iron depletion in regular blood donors and whether IV iron is more effective than oral to avoid iron depletion and symptoms thereof, especially restless legs syndrome (RLS). METHOD: One hundred and twenty blood donors with at least five previous whole blood donations were randomized to receive either IV iron sucrose (Venofer(®), RenaPharma/Vifor, Uppsala, Sweden), 200 mg, or to 20×100 mg of oral iron sulphate (Duroferon(®), GlaxoSmithKline, Stockholm, Sweden), after each blood donation during 1 year. Iron status and RLS incidence and severity were investigated. RESULTS: Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). The IV iron group increased storage iron to a greater extent than the oral iron group after 12 months (P=0·0043). Female donors were more responsive to IV iron sucrose compared to oral iron sulphate, particularly female donors below 50 years of age. RLS severity scores were significantly lower in the IV iron group. The two treatments were safe. CONCLUSION: Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. IV iron sucrose substitutes iron loss in blood donors more efficiently compared with oral iron sulphate, especially in women. Iron substitution to blood donors should be individualized and based on P-ferritin monitoring.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 889,
                "text": "Iron"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 459,
                "text": "IL-1β"
            }
        },
        {
            "context": "piggyBac is a flexible and highly active transposon as compared to sleeping beauty, Tol2, and Mos1 in mammalian cells. A nonviral vector for highly efficient site-specific integration would be desirable for many applications in transgenesis, including gene therapy. In this study we directly compared the genomic integration efficiencies of piggyBac, hyperactive Sleeping Beauty (SB11), Tol2, and Mos1 in four mammalian cell lines. piggyBac demonstrated significantly higher transposition activity in all cell lines whereas Mos1 had no activity. Furthermore, piggyBac transposase coupled to the GAL4 DNA-binding domain retains transposition activity whereas similarly manipulated gene products of Tol2 and SB11 were inactive. The high transposition activity of piggyBac and the flexibility for molecular modification of its transposase suggest the possibility of using it routinely for mammalian transgenesis.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 432,
                "text": "piggyBac"
            }
        },
        {
            "context": "Wilson's disease: clinical and radiological features. BACKGROUND: Wilson's disease is a treatable movement disorder with autosomal recessive inheritance which is associated with severe morbidity and mortality if not treated early. MATERIAL AND METHODS: The clinical and radiological features of 22 cases of Wilson's disease seen during January 1984 to December 1993 were analysed for clinical presentation and common radiological features. RESULTS: Among all the patients extrapyramidal features were the commonest (19/22 patients), followed closely by impaired higher mental functions (17/22 patients) and cerebellar signs (11/22 patients). In patients with onset of symptoms before 20 years, the common presentations were impaired higher mental functions, speech disturbance, dystonia and choreo-athetosis; whereas in patients with onset after 20 years cerebellar signs were commonest. The commonest CT head abnormality was basal ganglion hypodensity (10 patients) followed by brain stem hypodensity (6 patients). CONCLUSIONS: The clinical and CT scan features are evaluated and compared with reported series. Hypodensities of brain stem earlier reported a rarity, was seen in 6 out of 22 cases.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 121,
                "text": "autosomal recessive"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 0,
                "text": "CAGEr"
            }
        },
        {
            "context": "Living with Restless Legs Syndrome/Willis-Ekbom Disease. Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is commonly seen in patients with end-stage renal disease (ESRD), but this condition has not been properly recognized. The prevalence of RLS/WED in ESRD shows the ethnic variation (7%-68%), with the similar tendency of primary RLS/WED. Although RLS/WED in ESRD is defined in secondary RLS/WED, the factors of ESRD that are involved in the genesis of RLS/WED remain unknown. Even after renal transplantation, RLS/WED symptoms do not completely disappear, and genetic predisposition to RLS/WED may play an important role in causing RLS/WED. Long-term intervention for RLS/WED and ESRD will be necessary.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 12,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity. Methylation of certain lysine residues in the N-terminal tails of core histone proteins in nucleosome is of fundamental importance in the regulation of chromatin structure and gene expression. Such histone modification is catalyzed by protein lysine methyltransferases (PKMTs). PKMTs contain a conserved SET domain in almost all of the cases and may transfer one to three methyl groups from S-adenosyl-L-methionine (AdoMet) to the epsilon-amino group of the target lysine residue. Here, quantum mechanical/molecular mechanical molecular dynamics and free-energy simulations are performed on human PKMT SET7/9 and its mutants to understand two outstanding questions for the reaction catalyzed by PKMTs: the mechanism for deprotonation of positively charged methyl lysine (lysine) and origin of product specificity. The results of the simulations suggest that Tyr-335 (an absolute conserved residue in PKMTs) may play the role as the general base for the deprotonation after dissociation of AdoHcy (S-adenosyl-L-homocysteine) and before binding of AdoMet. It is shown that conformational changes could bring Y335 to the target methyl lysine (lysine) for proton abstraction. This mechanism provides an explanation why methyl transfers could be catalyzed by PKMTs processively. The free-energy profiles for methyl transfers are reported and analyzed for wild type and certain mutants (Y305F and Y335F) and the active-site interactions that are of importance for the enzyme's function are discussed. The results of the simulations provide important insights into the catalytic process and lead to a better understanding of experimental observations concerning the origin of product specificity for PKMTs.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 425,
                "text": "SET domain"
            }
        },
        {
            "context": "Diagnosis and treatment of plantar fasciitis. Plantar fasciitis, a self-limiting condition, is a common cause of heel pain in adults. It affects more than 1 million persons per year, and two-thirds of patients with plantar fasciitis will seek care from their family physician. Plantar fasciitis affects sedentary and athletic populations. Obesity, excessive foot pronation, excessive running, and prolonged standing are risk factors for developing plantar fasciitis. Diagnosis is primarily based on history and physical examination. Patients may present with heel pain with their first steps in the morning or after prolonged sitting, and sharp pain with palpation of the medial plantar calcaneal region. Discomfort in the proximal plantar fascia can be elicited by passive ankle/first toe dorsiflexion. Diagnostic imaging is rarely needed for the initial diagnosis of plantar fasciitis. Use of ultrasonography and magnetic resonance imaging is reserved for recalcitrant cases or to rule out other heel pathology; findings of increased plantar fascia thickness and abnormal tissue signal the diagnosis of plantar fasciitis. Conservative treatments help with the disabling pain. Initially, patient-directed treatments consisting of rest, activity modification, ice massage, oral analgesics, and stretching techniques can be tried for several weeks. If heel pain persists, then physician-prescribed treatments such as physical therapy modalities, foot orthotics, night splinting, and corticosteroid injections should be considered. Ninety percent of patients will improve with these conservative techniques. Patients with chronic recalcitrant plantar fasciitis lasting six months or longer can consider extracorporeal shock wave therapy or plantar fasciotomy.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 113,
                "text": "heel pain"
            }
        },
        {
            "context": "Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys. Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 705,
                "text": "L-Dopa"
            }
        },
        {
            "context": "Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.",
            "question": "Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?",
            "answers": {
                "answer_start": 53,
                "text": "Rotor syndrome"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1154,
                "text": "FSHD"
            }
        },
        {
            "context": "Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design. The exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase α from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1.",
            "question": "Which stapled peptide has been designed to target Ctf4?",
            "answers": {
                "answer_start": 817,
                "text": "The stapled Sld5 peptide"
            }
        },
        {
            "context": "Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 932,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. Incorporation of the 21st amino acid, selenocysteine, into proteins is specified in all three domains of life by dynamic translational redefinition of UGA codons. In eukarya and archaea, selenocysteine insertion requires a cis-acting selenocysteine insertion sequence (SECIS) usually located in the 3'UTR of selenoprotein mRNAs. Here we present comparative sequence analysis and experimental data supporting the presence of a second stop codon redefinition element located adjacent to a selenocysteine-encoding UGA codon in the eukaryal gene, SEPN1. This element is sufficient to stimulate high-level (6%) translational redefinition of the SEPN1 UGA codon in human cells. Readthrough levels further increased to 12% when tested in the presence of the SEPN1 3'UTR SECIS. Directed mutagenesis and phylogeny of the sequence context strongly supports the importance of a stem loop starting six nucleotides 3' of the UGA codon. Sequences capable of forming strong RNA structures were also identified 3' adjacent to, or near, selenocysteine-encoding UGA codons in the Sps2, SelH, SelO, and SelT selenoprotein genes.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 366,
                "text": "SECIS"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 1850,
                "text": "IL-1β"
            }
        },
        {
            "context": "Prominin-1 allows prospective isolation of neural stem cells from the adult murine hippocampus. Prominin-1 (CD133) is commonly used to isolate stem and progenitor cells from the developing and adult nervous system and to identify cancer stem cells in brain tumors. However, despite extensive characterization of Prominin-1(+) precursor cells from the adult subventricular zone, no information about the expression of Prominin-1 by precursor cells in the subgranular zone (SGZ) of the adult hippocampus has been available. We show here that Prominin-1 is expressed by a significant number of cells in the SGZ of adult mice in vivo and ex vivo, including postmitotic astrocytes. A small subset of Prominin-1(+) cells coexpressed the nonspecific precursor cell marker Nestin as well as GFAP and Sox2. Upon fluorescence-activated cell sorting, only Prominin-1/Nestin double-positive cells fulfilled the defining stem cell criteria of proliferation, self-renewal, and multipotentiality as assessed by a neurosphere assay. In addition, isolated primary Prominin-1(+) cells preferentially migrated to the neurogenic niche in the SGZ upon transplantation in vivo. Finally, despite its expression by various stem and progenitor cells, Prominin-1 turned out to be dispensable for precursor cell proliferation in vitro and in vivo. Nevertheless, a net decrease in hippocampal neurogenesis, by ∼30% was found in Prominin-1 knock-out mice, suggesting other roles in controlling adult hippocampal neurogenesis. Remarkably, an upregulation of Prominin-2 was detected in Prominin-1-deficient mice highlighting a potential compensatory mechanism, which might explain the lack of severe symptoms in individuals carrying mutations in the Prom1 gene.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 765,
                "text": "Nestin"
            }
        },
        {
            "context": "Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 504,
                "text": "7"
            }
        },
        {
            "context": "Analysis of mitochondrial DNA in discordant monozygotic twins with neurofibromatosis type 1. Neurofibromatosis type 1 (NF1) is the most frequent neurocutaneous disorder with autosomal dominant inheritance. Phenotype variability is high ranging from merely several café-au-lait spots to malignant peripheral nerve sheath tumors or severe disfigurement through plexiform neurofibromas. Identification of genetic factors that modify the NF1 phenotype would contribute to the understanding of NF1 pathophysiology and improve patient counselling. As even monozygotic (MZ) twins with NF1 may differ phenotypically, we wondered whether these variations might be inherited in a non-Mendelian fashion. Mitochondrial DNA (mtDNA) is inherited extrachromosomally through the cytoplasm of the oocyte and often harbours heteroplasmic sequence variations. At the time of blastomere separation, these variants may be skewedly distributed and effect phenotypic differences. Because of their co-localization with the tumor suppressor protein neurofibromin, which is mutated in NF1, mitochondria were particular attractive candidates for investigation. MtDNA was extracted from nucleated blood cells of four pairs of discordant MZ twins with NF1 and from cutaneous neurofibromas of one twin pair. We sequenced the entire mitochondrial genome and determined the state of heteroplasmy by investigating a microsatellite region of the mitochondrial D-loop (D310-tract). The clinical diagnosis was confirmed in all patients by detection of pathogenic mutations in the NF1 gene. Monozygosity was verified by genotyping. However, we did not detect evidence for mtDNA sequence differences or for different degrees of heteroplasmy between individuals of the same twin pair. The phenotypic discordance of MZ twins with NF1 cannot be explained by skewed distribution of mtDNA mutations or polymorphisms.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 1059,
                "text": "NF1"
            }
        },
        {
            "context": "A transient kinetic analysis of PRMT1 catalysis. Post-translational modifications (PTMs) are important strategies used by eukaryotic organisms to modulate their phenotypes. One of the well-studied PTMs, arginine methylation, is catalyzed by protein arginine methyltransferases (PRMTs) with SAM as the methyl donor. The functions of PRMTs have been broadly studied in different biological processes and diseased states, but the molecular basis for arginine methylation is not well-defined. In this study, we report the transient-state kinetic analysis of PRMT1 catalysis. The fast association and dissociation rates suggest that PRMT1 catalysis of histone H4 methylation follows a rapid equilibrium sequential kinetic mechanism. The data give direct evidence that the chemistry of methyl transfer is the major rate-limiting step and that binding of the cofactor SAM or SAH affects the association and dissociation of H4 with PRMT1. Importantly, from the stopped-flow fluorescence measurements, we have identified a critical kinetic step suggesting a precatalytic conformational transition induced by substrate binding. These results provide new insights into the mechanism of arginine methylation and the rational design of PRMT inhibitors.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 290,
                "text": "SAM"
            }
        },
        {
            "context": "Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. Mutations in the glucocerebrosidase (GBA) gene cause Gaucher disease (GD). The aim of this study was to characterise the GBA mutations and analyze genotype/phenotype relationships in 193 unrelated patients from the Spanish GD Registry. We have identified 98.7% of the mutated GBA alleles, finding 56 different GBA mutations and 66 genotypes causing GD in Spain: 47 previously described mutations and 9 novel mutations (4 missense R395C, R463H, W312R and V398I, 1 nonsense R359X, 4 frameshift c.708delC, c.1214-1215delGC, c.1439-1445del7 and c.42-65del24). The most prevalent mutations were N370S and L444P, accounting for 68.7% of the mutated alleles. A wide phenotypic difference was observed within each genotypic group, and 9% of diagnosed type 1 patients developed neurological involvement including parkisonism, tremor, hypoacusia and eye movements. All of these findings indicate that there is a significant genotypic heterogeneity that explains the huge phenotypic variation among Spanish GD patients.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 110,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Diazepam poisoning with one-month monitoring of diazepam and nordiazepam blood levels. A 54-y-old man ingested 2 g of bulk laboratory diazepam and was treated with activated charcoal, enhanced diuresis and flumazenil infusion. The treatment resulted in awakening, but the patient had drowsiness, dysarthria, diplopia, and dizziness for 9 d. Blood levels of diazepam and its main metabolite, nordiazepam, were obtained for 1 mo. The half-lives in this benzodiazepine overdose were longer than those seen with therapeutic doses. Benzodiazepines should not be readministrated when patients awake after suicide attempts.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 206,
                "text": "flumazenil"
            }
        },
        {
            "context": "Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells. The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for the combination of MLN4924 with autophagy inhibitors to enhance therapeutic efficacy.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 55,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "Expression and characterization of nonmammalian selenoprotein P in the zebrafish, Danio rerio. BACKGROUND: Selenoprotein P is a protein of considerable intrigue, due to its unusual composition and requirements for its biosynthesis. Whereas most selenoproteins contain a single selenocysteine residue, the human, bovine and rodent selenoprotein P genes encode proteins containing 10-12 selenocysteines. Selenoprotein P genes have, to date, only been reported in mammals, and the function of the protein remains elusive. RESULTS: Herein, we report the identification and characterization of nonmammalian selenoprotein P in the zebrafish Danio rerio. Sequencing of the cDNA revealed the presence of 17 selenocysteine codons, the highest number reported in any protein. Two histidine-rich regions present in the mammalian selenoprotein P sequences are conserved in the zebrafish protein, and two SECIS elements are present in the 3' untranslated region. Whole-mount in situ hybridization of zebrafish embryos revealed high levels of expression of selenoprotein P mRNA in fertilized eggs and in the yolk sac of developing embryos. Transient transfection of the cDNA in mammalian cells resulted in efficient expression of the full-length secreted selenoprotein. A single N-glycosylation site is predicted, and shown to be utilized. CONCLUSIONS: Discovery of selenoprotein P in the zebrafish opens a previously unavailable avenue for genetic investigation of the functions of this unusual protein.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 330,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 222,
                "text": "xa"
            }
        },
        {
            "context": "The natural history and management of intracranial dural arteriovenous fistulae. Part 1: benign lesions. The recently proposed classification scheme of Borden, Wu, and Shucart (Borden(*)) should have the ability to identify those intracranial dural arteriovenous fistulae (ICDAVF) which will continue to behave in a benign fashion. We examine for the first time the natural history of benign ICDAVF, including the predictive ability of this grading scale, and the implications for lesion management. A cohort of 55 Borden(*) grade I lesions was selected from a heterogeneous series of 102 consecutive lCDAVF seen at one institution between 1984 and 1995. Data were collected prospectively from 1991. Grade 1 lesions were those whose nidus drained directly into a dural venous sinus (DVS) or meningeal vein. The absence of retrograde leptomeningeal venous drainage (RLVD) was an important feature. Intracranial haemorrhage (ICH), non haemorrhagic neurological deficit (NHND), and death were considered aggressive features. There were 23 cavernous sinus, 2 foramen magnum, 1 middle cranial fossa, and 29 transverse sinus lesions. One patient received obliterative surgical treatment. Thirty-two lesions were observed only, and 22 patients developed symptoms or signs requiring palliative embolisation. Two minor complications occurred following embolisation: transient pulmonary aedema (1), and an asymptomatic pericallosal artery embolus (1). Follow-up was available on 48 (89%) patients for a total of 133 patient years (mean 33 months). This included 26 of the 32 patients observed and all 22 of the patients embolised. Aggressive interval behavior was seen in only one patient. Symptom improvement or resolution was observed in the majority of patients, whether observed only [21/26 (81%) j, or whether they required embolisation for symptom palliation [19/22 (86%)). Overall, 53 of the 54 (98%) of ICDAVF behaved in a benign fashion in the follow-up period. The predictable benign natural history of patients identified as Borden(*) grade I at presentation mandates a conservative approach to these ICDAVF. In some patients, when symptom severity demands, palliative embolisation is an effective and safe therapy.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 275,
                "text": "DAVF"
            }
        },
        {
            "context": "RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia. Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 787,
                "text": "RANKL"
            }
        },
        {
            "context": "FullSSR: Microsatellite Finder and Primer Designer. Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. The software was tested with 2000 sequences of Oryza sativa shotgun sequencing project from the National Center of Biotechnology Information Trace Archive and with partial genome sequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla platensis, and Zilchiopsis collastinensis. FullSSR performance was compared against other similar SSR search programs. The results of the use of this kind of approach depend on the parameters set by the user. In addition, results can be affected by the analyzed sequences because of differences among the genomes. FullSSR simplifies the detection of SSRs and primer design on a big data set. The command line interface of FullSSR was intended to be used as part of genomic analysis tools pipeline; however, it can be used as a stand-alone program because the results are easily interpreted for a nonexpert user.",
            "question": "Which tool exists for microsatellite (SSR) loci detection and primer design?",
            "answers": {
                "answer_start": 202,
                "text": "FullSSR"
            }
        },
        {
            "context": "Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 212,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model. OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. METHODS: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. RESULTS: Gait deficiency in untreated rats was present 3-7 days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. CONCLUSIONS: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 213,
                "text": "NGF"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 846,
                "text": "Genomiser"
            }
        },
        {
            "context": "Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. Tissue kallikreins are a group of serine proteases that are found in many organs and biologic fluids. Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3-4 as a gene cluster encoding 15 different serine proteases. In skin, two tissue kallikrein proteins, hK5 and hK7, are expressed in the stratum corneum and are known to be involved in desquamation of corneocytes. The possible involvement of other kallikrein proteins has not been clarified, however, nor has the significance of each member in the serine protease activity of skin been delineated. In the study described here, we examined expression and localization of KLK mRNA in normal human skin by means of RT-PCR and in situ hybridization. Quantitative RT-PCR analysis showed abundant expression of KLK1 and KLK11 mRNA, moderate expression of KLK4, KLK5, KLK6, KLK7, and KLK13 mRNA, and low expression of KLK8 mRNA in normal human skin. For KLK4, KLK8, and KLK13 mRNA, splice variants were identified to be their major mRNA species. Two variants for KLK13 mRNA were novel. The amount of the serine protease inhibitor Kazal-type 5 (SPINK5) mRNA was comparable to KLK1 and KLK11 mRNA. In situ hybridization revealed intense expression of all KLK mRNA studied except KLK12 mRNA in the stratum granulosum of normal epidermis, where SPINK5 mRNA coexisted. Excluding KLK13 mRNA, they are also expressed in hair sheath, eccrine sweat glands, and sebaceous glands. Coexpression of various KLK and SPINK5 mRNA suggests that their proteins are the candidates to balance and maintain serine protease activities in both the skin and appendages.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 284,
                "text": "15"
            }
        },
        {
            "context": "Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum. Myotonic dystrophy (DM) is caused by a CTG expansion in the 3'-untranslated region of a protein kinase gene (DMPK). Cardiovascular disease is one of the most prevalent causes of death in DM patients. Electrophysiological studies in cardiac muscles from DM patients and from DMPK(-/-) mice suggested that DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity. However, there are no data regarding the molecular signaling pathways involved in DM heart failure. Here we show that DMPK expression in cardiac myocytes is highly enriched in the sarcoplasmic reticulum (SR) where it colocalizes with the ryanodine receptor and phospholamban (PLN), a muscle-specific SR Ca(2+)-ATPase (SERCA2a) inhibitor. Coimmunoprecipitation studies showed that DMPK and PLN can physically associate. Furthermore, purified wild-type DMPK, but not a kinase-deficient mutant (K110A DMPK), phosphorylates PLN in vitro. Subsequent studies using the DMPK(-/-) mice demonstrated that PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice compared with wild-type mice both in vitro and in vivo. Finally, we show that Ca(2+) uptake in SR is impaired in ventricular homogenates from DMPK(-/-) mice. Together, our data suggest the existence of a novel regulatory DMPK pathway for cardiac contractility and provide a molecular mechanism for DM heart pathology.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 835,
                "text": "PLN"
            }
        },
        {
            "context": "Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p. Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 45,
                "text": "α-synuclein"
            }
        },
        {
            "context": "The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic. The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors. In tyrosine kinase inhibitor-resistant lung tumors, rociletinib and AZD9291 are highly active when T790M is present and modestly active when T790M is absent.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 200,
                "text": "EGFR"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 590,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Pain-mediated affect regulation is reduced after dialectical behavior therapy in borderline personality disorder: a longitudinal fMRI study. Borderline Personality Disorder (BPD) is characterized by affective instability, but self-injurious behavior appears to have an emotion-regulating effect. We investigated whether pain-mediated affect regulation can be altered at the neural level by residential Dialectical Behavior Therapy (DBT), providing adaptive emotion regulation techniques. Likewise, we investigated whether pain thresholds or the appraisal of pain change after psychotherapy. We investigated 28 patients with BPD undergoing DBT (self-referral), 15 patients with treatment as usual and 23 healthy control subjects at two time points 12 weeks apart. We conducted an fMRI experiment eliciting negative emotions with picture stimuli and induced heat pain to investigate the role of pain in emotion regulation. Additionally, we assessed heat and cold pain thresholds.At first measurement, patients with BPD showed amygdala deactivation in response to painful stimulation, as well as altered connectivity between left amygdala and dorsal anterior cingulate cortex. These effects were reduced after DBT, as compared with patients with treatment as usual. Pain thresholds did not differ between the patient groups. We replicated the role of pain as a means of affect regulation in BPD, indicated by increased amygdala coupling. For the first time, we could demonstrate that pain-mediated affect regulation can be changed by DBT.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 141,
                "text": "Borderline Personality Disorder"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 910,
                "text": "xa"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 563,
                "text": "FSHD"
            }
        },
        {
            "context": "Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 698,
                "text": "thyroid"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 0,
                "text": "RADAR"
            }
        },
        {
            "context": "Large-scale appearance of ultraconserved elements in tetrapod genomes and slowdown of the molecular clock. Mammalian genomes contain millions of highly conserved noncoding sequences, many of which are regulatory. The most extreme examples are the 481 ultraconserved elements (UCEs) that are identical over at least 200 bp in human, mouse, and rat and show 96% identity with chicken, which diverged approximately 310 MYA. If the substitution rate in UCEs remained constant, these elements should also be present with a high level of identity in fish (approximately 450 Myr), but this is not the case, suggesting that many appeared in the amniotes or tetrapods or that the molecular clock has slowed down in these lineages, or both. Taking advantage of the availability of multiple genomes, we identified 13,736 UCEs in the human genome that are identical over at least 100 bp in at least 3 of 5 placental mammals, including 2,189 sequences over at least 200 bp, thereby greatly expanding the repertoire of known UCEs, and investigated the evolution of these sequences in opossum, chicken, frog, and fish. We conclude that there was a massive genome-wide acquisition and expansion of UCEs during tetrapod and then amniote evolution, accompanied by a slowdown of the molecular clock, particularly in the amniotes, a process consistent with their functional exaptation in these lineages. The majority of tetrapod-specific UCEs are noncoding and associated with genes involved in regulation of transcription and development. In contrast, fish genomes contain relatively few UCEs, the majority of which are common to all bony vertebrates. These elements are different from other conserved noncoding elements and appear to be important regulatory innovations that became fixed following the emergence of vertebrates from the sea to the land.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 1507,
                "text": "development"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 10,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Familial Mediterranean fever, review of the literature. Familial Mediterranean fever (FMF) is the most common monogenic periodic fever syndrome and characterized by recurrent episodes of fever, serositis, arthritis, dermal manifestations, and long-term renal complications. The MEFV gene was described in 1997 as the gene responsible for FMF and is inherited in autosomal recessive manner. It encodes mutated protein pyrin, an important player in the innate immune system and the component of inflammasome which leads to exaggerated inflammatory response through uncontrolled production of interleukin-1. The recent progress in molecular genetics and understanding of pathogenesis showed a more complicated picture of FMF inheritance, penetrance, and pathogenesis. The pathogenesis is not completely understood although the gene responsible for FMF has been identified. Whether the pyrin mutation effect in FMF is due to a loss of function or a gain of function is still controversial. The diagnosis is mainly clinical and the genetic testing is indicated to support it. Colchicine remains the mainstay of treatment of FMF since 1972. It decreases the attacks, improves quality of life, and prevents amyloidosis. The recent advances in genetic testing and molecular studies has led to the development of new therapies of interleukin-1 inhibitors; anakinra, canakinumab, and rilonacept.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 278,
                "text": "MEFV gene"
            }
        },
        {
            "context": "The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. The p53 protein is the cell's principal bastion of defense against tumor-associated DNA damage. Commonly referred as a \"guardian of the genome\", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged. The development of tumors requires breaching this defense line. All known tumor cells either mutate the p53 gene, or in a similar number of cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable its function. The release of functional p53 from the inhibition by Mdm2 and Mdmx should in principle provide an efficient, nongenotoxic means of cancer therapy. In recent years substantial progress has been made in developing novel p53-activating molecules thanks to several reported crystal structures of Mdm2/x in complex with p53-mimicking peptides and nonpeptidic drug candidates. Understanding the structural attributes of ligand binding holds the key to developing novel, highly effective, and selective drug candidates. Two low-molecular-weight compounds have just recently progressed into early clinical studies.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 214,
                "text": "p53"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 395,
                "text": "CD38"
            }
        },
        {
            "context": "A comparison of cyclosporine binding by cyclophilin and calmodulin and the identification of a novel 45 KD cyclosporine-binding phosphoprotein in Jurkat cells. Cyclosporine mediates its immunosuppressive effect by preventing the synthesis of lymphokine mRNA during the process of T lymphocyte activation. Although the detailed molecular mechanism by which CsA achieves this effect is unknown, two proteins have been identified as putative intracellular CsA-receptor proteins. One of these, calmodulin, is an important Ca++-binding protein and enzyme cofactor and the other, cyclophilin, is a novel protein that is reported to have protein kinase activity. In this study the CsA-binding capacity of both these proteins has been assessed using CsA-coated ELISA plates and CsA-affinity gel matrices. CsA binding was shown by cyclophilin whereas no CsA-calmodulin binding could be detected under identical conditions. However, it was not possible to demonstrate any cyclophilin-associated protein kinase activity. Jurkat cells were probed for the presence of CsA-binding proteins using the CsA-affinity gel matrix; a 17 KD protein, most probably cyclophilin, was identified as the major CsA-binding protein. In addition, a previously unidentified CsA-binding 45 KD phosphoprotein was precipitated from 32P-labeled Jurkat cells. These results would support cyclophilin as the major, if not only, intracellular receptor protein for CsA. However, the relationship between binding of CsA to cyclophilin and/or the 45 KD phosphoprotein and the immunosuppressive effects of CsA is still unknown.",
            "question": "Which is the receptor for the immunosuppressive drug cyclosporin A (CsA)?",
            "answers": {
                "answer_start": 1352,
                "text": "cyclophilin"
            }
        },
        {
            "context": "Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 394,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Enhancer evolution and the origins of morphological novelty. A central goal of evolutionary biology is to understand the genetic origin of morphological novelties-i.e. anatomical structures unique to a taxonomic group. Elaboration of morphology during development depends on networks of regulatory genes that activate patterned gene expression through transcriptional enhancer regions. We summarize recent case studies and genome-wide investigations that have uncovered diverse mechanisms though which new enhancers arise. We also discuss how these enhancer-originating mechanisms have clarified the history of genetic networks underlying diversification of genital structures in flies, limbs and neural crest in chordates, and plant leaves. These studies have identified enhancers that were pivotal for morphological divergence and highlighted how novel genetic networks shaping form emerged from pre-existing ones.",
            "question": "Are human enhancers or promoters evolving faster?",
            "answers": {
                "answer_start": 506,
                "text": "enhancers"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 935,
                "text": "Xa"
            }
        },
        {
            "context": "Association of clinical and genetical features in FMF with focus on MEFV strip assay sensitivity in 452 children from western Anatolia, Turkey. The aim of this study was to determine the relationship between clinical findings and the most common mutated alleles of MEFV gene in a childhood population and to determine the sensitivity of the 12-mutation-strip assay test in familial Mediterranean fever (FMF). Records of 452 FMF children living in western Anatolia, Turkey, (12.3 ± 4.7 years mean) were retrospectively reviewed. Of the 408 patients who met the Tel-Hashomer criteria, 364 were classified into two main groups (two-mutant/one-mutant allele) either of which had three subgroups. The two-mutant allele frequency was 51% and one-mutant allele 38%; 1% had complex-mutant alleles and 10% no mutant-alleles. The mean severity score was 8.3 ± 2.5. Most common clinical features were fever (81.9%), abdominal pain (86.3%) and myalgia (58.8%), and the least common ones: diarrhea (1.7%), protracted febrile myalgia (1.2%) and acute orchitis (1.5%). We detected 33 different genotypes of the MEFV gene: the most common mutant allele was M694V followed by symptomatic allele mutation of E148Q. Although not significantly associated with clinical findings, P369S mutation was not rare (7.5%). Phenotype-genotype correlation revealed that patients with two-allele mutations had more severe clinical presentation and high constipation rate (22.5%); 32.6% of patients with M694V/M694V had splenomegaly. Acute orchitis and protracted febrile myalgia as rare clinical findings were more common in M694V homozygotes. Comparisons of clinical findings among patients with one-mutation allele were made for the first time, but no significant association was found. Positive predictive value of strip assay screening for 12 mutations was recorded as 89%. We suggest that whole sequence analysis for supportive diagnosis of FMF should be performed for selected patients only.",
            "question": "What gene is mutated in Familial Mediterranean Fever?",
            "answers": {
                "answer_start": 265,
                "text": "MEFV gene"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8 times"
            }
        },
        {
            "context": "Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 489,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 72,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan anemia. Mutations in the ribosomal protein (RP)S19 gene have been found in about 25% of the cases of Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia that includes variable physical malformations. Various mutations have been identified in the RPS19 gene, but no investigations regarding the effect of these alterations on RPS19 mRNA levels have been performed. It is well established that mutated mRNA containing a premature stop codon (PTC) or lacking a stop codon can be rapidly degraded by specific mechanisms called nonsense mediated decay (NMD) and nonstop decay. To study the involvement of such mechanisms in DBA, we analyzed immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. We found that RPS19 mRNA levels are decreased in the cells with allelic deletion and, to a variable extent, also in all the cell lines with PTC or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA. Our findings indicate that NMD and nonstop decay affect the expression of mutated RPS19 genes; this may help to clarify genotype-phenotype correlations in DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 212,
                "text": "DBA"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 240,
                "text": "IgG4"
            }
        },
        {
            "context": "Update of the FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation. The international Functional Annotation Of the Mammalian Genomes 4 (FANTOM4) research collaboration set out to better understand the transcriptional network that regulates macrophage differentiation and to uncover novel components of the transcriptome employing a series of high-throughput experiments. The primary and unique technique is cap analysis of gene expression (CAGE), sequencing mRNA 5'-ends with a second-generation sequencer to quantify promoter activities even in the absence of gene annotation. Additional genome-wide experiments complement the setup including short RNA sequencing, microarray gene expression profiling on large-scale perturbation experiments and ChIP-chip for epigenetic marks and transcription factors. All the experiments are performed in a differentiation time course of the THP-1 human leukemic cell line. Furthermore, we performed a large-scale mammalian two-hybrid (M2H) assay between transcription factors and monitored their expression profile across human and mouse tissues with qRT-PCR to address combinatorial effects of regulation by transcription factors. These interdependent data have been analyzed individually and in combination with each other and are published in related but distinct papers. We provide all data together with systematic annotation in an integrated view as resource for the scientific community (http://fantom.gsc.riken.jp/4/). Additionally, we assembled a rich set of derived analysis results including published predicted and validated regulatory interactions. Here we introduce the resource and its update after the initial release.",
            "question": "What was the purpose of the FANTOM4 project?",
            "answers": {
                "answer_start": 214,
                "text": "better understand the transcriptional network that regulates macrophage differentiation"
            }
        },
        {
            "context": "Pembrolizumab versus Ipilimumab in Advanced Melanoma. BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).",
            "question": "What is targeted by monoclonal antibody Pembrolizumab?",
            "answers": {
                "answer_start": 207,
                "text": "programmed cell death 1"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 987,
                "text": "53BP1"
            }
        },
        {
            "context": "Incremental diagnostic quality gain of CTA over V/Q scan in the assessment of pulmonary embolism by means of a Wells score Bayesian model: results from the ACDC collaboration. OBJECTIVE: Our objective was to evaluate the diagnostic value of computed tomography angiography (CTA) and ventilation perfusion (V/Q) scan in the assessment of pulmonary embolism (PE) by means of a Bayesian statistical model. METHODS: Wells criteria defined pretest probability. Sensitivity and specificity of CTA and V/Q scan for PE were derived from pooled meta-analysis data. Likelihood ratios calculated for CTA and V/Q were inserted in the nomogram. Absolute (ADG) and relative diagnostic gains (RDG) were analyzed comparing post- and pretest probability. Comparative gain difference was calculated for CTA ADG over V/Q scan integrating ANOVA p value set at 0.05. RESULTS: The sensitivity for CT was 86.0% (95% CI: 80.2%, 92.1%) and specificity of 93.7% (95% CI: 91.1%, 96.3%). The V/Q scan yielded a sensitivity of 96% (95% CI: 95%, 97%) and a specificity of 97% (95% CI: 96%, 98%). Bayes nomogram results for CTA were low risk and yielded a posttest probability of 71.1%, an ADG of 56.1%, and an RDG of 374%, moderate-risk posttest probability was 85.1%, an ADG of 56.1%, and an RDG of 193.4%, and high-risk posttest probability was 95.2%, an ADG of 36.2%, and an RDG of 61.35%. The comparative gain difference for low-risk population was 46.1%; in moderate-risk 41.6%; and in high-risk a 22.1% superiority. ANOVA analysis for LR+ and LR- showed no significant difference (p = 0.8745, p = 0.9841 respectively). CONCLUSIONS: This Bayesian model demonstrated a superiority of CTA when compared to V/Q scan for the diagnosis of pulmonary embolism. Low-risk patients are recognized to have a superior overall comparative gain favoring CTA.",
            "question": "What can be predicted with the Wells criteria?",
            "answers": {
                "answer_start": 337,
                "text": "pulmonary embolism"
            }
        },
        {
            "context": "Genetic Determinants of RNA Editing Levels of ADAR Targets in Drosophila melanogaster. RNA editing usually affects only a fraction of expressed transcripts and there is a vast amount of variation in editing levels of ADAR (adenosine deaminase, RNA-specific) targets. Here we explore natural genetic variation affecting editing levels of particular sites in 81 natural strains of Drosophila melanogaster. The analysis of associations between editing levels and single-nucleotide polymorphisms allows us to map putative cis-regulatory regions affecting editing of 16 A-to-I editing sites (cis-RNA editing quantitative trait loci or cis-edQTLs, P < 10(-8)). The observed changes in editing levels are validated by independent molecular technique. All identified regulatory variants are located in close proximity of modulated editing sites. Moreover, colocalized editing sites are often regulated by same loci. Similar to expression and splicing QTL studies, the characterization of edQTLs will greatly expand our understanding of cis-regulatory evolution of gene expression.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 46,
                "text": "ADAR"
            }
        },
        {
            "context": "First trimester maternal serum PAPP-A and free β-HCG levels in hyperemesis gravidarum. OBJECTIVE: To evaluate whether hyperemesis gravidarum (HG) affects first-trimester maternal serum PAPP-A and free β-hCG levels. METHOD: An observational study was conducted in 115 cases of HG and 110 control pregnancies who attended the first-trimester prenatal screening program between January 2006 and July 2010. RESULTS: Maternal serum TSH levels were lower and free T4, and transaminases (ALT, AST) levels were higher in pregnancies complicated with HG compared with controls (p < 0.05 for all). In HG cases, median values of maternal serum PAPP-A were significantly higher with respect to normal pregnancies (1.2 vs 1.0 MoM; p = 0.009). Similarly, median values of free β-hCG were 1.3 MoM in HG pregnancies and 1.0 MoM in controls (p = 0.006). Multivariate analysis revealed that PAPP-A and hCG were independently associated with HG after controlling for TSH, free T4, AST, and ALT. CONCLUSION: HG is associated with elevated levels of PAPP-A and free β-hCG, and such changes are independent of serum indicators of thyroid and liver function.",
            "question": "Which protein is associated with hyperemesis gravidarum during pregrancy?",
            "answers": {
                "answer_start": 49,
                "text": "HCG"
            }
        },
        {
            "context": "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs \"facing\" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.",
            "question": "What is the preferred orientation of CTCF binding sites for chromatin looping?",
            "answers": {
                "answer_start": 787,
                "text": "convergent orientation"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 909,
                "text": "53BP1"
            }
        },
        {
            "context": "Ideal vial size for bortezomib: real-world data on waste and cost reduction in treatment of multiple myeloma in Brazil. OBJECTIVES: Single-size vials of drugs may be a source of waste and increase in treatment costs. Bortezomib, indicated for multiple myeloma (MM) treatment, is available in 3.5-mg vials, a quantity higher than the average dose commonly prescribed. This analysis aimed to demonstrate, through real-world data, which would be the optimal vial presentation for bortezomib in Brazil and quantify the reduction in medication waste related to this option. METHODS: From November 2007 to October 2009 all patients with MM treated with bortezomib were identified via the Evidências database. Analysis of prescribed, dispensed, and wasted doses, their costs and projections of the ideal vial size were performed. RESULTS: Thirty-five patients (mean body surface area of 1.73 m(2)) received 509 infusions in 131 cycles of treatment (average of 3.77 cycles per patient). The average dose prescribed was 2.1 mg per infusion (95% confidence interval [CI] 1.97-2.26) with average waste of 39.5% of the vial content (95% CI 35.35-43.76). The mean waste per patient per day was 1.38 mg (95% CI 1.24-1.52). If a 3-mg vial were available, the average drug waste per patient per day would be 0.88 mg (95% CI 0.74-1.03) or 36.2% less. With a 2.5-mg vial the waste would be 1.05 mg (95% CI 0.81-1.29) or 23.9% less. If two presentations were available (2.5 mg and 0.5 mg), the waste would be 0.52 mg (95% CI 0.4-0.63) or 62.5% less. Considering the price of the different vials to be proportional to the original 3.5-mg vial, the cost would be also reduced by the same rates described above. CONCLUSIONS: A simple adjustment in vial size may reduce the waste of bortezomib by 36% to 62% and can also reduce the cost of treatment.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 243,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Interactions of ataxin-3 with its molecular partners in the protein machinery that sorts protein aggregates to the aggresome. Ataxin-3 (AT3) is the protein that triggers the inherited neurodegenerative disorder spinocerebellar ataxia type 3 when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length. AT3 consists of the N-terminal globular Josephin domain (JD) and the C-terminal disordered one. It cleaves isopeptide bonds between ubiquitin monomers, an event involved in protein quality control mechanisms. AT3 has been implicated in the pathway that sorts aggregated protein to aggresomes via microtubules, in which dynein and histone deacetylase 6 (HDAC6) also seem to be involved. By taking advantage of small angle X-ray scattering (SAXS) and surface plasmon resonance (SPR), we have investigated the interaction of AT3 with tubulin and HDAC6. Based on SAXS results, the AT3 oligomer, consisting of 6-7 subunits, tightly binds to the tubulin hexameric oligomer in a \"parallel\" fashion. By SPR analysis we have demonstrated that AT3 binds to tubulin dimer with a 50nM affinity. Binding fits with a Langmuir 1:1 model and involves a single binding interface. Nevertheless, the interaction surface consists of three distinct, discontinuous tubulin-binding regions (TBR), one located in the JD, and the two others in the disordered domain, upstream and downstream of the polyQ stretch. In the absence of any of the three TBRs, the affinity is drastically reduced. By SPR we have also provided the first evidence of direct binding of AT3 to HDAC6, with affinity in the range 0.1-1μM. These results shed light on the interactions among the components of the transport machinery that sorts aggregate protein to the aggresome, and pave the way to in vivo studies aimed at further clarifying their roles.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 126,
                "text": "Ataxin-3"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 180,
                "text": "stroke"
            }
        },
        {
            "context": "Molecular mechanism underlying activation of superoxide-producing NADPH oxidases: roles for their regulatory proteins. The phagocyte NADPH oxidase is dormant in resting cells but becomes activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defence. The catalytic core of this enzyme comprises the two membranous subunits gp91phox/Nox2 and p22phox. The oxidase activation requires the small GTPase Rac and the SH3 domain-containing proteins p47phox and p67phox; they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47phox, which leads to the SH3 domain-mediated interaction with p22phox, a binding required for the gp91phox/Nox2-dependent superoxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47phox and p67phox, designated Noxo1 and Noxa1, respectively. Noxo1 and Noxa1, both expressed abundantly in the colon, are capable of constitutively activating Nox1. The constitutive activation may be due to the property of Noxo1: in contrast with p47phox, Noxo1 seems to normally associate with p22phox, which is required for the Nox1 activation. We will also describe the mechanism underlying regulation of the third oxidase Nox3, which exits in fetal kidney and inner ears.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 865,
                "text": "Nox1"
            }
        },
        {
            "context": "Epigenetic regulation of estrogen receptor alpha gene expression in the mouse cortex during early postnatal development. Estrogens play a critical role in brain development by acting on areas that express estrogen receptors. In the rodent cortex, estrogen receptor alpha (ER alpha) mRNA expression is high early in postnatal development but declines starting at postnatal day (PND) 10 and is virtually absent in the adult cortex. The mechanisms controlling this regulation are largely unknown. Methylation is important for gene silencing during development in many tissues, including the brain. In the present study, we examined the methylation status of ER alpha 5' untranslated exons during early postnatal development in male and female mice using methylation-specific PCR and pyrosequencing. Several regions of ER alpha promoter displayed a significant increase in methylation at PND 18 and 25 compared with PND 4. DNA methyltransferases (DNMT) are important for the initiation and maintenance of methylation. Real-time PCR showed that DNMT3A, the de novo DNMT peaked at PND 10 and was decreased by PND 25. DNMT1, which is important for maintenance of methylation, increased across development and stayed high in adult cortex. The methyl-CpG-binding protein 2 (MeCP2) is also important for stabilization of methylation. A chromatin immunoprecipitation assay showed a correlation between association of MeCP2 with ER alpha promoter and the increase in methylation and decrease in ER alpha expression after PND 10. In mice containing a mutant MeCP2 protein, ER alpha mRNA expression and promoter methylation patterns across development were different compared with wild-type mice. These data suggest that methylation of ER alpha promoters regulates ER alpha mRNA expression in the cortex during postnatal development in a MeCP2-dependent fashion.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1111,
                "text": "DNMT1"
            }
        },
        {
            "context": "Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.",
            "question": "Which antibodies cause Riedel thyroiditis?",
            "answers": {
                "answer_start": 673,
                "text": "IgG4"
            }
        },
        {
            "context": "Temperature-dependent sensitivity enhancement of solid-state NMR spectra of alpha-synuclein fibrils. The protein alpha-synuclein (AS) is the primary fibrillar component of Lewy bodies, the pathological hallmark of Parkinson's disease. Wild-type human AS and the three mutant forms linked to Parkinson's disease (A53T, A30P, and E46K) all form fibrils through a nucleation-dependent pathway; however, the biophysical details of these fibrillation events are not yet well understood. Atomic-level structural insight is required in order to elucidate the potential role of AS fibrils in Parkinson's disease. Here we show that low temperature acquisition of magic-angle spinning NMR spectra of wild type AS fibrils-greatly enhances spectral sensitivity, enabling the detection of a substantially larger number of spin systems. At 0 +/- 3 degrees C sample temperature, cross polarization (CP) experiments yield weak signals. Lower temperature spectra (-40 +/- 3 degrees C) demonstrated several times greater signal intensity, an effect further amplified in 3D 15N-13C-13C experiments, which are required to perform backbone assignments on this sample. Thus 3D experiments enabled assignments of most amino acids in the rigid part of the fibril (approximately residues 64 to 94), as well as tentative site-specific assignments for T22, V26, A27, Y39, G41, S42, H50, V52, A53, T54, V55, V63, A107, I112, and S129. Most of these signals were not observed in 2D or 3D spectra at 0 +/- 3 degrees C. Spectra acquired at low temperatures therefore permitted more complete chemical shift assignments. Observation of the majority of residues in AS fibrils represents an important step towards solving the 3D structure.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 113,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Davidson Trauma Scale (DTS): normative scores in the general population and effect sizes in placebo-controlled SSRI trials. The Davidson Trauma Scale (DTS) was developed as a self-rating for use in diagnosing and measuring symptom severity and treatment outcome in post-traumatic stress disorder (PTSD); 630 subjects were identified by random digit dialing and evaluated for a history of trauma. Prevalence rates of PTSD and subthreshold PTSD with impairment were 2.2 and 4.1%, respectively. In this general population sample, 438 subjects endorsed at least one trauma, and four groups were generated: A) threshold PTSD (n = 13), B) subthreshold PTSD with impairment (n = 26), C) subthreshold PTSD without impairment (n = 78), and D) no PTSD (n = 321). Mean (SD) DTS score in the entire population was 11.0 +/- 18.1. Differences were found in four of the five pairwise between-group contrasts. In a second sample of 447 clinical trial participants from three SSRI vs. placebo studies, we assessed treatment effect size according to different measures. In all three clinical trials, effect size with the DTS was equal to, or better than, those found for the Impact of Event Scale (IES), Clinician Administered PTSD Scale (CAPS), and Structured Interview for PTSD (SIP). These results further affirm the utility of the DTS as a self-rating measure of PTSD symptom severity and in evaluating treatment response.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 297,
                "text": "PTSD"
            }
        },
        {
            "context": "[Reported use of thalidomide in multiple myeloma: presentation of problems in the Thaled® outpatient department]. BACKGROUND: Thalidomide was approved in Japan for multiple myeloma treatment in October 2008. A program called the Thalidomide Education and Risk Management System (TERMS®) was established to help ensure that every effort is made to use the drug safely. PURPOSE: We report the use of thalidomide to treat multiple myeloma, and describe problems arising in the Thaled® outpatient department. PATIENTS AND METHODS: Multiple myeloma patients treated with thalidomide at Hitachi General Hospital. INTERVENTION: Monitoring of the efficacy and safety of thalidomide, and a questionnaire survey conducted at the Thaled® outpatient department. RESULTS: The thalidomide response rate was 41. 7%. In 5 cases, all patients received steroids along with thalidomide. After auto-PBSCT, 1 of 2 cases demonstrated a good response (PR 1). After treatment with bortezomib, 1 of 2 cases demonstrated a good response (MR 1). After auto-PBSCT and treatment with bortezomib, 1 of 4 cases demonstrated a good response (PR 1). In a case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), administration was discontinued. Regarding problems in the Thaled® outpatient department, the medical staff indicated that TERMS® is a very complicated program, while the patients requested prolongation of the prescription days and reduction of the economic burden of medication costs. CONCLUSION: Thalidomide showed some success in treating multiple myeloma either after auto-PBSCT or following treatment with bortezomib. In the case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), grave complications could have very easily developed, thus underscoring the importance of careful monitoring. Based on a questionnaire survey conducted in the Thaled® outpatient department, the medical staff made comments and patients raised issues that should be examined in the future.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 1536,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 288,
                "text": "xa"
            }
        },
        {
            "context": "Inhibitory Effect of Algal Extracts on Mycelial Growth of the Tomato-Wilt Pathogen, Fusarium oxysporum f. sp. lycopersici. The present study was undertaken to explore the inhibitory effect of cyanobacterial extracts of Nostoc commune FA-103 against the tomato-wilt pathogen, Fusarium oxysporum f. sp. lycopersici. In an optimal medium, cell growth, antifungal activity, and antifungal compound production could be increased 2.7-fold, 4.1-fold, and 13.4-fold, respectively. A crude algal extract had a similar effect as mancozeb at the recommended dose, both in laboratory and pot tests. In vitro and in vivo fungal growth, spore sporulation and fungal infection of wilt pathogen in tomato seeds were significantly inhibited by cyanobacterial extracts. Nostoc commune FA-103 extracts have potential for the suppression of Fusarium oxysporum f. sp. lycopersici.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 62,
                "text": "Tomato"
            }
        },
        {
            "context": "Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor beta gene and has been given the acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.",
            "question": "Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome?",
            "answers": {
                "answer_start": 850,
                "text": "MCT8"
            }
        },
        {
            "context": "Heme and FLVCR-related transporter families SLC48 and SLC49. Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.",
            "question": "Which SLC family is FLVCR1 a member of?",
            "answers": {
                "answer_start": 265,
                "text": "SLC49"
            }
        },
        {
            "context": "Prevention of cryptococcosis in HIV-infected patients with limited access to highly active antiretroviral therapy: evidence for primary azole prophylaxis. Despite advances in the treatment of HIV disease, the incidence and mortality of invasive cryptococcal disease remain significant. A matched, case-control study was performed to examine the impact of highly active antiretroviral therapy (HAART) and azole use on the incidence of invasive cryptococcal disease in HIV-infected patients. The study was performed at a metropolitan hospital with a large indigent population and an incidence of seven cases of cryptococcal disease per 1000 persons with AIDS. Bivariate analysis, matched on CD4 count, revealed that both HAART use [odds ratio (OR) 0.43; 95% confidence interval (CI) 0.23-0.99] and azole use (OR 0.14; 95% CI 0.06-0.34) had a protective effect. Conditional logistic regression stratified on CD4 lymphocyte count revealed a protective role for azole use (OR 0.15; 95% CI 0.06-0.40) but not for HAART use (OR 0.47; 95% CI 0.18-1.26). Of note, the prevalence of HAART use was low in both cases and controls, with only 12% of cases and 23% of controls on HAART. The results of this study support previous evidence that azole use prevents invasive cryptococcal disease. Although current guidelines for the prophylaxis of opportunistic infections do not suggest routine prophylaxis for cryptococcal infection, this issue should be reconsidered, especially in populations that have a low prevalence of HAART use.",
            "question": "Which is the main reason for the increase in the incidence of cryptococcal disease?",
            "answers": {
                "answer_start": 192,
                "text": "HIV"
            }
        },
        {
            "context": "Monitoring plasma levels of factor Xa inhibitors: how, why and when? New oral anticoagulants are directed towards a single target, essentially factor Xa (FXa) or factor IIa. They do not require routine coagulation monitoring. However, in special clinical settings (emergency surgery, bleeding, thrombosis, control of the patient's compliance, suspected overdose, potential drug interference, and so on), measurement of plasma levels is needed. Several available anti-FXa assays are used for monitoring anticoagulant activity of heparins and fondaparinux. They must be modified and standardized for the measurement of direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban and others). The use of calibrators (lyophilized plasma with a known concentration of drug) allows an expression of the results in ng per ml of plasma. Two categories of assays - endogenous and exogenous assays are available. Endogenous assays are useful in pharmaceutical research, while exogenous assays are used in clinical laboratories. The preferred anti-FXa assay is a specific method in contrast to prothrombin time and activated partial thromboplastin time, but it is not available everywhere at any time. A specific measurement of direct FXa inhibitors is feasible with the use of a new test developed by the authors' group. The physicians must be aware of the possibility to measure the plasma concentration of FXa inhibitors in patients at high risk of bleeding and in several other special clinical situations.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 666,
                "text": "xa"
            }
        },
        {
            "context": "A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 208,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ. These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy result in Danon disease characterized by hypertrophic cardiomyopathy. The ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte excitation-contraction and its dysfunction can lead to cardiac failure. Whether RyR2 is degraded by CMA is unknown. METHODS AND RESULTS: To induce CMA, cultured neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote protein degradation through this pathway. GA increased LAMP-2A levels together with its redistribution and colocalization with Hsc70 in the perinuclear region, changes indicative of CMA activation. The inhibition of lysosomes but not proteasomes prevented the loss of RyR2. The recovery of RyR2 content after incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ motifs which are required for the recognition Hsc70 and its degradation via CMA. Our data suggest that presenilins are involved in RyR2 degradation by CMA. CONCLUSION: These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 84,
                "text": "Chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Forty percent of the patients are blood transfusion-dependent. Recent reports show that the ribosomal protein S19 (RPS19) gene is mutated in 25% of all patients with DBA. We constructed oncoretroviral vectors containing the RPS19 gene to develop gene therapy for RPS19-deficient DBA. These vectors were used to introduce the RPS19 gene into CD34(+) bone marrow (BM) cells from 4 patients with DBA with RPS19 gene mutations. Overexpression of the RPS19 transgene increased the number of erythroid colonies by almost 3-fold. High expression levels of the RPS19 transgene improved erythroid colony-forming ability substantially whereas low expression levels had no effect. Overexpression of RPS19 had no detrimental effect on granulocyte-macrophage colony formation. Therefore, these findings suggest that gene therapy for RPS19-deficient patients with DBA using viral vectors that express the RPS19 gene is feasible.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 130,
                "text": "DBA"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 1485,
                "text": "53BP1"
            }
        },
        {
            "context": "Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 45,
                "text": "XK"
            }
        },
        {
            "context": "Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 1348,
                "text": "human telomerase reverse transcriptase"
            }
        },
        {
            "context": "PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 446,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Christianson syndrome: spectrum of neuroimaging findings. Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. The clinical phenotypes of CS and Angelman syndrome (AS) are similar. Differentiation between CS and AS is important in terms of genetic counseling. We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. Cerebellar atrophy (CA) occurs in approximately 60% of the patients with CS and develops after the age of 12 months. Hyperintense signal of the cerebellar cortex (CbC) is less common, and may be diffuse, patchy, or involve only the inferior part of the cerebellum and is best seen on coronal fluid attenuation inversion recovery images. CA and CbC-hyperintensity are not neuroimaging features of AS. In a child with the phenotype of AS, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 461,
                "text": "SLC9A6"
            }
        },
        {
            "context": "[Causes of sudden cardiac death in athletes]. INTRODUCTION: Sudden cardiac death in athletes is a growing problem, despite the huge existing knowledge in medicine and sports. EFFECTS OF VIGOROUS PHYSICAL ACTIVITY: In response to vigorous physical activity, the body undergoes profound morphologic and functional changes. These changes are usually healthy, but sometimes may gravitate to some cardiac diseases. But still, most saudden cardiac deaths are due to previous unknown diseases. CAUSES OF SUDDEN CARDIAC DEATH: The most common cause of sudden cardiac death in athletes is hypertrophic cardiomyopathy. Other reasons are congenital coronary artery anomalies, nivocarditis, dilatative cardiomyopathy, arrhythmogenic cardiomyopathy of the right ventricle, sarcoidosis, mitral valve prolapse, aortic valve stenosis, atherosclerosis, long QT syndrome, and blunt impact to the chest. CONCLUSION: Bearing in mind the above mentioned, more frequent physical examinations of athletes are recommended.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 580,
                "text": "hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "Cyclin-dependent kinase pathways as targets for women's cancer treatment. PURPOSE OF REVIEW: In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development. RECENT FINDINGS: Targeting CDKs has been the focus of considerable basic science and clinical research. The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle. Currently, palbociclib (PD0332991, Pfizer), abemaciclib (LY2835219, Lilly) and ribociclib (LEE011, Novartis) are being investigated in clinical trials. These oral agents offer the hope of clinical efficacy in many tumor types, and have been associated with minimal toxicity. Amplification/overexpression of cyclin D, loss of CDKN2A (p16) and amplification/overexpression of CDK4 are proposed biomarkers of improved response to CDK4/6 inhibition. SUMMARY: Palbociclib, abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer, liposarcoma, mantel cell lymphoma and melanoma. Moreover, CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma, renal and ovarian cancer models that may provide directions for their future clinical development. Further preclinical and clinical research is needed to better understand mechanisms of resistance and develop rational combination therapies with other targeted agents.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 1306,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 33,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Positive and negative selection in murine ultraconserved noncoding elements. There are many more selectively constrained noncoding than coding nucleotides in the mammalian genome, but most mammalian noncoding DNA is subject to weak selection, on average. One of the most striking discoveries to have emerged from comparisons among mammalian genomes is the hundreds of noncoding elements of more than 200 bp in length that show absolute conservation among mammalian orders. These elements represent the tip of the iceberg of a much larger class of conserved noncoding elements (CNEs). Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development. Here, we quantify negative and positive selection acting in murine CNEs by analyzing within-species nucleotide variation and between-species divergence of CNEs that we identified using a phylogenetically independent comparison. The distribution of fitness effects of new mutations in CNEs, inferred from within-species polymorphism, suggests that CNEs receive a higher number of strongly selected deleterious mutations and many fewer nearly neutral mutations than amino acid sites of protein-coding genes or regulatory elements close to genes. However, we also show that CNEs experience a far higher proportion of adaptive substitutions than any known category of genomic sites in murids. The absolute rate of adaptation of CNEs is similar to that of amino acid sites of proteins. This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 746,
                "text": "development"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 15,
                "text": "53BP1"
            }
        },
        {
            "context": "Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 201,
                "text": "thyroid"
            }
        },
        {
            "context": "The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II. The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 424,
                "text": "TFIIS"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 129,
                "text": "naloxone"
            }
        },
        {
            "context": "The dorsal neural tube: a dynamic setting for cell fate decisions. The dorsal neural tube first generates neural crest cells that exit the neural primordium following an epithelial-to-mesenchymal conversion to become sympathetic ganglia, Schwann cells, dorsal root sensory ganglia, and melanocytes of the skin. Following the end of crest emigration, the dorsal midline of the neural tube becomes the roof plate, a signaling center for the organization of dorsal neuronal cell types. Recent lineage analysis performed before the onset of crest delamination revealed that the dorsal tube is a highly dynamic region sequentially traversed by fate-restricted crest progenitors. Furthermore, prospective roof plate cells were shown to originate ventral to presumptive crest and to progressively relocate dorsalward to occupy their definitive midline position following crest delamination. These data raise important questions regarding the mechanisms of cell emigration in relation to fate acquisition, and suggest the possibility that spatial and/or temporal information in the dorsal neural tube determines initial segregation of neural crest cells into their derivatives. In addition, they emphasize the need to address what controls the end of neural crest production and consequent roof plate formation, a fundamental issue for understanding the separation between central and peripheral lineages during development of the nervous system.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 106,
                "text": "neural crest cells"
            }
        },
        {
            "context": "The glucocerebrosidase D409H mutation in Gaucher disease. Gaucher disease, resulting from the decreased activity of the lysosomal enzyme glucocerebrosidase, is the most prevalent sphingolipid storage disease. Due to considerable heterogeneity of phenotypic expression, it has been subdivided into the nonneurological type 1 disease, and types 2 and 3, the neurological types. We describe homozygosity for the D409H mutation within the glucocerebrosidase gene associated with a unique form of type 3 Gaucher disease. Twelve patients, originating from three Arab sibships, were found to be homozygous for the D409H mutation. They all presented with oculomotor apraxia and a progressive cardiac valve defect with minimal organomegaly. When expressed in human cells in tissue culture, using the T7/EMC/vaccinia virus hybrid expression system, we were able to demonstrate that the mRNA carrying the D409H mutation was less stable than the normal counterpart. Pulse-chase experiments demonstrated that the mutated protein exhibited lower stability than the normal counterpart. Its activity toward the artificial substrate 4-methyl umbelliferyl glucopyranoside was similar to that of the mutated enzymes carrying the N370S or the L444P mutations. However, in loading experiments using lissamine-rhodamine conjugated glucosyl ceramide as a substrate, the recombinant mutated protein carrying the D409H mutation exhibited 28.63 +/- 6.05% of the activity exhibited by the normal enzyme. L444P and N370S mutations exhibited 51.90 +/- 7.16 and 115.75 +/- 12.64% of normal enzyme activity, respectively. Loading of cells homozygous for the D409H mutation demonstrated 10. 05% of the activity shown by normal cells. L444P and N370S homozygous cells demonstrated 25.3 and 98.5% of foreskin fibroblast glucocerebrosidase activity, respectively. We demonstrate that homozygosity for the D409H mutation is a unique case of a peculiar phenotype associated with a specific intracellular glucocerebrosidase activity.",
            "question": "What is the gene mutated in the Gaucher disease?",
            "answers": {
                "answer_start": 137,
                "text": "glucocerebrosidase"
            }
        },
        {
            "context": "Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p. Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 45,
                "text": "α-synuclein"
            }
        },
        {
            "context": "Zebrafish as a model for monocarboxyl transporter 8-deficiency. Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8 knock-out mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neural development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8 deficiency that exhibits a neurological phenotype.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 191,
                "text": "thyroid"
            }
        },
        {
            "context": "Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia. BACKGROUND: Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS: A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS: Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS: Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 0,
                "text": "Telomerase"
            }
        },
        {
            "context": "BACE-1 inhibition prevents the γ-secretase inhibitor evoked Aβ rise in human neuroblastoma SH-SY5Y cells. BACKGROUND: Accumulation of amyloid β-peptide (Aβ) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aβ peptides. Preventing Aβ formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development. METHODS: Combining BACE-1 and γ-secretase inhibition on Aβ secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Aβ40 and Aβ42 levels were measured from SH-SY5Y cells stably transfected with APPwt or APPswe genes. A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase. RESULTS: LY450139 increased Aβ40 and Aβ42 secretion from SH-SY5Y APPwt cells at low concentrations (by 60% at 3 nM) followed by subsequent inhibition at higher concentrations (IC(50) 90 nM). Washout studies showed that the Aβ increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Aβ formation. By contrast, LY450139 inhibited Aβ formation from SH-SY5Y APPswe in a monophasic manner (IC(50) 18 nM). The BACE inhibitor per se inhibited Aβ secretion from both SH-SY5Y APPwt and SH-SY5Y APPswe cells with IC(50)s ranging between 7 - 18 nM and also prevented the increased Aβ secretion evoked by 3 nM LY450139. Combining the BACE inhibitor with higher inhibitory concentrations of LY450139 failed to demonstrate any clear additive or synergistic effects. CONCLUSION: BACE-1 inhibition attenuates the Aβ increase evoked by LY450139 while not providing any obvious synergistic effects on LY450139-mediated inhibition.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 854,
                "text": "semagacestat"
            }
        },
        {
            "context": "Targeting anaplastic lymphoma kinase in lung cancer. Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non-small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to \"oncogene addiction\" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 532,
                "text": "cancer"
            }
        },
        {
            "context": "SEF, a new protein required for flowering repression in Arabidopsis, interacts with PIE1 and ARP6. The SWR1/SRCAP complex is a chromatin-remodeling complex that has been shown to be involved in substitution of histone H2A by the histone variant H2A.Z in yeast (Saccharomyces cerevisiae) and animals. Here, we identify and characterize SERRATED LEAVES AND EARLY FLOWERING (SEF), an Arabidopsis (Arabidopsis thaliana) homolog of the yeast SWC6 protein, a conserved subunit of the SWR1/SRCAP complex. SEF loss-of-function mutants present a pleiotropic phenotype characterized by serrated leaves, frequent absence of inflorescence internodes, bushy aspect, and flowers with altered number and size of organs. sef plants flower earlier than wild-type plants both under inductive and noninductive photoperiods. This correlates with strong reduction of FLOWERING LOCUS C and MADS-AFFECTING FLOWERING4 transcript levels and up-regulation of FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 gene expression. The sef phenotype is similar to that of the photoperiod-independent early flowering1 (pie1) and the actin-related protein 6 (arp6) mutants. PIE1 and ARP6 proteins are also homologs of SWR1/SRCAP complex subunits. Analysis of sef pie1 double mutants demonstrates genetic interaction between these two genes. We also show physical interactions between SEF, ARP6, and PIE1 proteins. Taken together, our data indicate that SEF, ARP6, and PIE1 might form a molecular complex in Arabidopsis related to the SWR1/SRCAP complex identified in other eukaryotes.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 478,
                "text": "SWR1"
            }
        },
        {
            "context": "The RESID Database of Protein Modifications as a resource and annotation tool. The RESID Database of Protein Modifications is a comprehensive collection of annotations and structures for protein modifications and cross-links including pre-, co-, and post-translational modifications. The database provides: systematic and alternate names, atomic formulas and masses, enzymatic activities that generate the modifications, keywords, literature citations, Gene Ontology (GO) cross-references, protein sequence database feature table annotations, structure diagrams, and molecular models. This database is freely accessible on the Internet through resources provided by the European Bioinformatics Institute (http://www.ebi.ac.uk/RESID), and by the National Cancer Institute--Frederick Advanced Biomedical Computing Center (http://www.ncifcrf.gov/RESID). Each RESID Database entry presents a chemically unique modification and shows how that modification is currently annotated in the protein sequence databases, Swiss-Prot and the Protein Information Resource (PIR). The RESID Database provides a table of corresponding equivalent feature annotations that is used in the UniProt project, an international effort to combine the resources of the Swiss-Prot, TrEMBL and PIR. As an annotation tool, the RESID Database is used in standardizing and enhancing modification descriptions in the feature tables of Swiss-Prot entries. As an Internet resource, the RESID Database assists researchers in high-throughput proteomics to search monoisotopic masses and mass differences and identify known and predicted protein modifications.",
            "question": "What is the RESID database?",
            "answers": {
                "answer_start": 79,
                "text": "The RESID Database of Protein Modifications is a comprehensive collection of annotations and structures for protein modifications and cross-links including pre-, co-, and post-translational modifications"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 1010,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 35,
                "text": "Alzheimer's Disease"
            }
        },
        {
            "context": "Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is universally fatal. Despite surgical resection, radiotherapy, and systemic chemotherapy, the median overall survival is less than 15 months. As current therapies are not tumor-specific, treatment commonly results in toxicity. The epidermal growth factor receptor variant III (EGFRvIII) is a naturally occurring mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune responses. Phase I and II clinical trials have demonstrated significantly higher progression-free and overall survival times in vaccinated patients with EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it is a promising therapy for patients with GBM. Currently, rindopepimut is undergoing clinical testing in an international Phase III trial for newly diagnosed GBM and a Phase II trial for relapsed GBM.",
            "question": "Rindopepimut is an analog of which growth factor?",
            "answers": {
                "answer_start": 708,
                "text": "EGFRvIII"
            }
        },
        {
            "context": "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. OBJECTIVE: To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. RESULTS: Mean interval from crew arrival to respiratory rate > or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 1367,
                "text": "naloxone"
            }
        },
        {
            "context": "Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase. Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARγ antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 1519,
                "text": "JNK"
            }
        },
        {
            "context": "Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. UNLABELLED: Donohue syndrome (leprechaunism; OMIM *246200) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene (INSR) causing either defects in insulin binding or receptor autophosphorylation and tyrosine kinase activity. We report a patient with pronounced clinical picture of leprechaunism who developed severe progressive hypertrophic obstructive cardiomyopathy (HOCM) and renal tubular dysfunction which improved on continuous subcutaneous infusion of recombinant human insulin-like growth factor-1 (rhIGF-I). INSR gene molecular analysis and insulin receptor (IR) autophosphorylation on cultured fibroblasts were performed. A novel homozygous missense mutation p.Leu795Pro was found, located in the extracellular portion of the β subunit of the insulin receptor. The post-binding defect of the insulin receptor signaling in cultured fibroblasts demonstrated decreased insulin receptor autophosphorylation. CONCLUSION: Treatment with rhIGF-I partially reversed severe progressive HOCM and renal tubular dysfunction in a patient with Donohue syndrome associated with a novel p.Leu795Pro INSR gene mutation causing a severe decrease in IR autophosphorylation.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 333,
                "text": "insulin receptor"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 784,
                "text": "traseR"
            }
        },
        {
            "context": "Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 4,
                "text": "xa"
            }
        },
        {
            "context": "Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. UNLABELLED: Thyroid hormones are known to be essential for growth, development, and metabolism. Recently, the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter, and MCT8 mutations have been associated with Allan-Herndon-Dudley syndrome, an X linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. Here we describe in detail the clinical and biochemical features and the response to thyroid hormone (L-thyroxine (LT4)) administration in a boy with an MCT8 mutation (c.1649delA) that truncates the protein in the twelfth transmembrane domain. It is of note that brain magnetic resonance imaging (MRI) revealed delayed myelination from infancy. Endocrine functions other than thyroid hormone regulation and metabolism were intact, resulting in normal hypothalamic/pituitary function tests. While LT4 administration suppressed thyrotropin (TSH) secretion, no significant changes in thyroid hormone values or clinical symptoms were observed. CONCLUSION: the characteristic thyroid hormone function tests and brain MRI findings may allow screening of high-risk populations for a better understanding of MCT8 pathophysiology.",
            "question": "Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?",
            "answers": {
                "answer_start": 1209,
                "text": "thyroid"
            }
        },
        {
            "context": "Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease. One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 165,
                "text": "AD"
            }
        },
        {
            "context": "Urethral sphincter innervation and clitoral blood flow after the transobturator (TOT) approach. INTRODUCTION AND HYPOTHESIS: The aim of the study was to exclude neurovascular damage due to prosthetic mini-invasive surgery using transobturator tape (TOT) by pre- and postoperative electromyography (EMG) of the striated urethral sphincter and a color Doppler ultrasonography evaluation of clitoral blood flow. METHODS: A total of 25 women affected by clinical stress urinary incontinence (SUI) were enrolled. After undergoing urodynamic assessment, pelvic organ prolapse quantification, urine culture, Q-tip test, and stress test, each subject underwent color Doppler ultrasonography to record clitoral blood flow and EMG of the urethral sphincter with a needle electrode inserted through the mucosa into the muscle tissue before surgery. A single urogynecologist performed the TOT surgical technique for the treatment of all patients. Urogynecologic examination, EMG, and color Doppler ultrasound follow-up were performed at 1 and 6 months after surgery. RESULTS: At the urogynecologic examination performed 1 and 6 months after the TOT approach the stress test was negative, urethral hypermobility was reduced, and sling exposure was not observed for each patient. There was no statistically significant difference in electromyographic values (p > 0.05) in both the follow-ups with regard to baseline values. Pulsatility index (PI), resistance index (RI), and peak systolic velocity (PSV) values increased during the first follow-up (p < 0.01); PI and RI values increased during the second follow-up with respect to baseline values (p < 0.01) CONCLUSIONS: TOT prosthesis surgery, avoiding denervation and devascularization of pelvic structures, does not damage the urethral sphincter.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 459,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Global DNA hypomethylation-induced ΔNp73 transcriptional activation in non-small cell lung cancer. p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic ΔΝp73 isoforms respectively. In this study, we investigated the DNA methylation status of both promoters as a means of epigenetic transcriptional control of their corresponding isoforms in 102 primary non-small cell lung carcinomas (NSCLCs). We demonstrated that while P1 hypermethylation-associated reduction of TAp73 mRNA levels is relatively infrequent, the P2 hypomethylation-associated over-expression of ΔΝp73 mRNA is a frequent event, particularly among squamous cell carcinomas. P2 hypomethylation strongly correlated with LINE-1 element hypomethylation, indicating that ΔΝp73 over-expression may be a passive consequence of global DNA hypomethylation.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 218,
                "text": "7"
            }
        },
        {
            "context": "Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. INTERPRETATION: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 481,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Clinical experience with the benzodiazepine antagonist flumazenil in suspected benzodiazepine or ethanol poisoning. The clinical efficacy of different doses of the specific benzodiazepine antagonist flumazenil was studied in a total of 72 patients with benzodiazepine or ethanol overdose. In a randomized double-blind study, 18 patients (group 1) and eight patients (group 2) with suspected benzodiazepine overdose received 5 mg (group 1) or 1 mg (group 2) flumazenil or placebo, respectively. The stage of coma, heart rate, blood pressure and respiratory rate were monitored within the following 15 min. If no change in the stage of coma was observed, 5 mg (group 1) or 1 mg (group 2) flumazenil were given, and the stage of coma, heart rate and blood pressure were again monitored. In a similar way, the effect of 5 and 1 mg flumazenil was investigated in 13 patients (group 3) and four patients (group 4) with ethanol intoxication. In an open trial, the clinical efficacy of flumazenil for the diagnosis of benzodiazepine or ethanol overdose was studied in 29 patients (group 5). In all patients, a toxicological screening confirmed benzodiazepine or ethanol overdose. None of the patients receiving placebo showed effects on stage of coma, heart rate, blood pressure or respiratory rate. Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection. The effect of 1 mg flumazenil (group 2) on benzodiazepine-induced coma was less pronounced. In patients with ethanol overdose (group 3), ethanol-induced coma was reversed after 5 mg flumazenil more slowly than in patients of group 1. No effect of flumazenil on ethanol-induced coma was observed in group 4. In group 5, flumazenil proved to be useful for diagnosing benzodiazepine or ethanol intoxication. In one patient with coma due to carbamazepine overdose, flumazenil was also found to be effective. Additionally, a possible analytical interference of flumazenil and its metabolites with the identification of other benzodiazepines by a toxicological screening procedure was studied. Even after an oral dose of 200 mg flumazenil, no interference with immunological benzodiazepine assays (EMIT, TDX, and RIA) was found. A metabolite and an artifact of flumazenil could be identified in urine by gas chromatography/mass spectrometry.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1348,
                "text": "flumazenil"
            }
        },
        {
            "context": "Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis. AIMS: This population pharmacokinetic analysis of the investigational oral proteasome inhibitor ixazomib assessed the feasibility of switching from body surface area (BSA)-based to fixed dosing, and the impact of baseline covariates on ixazomib pharmacokinetics. METHODS: Data were pooled from 226 adult patients with multiple myeloma, lymphoma or solid tumours in four phase 1 studies, in which ixazomib dosing (oral/intravenous, once/twice weekly) was based on BSA. Population pharmacokinetic modelling was undertaken using nonmem version 7.2. RESULTS: Ixazomib pharmacokinetics were well described by a three compartment model with first order absorption and linear elimination. Ixazomib was absorbed rapidly (Ka 0.5 h(-1)), with dose- and time-independent pharmacokinetics. Estimated absolute bioavailability and clearance were 60% and 2l h(-1), respectively. Although a small effect of BSA (range 1.3-2.6 m(2)) was observed on the peripheral volume of distribution (V4), reducing the corresponding inter-individual variability by 12.9%, there was no relationship between BSA and ixazomib clearance (the parameter that dictates total systemic exposure following fixed dosing). Consistently, based on simulations (n = 1000), median AUCs (including interquartile range) were similar after BSA-based (2.23 mg m(-2)) and fixed (4 mg) oral dosing with no trend in simulated AUC vs. BSA for fixed dosing (P = 0.42). No other covariates, including creatinine clearance (22-213.7 ml min(-1)) and age (23-86 years), influenced ixazomib pharmacokinetics. CONCLUSIONS: This analysis supports a switch from BSA-based to fixed dosing, without dose modification for mild/moderate renal impairment or age, in future adult studies of ixazomib, simplifying dosing guidance and clinical development.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 224,
                "text": "proteasome"
            }
        },
        {
            "context": "Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 1262,
                "text": "CD38"
            }
        },
        {
            "context": "Selective therapeutic targeting of the anaplastic lymphoma kinase with liposomal siRNA induces apoptosis and inhibits angiogenesis in neuroblastoma. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is involved in the pathogenesis of different types of human cancers, including neuroblastoma (NB). In NB, ALK overexpression, or point mutations, are associated with poor prognosis and advanced stage disease. Inhibition of ALK kinase activity by small-molecule inhibitors in lung cancers carrying ALK translocations has shown therapeutic potential. However, secondary mutations may occur that, generate tumor resistance to ALK inhibitors. To overcome resistance to ALK inhibitors in NB, we adopted an alternative RNA interference (RNAi)-based therapeutic strategy that is able to knockdown ALK, regardless of its genetic status [mutated, amplified, wild-type (WT)]. NB cell lines, transduced by lentiviral short hairpin RNA (shRNA), showed reduced proliferation and increased apoptosis when ALK was knocked down. In mice, a nanodelivery system for ALK-specific small interfering RNA (siRNA), based on the conjugation of antibodies directed against the NB-selective marker GD(2) to liposomes, showed strong ALK knockdown in vivo in NB cells, which resulted in cell growth arrest, apoptosis, and prolonged survival. ALK knockdown was associated with marked reductions in vascular endothelial growth factor (VEGF) secretion, blood vessel density, and matrix metalloproteinases (MMPs) expression in vivo, suggesting a role for ALK in NB-induced neoangiogenesis and tumor invasion, confirming this gene as a fundamental oncogene in NB.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 281,
                "text": "cancer"
            }
        },
        {
            "context": "Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.",
            "question": "What is the role of eteplirsen in DMD patients?",
            "answers": {
                "answer_start": 325,
                "text": "skipping of dystrophin exon 51"
            }
        },
        {
            "context": "A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. BACKGROUND: Serum interleukin (IL)-6 levels correlate with disease outcomes in renal cell carcinoma (RCC) patients. Siltuximab, a chimeric, murine-human mAb against IL-6, was evaluated in a three-part phase I/II study in patients with progressive metastatic RCC. METHODS: In part 1, 11 patients received 1, 3, 6, or 12mgkg-¹ at weeks 1, 4 and q2w × 2 thereafter; in part 2, 37 patients randomly received 3 or 6 mgkg-¹ q3w × 4; in part 3, 20 low-risk patients received 6mgkg-¹ q2w × 6. Modified WHO response criteria were assessed at weeks 7, 11, the 6-week follow-up, and when clinically indicated. RESULTS: Siltuximab was well tolerated overall, with no maximum tolerated dose or immune response observed. In all, 5 out of 11, 17 out of 37, and 9 out of 20 patients in parts 1, 2, and 3, respectively, received extended treatment beyond 4-6 initial infusions. In part 2, stable disease (SD) ( > 11weeks) or better was achieved by 11 out of 17 (65%) 3 mgkg-¹ treated patients (one partial response (PR) ~8 months, 10 SD) and 10 out of 20 (50%) 6mgkg-¹ treated patients (10 SD). In part 3, documented complete or PR was not observed, but 13 out of 20 (65%) patients achieved SD. CONCLUSION: Siltuximab stabilised disease in >50% of progressive metastatic RCC patients. One PR was observed. Given the favourable safety profile of siltuximab and poor correlation of tumour shrinkage with clinical benefit demonstrated for other non-cytotoxic therapies, further evaluation of dose-escalation strategies and/or combination therapy may be considered for patients with RCC.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 53,
                "text": "interleukin-6"
            }
        },
        {
            "context": "An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Proteasome inhibition represents one of the more important therapeutic targets in the treatment of multiple myeloma (MM), since by suppressing nuclear factor-κB activity, which promotes myelomagenesis, it makes plasma cells susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor approved for MM therapy, has been shown to increase response rate and improve outcome in patients with relapsed/refractory disease and in the frontline setting, particularly when combined with immunomodulatory drugs and alkylating agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss. Ixazomib was found to overcome bortezomib resistance and to trigger synergistic antimyeloma activity with dexamethasone, lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a single agent, showing important activity in this difficult-to-treat plasma-cell dyscrasia. More frequent side effects observed during administration of ixazomib were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas severe peripheral neuropathy was rare. Here, we review the chemical characteristics of ixazomib, as well as its mechanism of action and results from preclinical and clinical trials.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 99,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating enzyme inhibitor, MLN4924, using AlphaScreen. Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct. The inhibited enzyme can no longer transfer Nedd8 downstream to modify and activate the E3 cullin-RING ligases. This results in the stabilization of proteins regulated by the proteasome, leading to cell death. These studies monitored the endogenous cellular changes to NAE∼Nedd8 thioester, the formation of the Nedd8-MLN4924 adduct, and the reduction in the Cul1-Nedd8. Lysates derived from MLN4924-treated HCT116 cells showed that whereas the β-subunit of NAE remained constant, reductions of both NAE∼Nedd8 thioester and Cul1-Nedd8 levels occurred with a concomitant rise of the adduct. Moreover, the formation of the Nedd8-MLN4924 adduct was approximately stoichiometric with the concentration of NAEβ. Higher density 384-well cell-based assays illustrated the kinetics of enzyme inactivation across a wider range of MLN4924 concentrations, showing a rapid loss of NAE∼Nedd8 thioester and Cul1-Nedd8. The reduction of NAE∼Nedd8 thioester precedes the loss of Cul1-Nedd8 at twice the rate. Finally, these results clearly demonstrate the utility of the homogeneous assay for quantitative assessment of these endogenous cellular components in a 384-well plate in response to inhibition of NAE by MLN4924.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 143,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 644,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 596,
                "text": "xa"
            }
        },
        {
            "context": "Transcripts of Grg4, a murine groucho-related gene, are detected in adjacent tissues to other murine neurogenic gene homologues during embryonic development. The groucho-related genes (Grg) of the mouse comprise at least four family members. In Drosophila, groucho is one of the neurogenic genes that participates in the Notch signalling pathway. The Groucho protein interacts with Hairy-related transcription factors to regulate segmentation, neurogenesis and sex determination. Thus, by analogy to the Drosophila proteins, murine Grg proteins may interact with mammalian Hairy and E(spl) homologues (Hes proteins) and take part in a signalling pathway downstream of murine Notch. We have isolated murine Grg4 cDNAs and examined Grg4 expression during embryogenesis. Transcripts of Grg4 were detected in proliferating epithelial tissues undergoing mesenchymal induction, overlapping with Grg3, Notch1 and Hes1 expression. Grg4 was also expressed in the central nervous system and somites, but in cells adjacent to Grg3-, Notch1-, and Hes1-expressing cells. This distinct pattern of expression suggests a role for Grg4 in later stages of cell differentiation than for the other mouse neurogenic gene homologues.",
            "question": "How many Groucho-related genes (GRG) are contained in the mouse genome?",
            "answers": {
                "answer_start": 221,
                "text": "four"
            }
        },
        {
            "context": "Daratumumab granted breakthrough drug status. Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 586,
                "text": "CD38"
            }
        },
        {
            "context": "Clinical scores for the identification of stroke and transient ischaemic attack in the emergency department: a cross-sectional study. OBJECTIVE: To compare the sensitivity and specificity of bedside diagnostic stroke scales in patients with suspected stroke. DESIGN: A cross-sectional observational study of patients with suspected acute stroke in an emergency department in a UK hospital. DIAGNOSTIC SCALES: The results of an assessment with the Recognition of Stroke in the Emergency Room (ROSIER) scale, the Face Arm Speech Test (FAST) scale and the diagnosis of definite or probable stroke by an emergency department. Reference standard A consensus diagnosis of stroke or transient ischaemic attack (TIA) made after discussion by an expert panel (members included stroke physicians, neurologists and neuroradiologists), who had access to the clinical findings, imaging and subsequent clinical course, but were blinded to the results of the assessments by emergency-department staff. RESULTS: In 356 patients with complete data, the expert panel assigned a diagnosis of acute stroke or TIA in 246 and a diagnosis of mimic in 110. The ROSIER had a sensitivity of 83% (95% CI 78 to 87) and specificity of 44% (95% CI 34 to 53), and the FAST had a sensitivity of 81% (95% CI 76 to 86) and a specificity of 39% (95% CI 30 to 48). There was no detectable difference between the scales in sensitivity (p = 0.39) or specificity (p = 0.30). CONCLUSIONS: The simpler FAST scale could replace the more complex ROSIER for the initial assessment of patients with suspected acute stroke in the emergency department.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 1570,
                "text": "stroke"
            }
        },
        {
            "context": "BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1248,
                "text": "7"
            }
        },
        {
            "context": "Stereotactic radiosurgery for intracranial dural arteriovenous fistulas: a systematic review. OBJECT: The goal of this study was to evaluate the obliteration rate of intracranial dural arteriovenous fistulas (DAVFs) in patients treated with stereotactic radiosurgery (SRS), and to compare obliteration rates between cavernous sinus (CS) and noncavernous sinus (NCS) DAVFs, and between DAVFs with and without cortical venous drainage (CVD). METHODS: A systematic literature review was performed using PubMed. The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. The DAVFs were also categorized by location and by the presence of CVD. Statistical analyses of pooled data were conducted to assess complete obliteration rates in CS and NCS DAVFs, and in DAVFs with and without CVD. RESULTS: Nineteen studies were included, comprising 729 patients harboring 743 DAVFs treated with SRS. The mean obliteration rate was 63% (95% CI 52.4%-73.6%). Complete obliteration for CS and NCS DAVFs was achieved in 73% and 58% of patients, respectively. No significant difference in obliteration rates between CS and NCS DAVFs was found (OR 1.72, 95% CI 0.66-4.46; p=0.27). Complete obliteration in DAVFs with and without CVD was observed in 56% and 75% of patients, respectively. A significantly higher obliteration rate was observed in DAVFs without CVD compared with DAVFs with CVD (OR 2.37, 95% CI 1.07-5.28; p=0.03). CONCLUSIONS: Treatment with SRS offers favorable rates of DAVF obliteration with low complication rates. Patients harboring DAVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using SRS.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 533,
                "text": "DAVF"
            }
        },
        {
            "context": "Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 889,
                "text": "xa"
            }
        },
        {
            "context": "Origin of human chromosome 2: an ancestral telomere-telomere fusion. We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG)n-(CCCTAA)m3'. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 864,
                "text": "2"
            }
        },
        {
            "context": "Acute mitral regurgitation due to chordal rupture in a patient with neonatal Marfan syndrome caused by a deletion in exon 29 of the FBN1 gene. The neonatal Marfan syndrome is an autosomal dominantly inherited disease with an extremely poor prognosis. This report gives a clinical and echocardiographic description of an infant with a mutation in exon 29 of the fibrillin-1 gene (FBN1), a region in which this severe form of Marfan syndrome seems to cluster. The infant died at the age of 3 months due to severe acute mitral regurgitation leading to intractable heart failure.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 132,
                "text": "FBN1"
            }
        },
        {
            "context": "Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.",
            "question": "Which enzyme is inhibited by Orteronel?",
            "answers": {
                "answer_start": 2392,
                "text": "CYP17A1"
            }
        },
        {
            "context": "The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.",
            "question": "Which peptide plays a pivotal role in human cystatin C fibrillization?",
            "answers": {
                "answer_start": 384,
                "text": "LQVVR"
            }
        },
        {
            "context": "Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation. Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively.",
            "question": "Orteronel was developed for treatment of which cancer?",
            "answers": {
                "answer_start": 341,
                "text": "castration-resistant prostate cancer"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 22,
                "text": "TYR"
            }
        },
        {
            "context": "New evidence on the relationship between Microsporidia and Fungi: a genome-wide analysis by DarkHorse software. Microsporidia are a group of obligate intracellular eukaryotic parasites that infect a wide variety of species, including humans. Phylogenetic analysis indicates a relationship between the Microsporidia and the Fungi. However, most results are based on the analysis of relatively few genes. DarkHorse analysis involves the transformation of BLAST results into a lineage probability index (LPI) value and allows for the comparison of genes for an entire genome with those of other genomes. Thus, we can see which genes from the microsporidia score most closely based on the LPI with other eukaryotic organisms. In this analysis, we calculated the LPI for each gene from the genomes of 7 Microsporidia, Antonospora locustae, Enterocytozoon bieneusi, Encephalitozoon cuniculi, Encephalitozoon intestinalis, Nosema bombycis, Nosema ceranae, and Nematocida parisii, to analyze the genetic relationships between Microsporidia and other species. It was found that many (91%) genes were most closely correlated with genes from other microsporidial genomes and had the highest mean LPI (0.985), indicating a monophyletic origin of the Microsporidia. In a subsequent analysis, we excluded the other Microsporidia from the analysis to look for relationships before the divergence of Microsporidia, and found that 43% of the microsporidial genes scored highest with fungal genes, and a higher mean LPI was found with Fungi than with other kingdoms, suggesting that Microsporidia is closely related to Fungi at the genomic level. Microsporidial genes were functionally clustered based on the KOG (Eukaryotic COG) database, and the possible lineages for each gene family were discussed in concert with the DarkHorse results.",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1517,
                "text": "Fungi"
            }
        },
        {
            "context": "The dual role of p53: DNA protection and antioxidant. The classical functions of p53 protein are those related to its role on DNA damage, cell growth arrest, senescence and apoptosis. For this reason it is called 'the guardian of the genome' and is considered one of the most important players in the development of cancer. However, more recently it has been show that p53 is not only involved in cancer, but also in ageing. p53 is stimulated by stress, which in turn results in the activation of a wide range of transcriptional targets. Low-intensity stress will activate p53 in a manner which results in antioxidant response, thus protecting against ageing because of its antioxidant function. On the contrary, high-intensity activation of p53 will result in an increase of oxidative stress by activation of p53-mediated pro-oxidant targets, thus increasing the rate of ageing, but protecting against cancer.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 81,
                "text": "p53"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 215,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Transcriptional regulator PRDM12 is essential for human pain perception. Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.",
            "question": "What is the phenotype of people carrying mutations in the gene PRDM12?",
            "answers": {
                "answer_start": 434,
                "text": "congenital insensitivity to pain"
            }
        },
        {
            "context": "Genetic approaches to studying adenosine-to-inosine RNA editing. Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 690,
                "text": "ADAR"
            }
        },
        {
            "context": "The cyclic pattern of blood alcohol levels during continuous ethanol feeding in rats: the effect of feeding S-adenosylmethionine. S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver. The following parameters were studied to determine the effects of SAMe; liver histology, the blood alcohol cycle (BAL), changes in gene expression mined from microarray analysis, changes in histone methylation, changes in liver SAMe levels and its metabolites and ADH. SAMe changed the type of fatty liver, reduced liver ALT levels and prevented the BAL cycle caused by intragastric ethanol feeding. Microarray analysis showed that SAMe feeding prevented most of the changes in gene expression induced by ethanol feeding, presumably by inducing H3K27me3 and gene silencing. H3K27me3 was significantly increased by SAMe with or without ethanol feeding. It is concluded that SAMe feeding stabilized global gene expression so that the changes in gene expression involved in the blood alcohol cycle were prevented.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 130,
                "text": "S-adenosylmethionine"
            }
        },
        {
            "context": "Valsalva leak point pressure-associated Q-tip angle and simple female stress urinary incontinence symptoms. PURPOSE: To clarify the association between clinically defined simple stress urinary incontinence (SUI) symptoms and urodynamic SUI, we examined the relationship between Valsalva leak point pressure (VLPP) as measured by the Q-tip test and Stamey grade in simple female SUI. METHODS: Two hundred grade I or II female SUI patients with SUI symptom were examined by reviewing medical history; physical examination; urethral mobility as assessed by Q-tip test; stress test; and cystometry, including VLPP measurement. On the basis of the VLPP, patients were classified into urethral hypermobility [UH, subdivided into anatomical incontinence (AI) and equivocal incontinence (EI)] or intrinsic sphincter deficiency groups for analysis of the relationship between VLPP and Stamey grade and Q-tip angle. RESULTS: Seventy-eight patients were included, and the mean patient age was 54 ± 7.5 years, mean SUI symptom duration 2.8 years (range 0.5-6 years), mean VLPP 103.6 ± 18.4 cm H2O, and mean Q-tip angle 28.6° ± 7.2°. Fifty-three patients were categorized as Stamey grade I, 25 as Stamey grade II, 51 as AI, and 27 as EI. VLPP was found to be negatively correlated with Q-tip angle (Rs = -0.798, Y = -0.313X + 60.95, P < 0.001), and classifications of VLPP and Stamey grade have positive correlation (χ (2) = 4.9130, P = 0.0267). CONCLUSIONS: In simple female SUI, VLPP is associated with the Q-tip angle and Stamey grade, which may help to reduce some of urodynamic items.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 70,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "Tumor necrosis factor alpha activates transcription of the NADPH oxidase organizer 1 (NOXO1) gene and upregulates superoxide production in colon epithelial cells. NADPH oxidase 1 (Nox1) is a multicomponent enzyme consisting of p22(phox), Nox organizer 1 (NOXO1), Nox1 activator 1, and Rac1. Interleukin-1beta, flagellin, interferon-gamma, and tumor necrosis factor alpha (TNF-alpha) similarly induced Nox1 in a colon cancer cell line (T84), whereas only TNF-alpha fully induced NOXO1 and upregulated superoxide-producing activity by ninefold. This upregulation was canceled by knockdown of NOXO1 with small interfering RNAs. TNF-alpha rapidly phosphorylated p38 mitogen-activated protein kinase and c-Jun N-terminal kinase 1/2, followed by phosphorylation of c-Jun and c-Fos and appearance of an AP-1 binding activity within 30 min. We cloned the 5' flank of the human NOXO1 gene (-3888 to +263 bp), and found that the region between -585 and -452 bp, which contains consensus elements of YY-1, AP-1, and Ets, and the GC-rich region encoding three putative binding sites for SP-1, was crucial for TNF-alpha-dependent promoter activity. Serial mutation analysis of the elements identified an AP-1 binding site (from -561 to -551 bp, agtAAGtcatg) as a crucial element for TNF-alpha-stimulated transcription of the human NOXO1 gene, which was also confirmed by the AP-1 decoy experiments. Thus, TNF-alpha acts as a potent activator of Nox1-based oxidase in colon epithelial cells, suggesting a potential role of this oxidase in inflammation of the colon.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 163,
                "text": "NADPH oxidase 1"
            }
        },
        {
            "context": "The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation. Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates. Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 954,
                "text": "SET domain"
            }
        },
        {
            "context": "Genetic variations associated with red hair color and fear of dental pain, anxiety regarding dental care and avoidance of dental care. BACKGROUND: Red hair color is caused by variants of the melanocortin-1 receptor (MC1R) gene. People with naturally red hair are resistant to subcutaneous local anesthetics and, therefore, may experience increased anxiety regarding dental care. The authors tested the hypothesis that having natural red hair color, a MC1R gene variant or both could predict a patient's experiencing dental care-related anxiety and dental care avoidance. METHODS: The authors enrolled 144 participants (67 natural red-haired and 77 dark-haired) aged 18 to 41 years in a cross-sectional observational study. Participants completed validated survey instruments designed to measure general and dental care-specific anxiety, fear of dental pain and previous dental care avoidance. The authors genotyped participants' blood samples to detect variants associated with natural red hair color. RESULTS: Eighty-five participants had MC1R gene variants (65 of the 67 red-haired participants and 20 of the 77 dark-haired participants) (P < .001). Participants with MC1R gene variants reported significantly more dental care-related anxiety and fear of dental pain than did participants with no MC1R gene variants. They were more than twice as likely to avoid dental care as were the participants with no MC1R gene variants, even after the authors controlled for general trait anxiety and sex. CONCLUSION: Dental care-related anxiety, fear of dental pain and avoidance of dental care may be influenced by genetic variations. CLINICAL IMPLICATIONS: Dentists should evaluate all patients, but especially those with naturally red hair, for dental care-related anxiety and use appropriate modalities to manage the patients' anxiety.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 216,
                "text": "MC1R"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1120,
                "text": "thyroid"
            }
        },
        {
            "context": "Effect of Fusarium oxysporum f. sp. lycopersici on the soil-to-root translocation of heavy metals in tomato plants susceptible and resistant to the fungus. The purpose of this work was to gain an insight on the potential role of the phytopathogenic fungus Fusarium oxysporum f. sp. lycopersici in the translocation of metals and metalloids from soil to plant roots in tomato (Lycopersicum esculentum). Two varieties of tomato (one susceptible and another resistant to infection by Fusarium oxysporum f. sp. lycopersici) were challenged with the fungus for different periods of time, and several elements (V, Cr, Mn, Co, Cu, Zn, As, Se, Mo, Ag, Cd, Pb) were determined in roots and in soil substrate. Additionally, phenolic plant products were also analyzed for the evaluation of the plant response to biotic stress. In order to obtain representative results for plants cultivated in noncontaminated environments, the infected and control plants were grown in commercial soil with natural, relatively low metal concentrations, partly associated with humic substances. Using such an experimental design, a specific role of the fungus could be observed, while possible effects of plant exposure to elevated concentrations of heavy metals were avoided. In the infected plants of two varieties, the root concentrations of several metals/metalloids were increased compared to control plants; however, the results obtained for elements and for phenolic compounds were significantly different in the two plant varieties. It is proposed that both Lycopersicum esculentum colonization by Fusarium oxysporum f. sp. lycopersici and the increase of metal bioavailability due to fungus-assisted solubilization of soil humic substances contribute to element traffic from soil to roots in tomato plant.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 368,
                "text": "tomato"
            }
        },
        {
            "context": "The incidence of cystic fibrosis in Caucasian populations. Estimates of the newborn frequency of cystic fibrosis in different Caucasian groups range from 4 times more to 40 times less common than the generally accepted figure of 1:2000. Current meconium screening trials which may be effective in populations with the incidence equal to or greater than 1:2000, may be useful for populations with an incidence as low as 1:7000 only after maximum improvement of the methods. Once the true incidence or the variable incidence is proven for Caucasian populations, screening trails in Negro, Oriental and Indian populations will be required.",
            "question": "What is the incidence of cystic fibrosis in the caucasian population?",
            "answers": {
                "answer_start": 353,
                "text": "1:2000"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1243,
                "text": "CD38"
            }
        },
        {
            "context": "Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options. The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1283,
                "text": "xa"
            }
        },
        {
            "context": "Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011. Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD--consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease--is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 180,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 371,
                "text": "CD38"
            }
        },
        {
            "context": "Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. UNLABELLED: Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. PERSPECTIVE: This study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 290,
                "text": "NF1"
            }
        },
        {
            "context": "Processive selenocysteine incorporation during synthesis of eukaryotic selenoproteins. Selenoproteins are a family of proteins that share the common feature of containing selenocysteine, the \"twenty-first\" amino acid. Selenocysteine incorporation occurs during translation of selenoprotein messages by redefinition of UGA codons, which normally specify termination of translation. Studies of the eukaryotic selenocysteine incorporation mechanism suggest that selenocysteine insertion is inefficient compared with termination. Nevertheless, selenoprotein P and several other selenoproteins are known to contain multiple selenocysteines. The production of full-length (FL) protein from these messages would seem to demand highly efficient selenocysteine incorporation due to the compounding effect of termination at each UGA codon. We present data demonstrating that efficient incorporation of multiple selenocysteines can be reconstituted in rabbit reticulocyte lysate translation reactions. Selenocysteine incorporation at the first UGA codon is inefficient but increases by approximately 10-fold at subsequent downstream UGA codons. We found that ribosomes in the \"processive\" phase of selenocysteine incorporation (i.e., after decoding the first UGA codon as selenocysteine) are fully competent to terminate translation at UAG and UAA codons, that ribosomes become less efficient at selenocysteine incorporation as the distance between UGA codons is increased, and that efficient selenocysteine incorporation is not dependent on cis-acting elements unique to selenoprotein P. Furthermore, we found that the percentage of ribosomes decoding a UGA codon as selenocysteine rather than termination can be increased by 3- to 5-fold by placing the murine leukemia virus UAG read-through element upstream of the first UGA codon or by providing a competing messenger RNA in trans. The mechanisms of selenocysteine incorporation and selenoprotein synthesis are discussed in light of these results.",
            "question": "Which is the human selenoprotein that contains several Se-Cys residues?",
            "answers": {
                "answer_start": 540,
                "text": "selenoprotein P"
            }
        },
        {
            "context": "Subependymal periventricular heterotopias in a patient with ehlers-danlos syndrome: a new case. Ehlers-Danlos syndrome is a complex hereditary connective tissue disorder that is characterized by abnormalities of the skin and joints and visceral and neurological manifestations. At present, at least 11 forms are recognized on the basis of their clinical characteristics, methods of transmission, and biochemical defect. The neurologic manifestations include cerebrovascular disease, peripheral neuropathy, plexopathy, periventricular subependymal heterotopias, and epilepsy. Previously, 2 females were reported to be affected with subependimal periventricular heterotopias and Ehlers-Danlos syndrome type 1. The authors report a new case of a 12-year-old girl with similar clinical and neuroradiological features.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 143,
                "text": "connective tissue"
            }
        },
        {
            "context": "Development of a surveillance system for methicillin-resistant Staphylococcus aureus in German hospitals. OBJECTIVE: To determine the appropriate method to calculate the rate of methicillin-resistant Staphylococcus aureus (MRSA) infection and colonization (hereafter, MRSA rates) for interhospital comparisons, such that the large number of patients who are already MRSA positive on admission is taken into account. DESIGN: A prospective, multicenter, hospital-based surveillance of MRSA-positive case patients from January through December 2004. SETTING: Data from 31 hospitals participating in the German national nosocomial infections surveillance system (KISS) were recorded during routine surveillance by the infection control team at each hospital. RESULTS: Data for 4,215 MRSA-positive case patients were evaluated. From this data, the following values were calculated. The median incidence density was 0.71 MRSA-positive case patients per 1,000 patient-days, and the median nosocomial incidence density was 0.27 patients with nosocomial MRSA infection or colonization per 1,000 patient-days (95% CI, 0.18-0.34). The median average daily MRSA burden was 1.13 MRSA patient-days per 100 patient-days (95% CI, 0.86-1.51), with the average daily MRSA burden defined as the total number of MRSA patient-days divided by the total number of patient-days times 100. The median MRSA-days-associated nosocomial MRSA infection and colonization rate, which describes the MRSA infection risk for other patients in hospitals housing large numbers of MRSA-positive patients and/or many patients who were MRSA positive on admission, was 23.1 cases of nosocomial MRSA infection and colonization per 1,000 MRSA patient-days (95% CI, 17.4-28.6). The values were also calculated for various MRSA screening levels. CONCLUSIONS: The MRSA-days-associated nosocomial MRSA rate allows investigators to assess the extent of MRSA colonization and infection at each hospital, taking into account cases that have been imported from other hospitals, as well as from the community. This information provides an appropriate incentive for hospitals to introduce further infection control measures.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 223,
                "text": "MRSA"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 1309,
                "text": "thyroid"
            }
        },
        {
            "context": "Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 gene in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 426,
                "text": "FBN1"
            }
        },
        {
            "context": "Development of an early biomarker for the ovarian liability of selective estrogen receptor modulators in rats. Selective estrogen receptor modulators (SERMs) have the potential to treat estrogen sensitive diseases such as uterine leiomyoma and endometriosis, which are prevalent in reproductive age women. However, SERMs also increase the risk of developing ovarian cysts in this population, a phenomenon that is not seen in postmenopausal women. It is believed that current SERMs partially block estradiol's ability to downregulate gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus thereby interfering with estradiol's negative feedback, leading to increased ovarian stimulation by gonadotropins, and cyst formation. It has been postulated that a SERM with poor brain exposure would have less negative effect on the HPO axis, therefore reducing the risk of developing ovarian cysts. In order to test this hypothesis, we identified an early marker of SERM-dependent ovarian effects: upregulation of Cyp17a1 mRNA. SERMs known to cause ovarian cysts upregulate Cyp17a1 after only 4 days of dosing and suppression of the HPO axis prevented this regulation, indicating that ovarian expression of Cyp17a1 was secondary to SERM's effect on the brain. We then characterized three SERMs with similar binding affinity and antagonist effects on the uterus for their relative brain/plasma exposure and ovarian effects. We found that the degree of brain exposure correlated very well with Cyp17a1 expression.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 111,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "[Reported use of thalidomide in multiple myeloma: presentation of problems in the Thaled® outpatient department]. BACKGROUND: Thalidomide was approved in Japan for multiple myeloma treatment in October 2008. A program called the Thalidomide Education and Risk Management System (TERMS®) was established to help ensure that every effort is made to use the drug safely. PURPOSE: We report the use of thalidomide to treat multiple myeloma, and describe problems arising in the Thaled® outpatient department. PATIENTS AND METHODS: Multiple myeloma patients treated with thalidomide at Hitachi General Hospital. INTERVENTION: Monitoring of the efficacy and safety of thalidomide, and a questionnaire survey conducted at the Thaled® outpatient department. RESULTS: The thalidomide response rate was 41. 7%. In 5 cases, all patients received steroids along with thalidomide. After auto-PBSCT, 1 of 2 cases demonstrated a good response (PR 1). After treatment with bortezomib, 1 of 2 cases demonstrated a good response (MR 1). After auto-PBSCT and treatment with bortezomib, 1 of 4 cases demonstrated a good response (PR 1). In a case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), administration was discontinued. Regarding problems in the Thaled® outpatient department, the medical staff indicated that TERMS® is a very complicated program, while the patients requested prolongation of the prescription days and reduction of the economic burden of medication costs. CONCLUSION: Thalidomide showed some success in treating multiple myeloma either after auto-PBSCT or following treatment with bortezomib. In the case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), grave complications could have very easily developed, thus underscoring the importance of careful monitoring. Based on a questionnaire survey conducted in the Thaled® outpatient department, the medical staff made comments and patients raised issues that should be examined in the future.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 419,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 1206,
                "text": "CAGEr"
            }
        },
        {
            "context": "Large pleural tumor revealed by severe hypoglycemia: Doege-Potter syndrome. AIM: Doege-Potter syndrome is a rare condition consisting of a mesenchymal tumor, either benign or malignant, accompanied by severe hypoglycemia. The syndrome was first described independently by two American physicians, Karl Walter Doege (1867-1932) and Roy Pilling Potter (1879-1968), in 1930, but it was not before 1988 that it was associated with non-islet cell tumor production of insulin growth factor (IGF) that induces hypoglycemia as a paraneoplastic syndrome. CASE PRESENTATION: We present the case of a 61-year-old woman with severe hypoglycemia that induced seizures. On the general check-up, a massive tumor occupying the lower part of left hemi-thorax was discovered. Initially, corticosteroids, glucose i.v. and high carbohydrate diet managed to prevent the severe blood glucose drop. Surgery exposed a massive well-defined pleural tumor. After surgical removal, blood glucose stabilized. Histological examination confirmed the fibrous tumor that proved to be malignant on immunochemistry. DISCUSSION: The authors discuss other cases reported in the literature of this rare condition and its pathogenic mechanisms, the presented case being the first reported in Romania. CONCLUSIONS: The clinician should be aware of the possible existence of a pleural tumor in a patient presenting an unexplained hypoglycemia because the surgical removal of the tumor can solve the clinical manifestations.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 39,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1249,
                "text": "Xa"
            }
        },
        {
            "context": "Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Although no specific phenotype was found to be associated with mutations in either gene, clinical and histological features together with pedigree data may be used in guiding mutation detection. Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication.",
            "question": "What is the mode of inheritance of nemaline myopathy?",
            "answers": {
                "answer_start": 477,
                "text": "Autosomal recessive"
            }
        },
        {
            "context": "Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative disorder of childhood, is caused by mutations in a recently identified gene ( CLN3 ) localized to chromosome 16p11.2-12.1. To elucidate the biosynthesis and localization of the CLN3 protein, we expressed CLN3 cDNA in COS-1 and HeLa cell lines. In vitro translation, immunoprecipitation and Western blotting analyses detected an approximately 43 kDa polypeptide. Pulse-chase experiments indicated that the CLN3 protein is synthesized as an N -glycosylated single-chain polypeptide, which was not detected in growth medium. Confocal immunofluorescence microscopy revealed that the CLN3 protein is localized to the lysosomal compartment. These results provide evidence that Batten disease can be classified as a member of lysosomal diseases.",
            "question": "What is the effect of a defective CLN3 gene?",
            "answers": {
                "answer_start": 90,
                "text": "Batten disease"
            }
        },
        {
            "context": "Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 823,
                "text": "FSHD"
            }
        },
        {
            "context": "Peritraumatic heart rate and posttraumatic stress disorder in patients with severe burns. OBJECTIVE: Previous studies have suggested a link between heart rate (HR) following trauma and the development of posttraumatic stress disorder (PTSD). This study expands on previous work by evaluating HR in burn patients followed longitudinally for symptoms of acute stress disorder (ASD) and PTSD. METHOD: Data were collected from consecutive patients admitted to the Johns Hopkins Burn Center, Baltimore, Maryland, between 1997 and 2002. Patients completed the Stanford Acute Stress Reaction Questionnaire (n = 157) to assess symptoms of ASD. The Davidson Trauma Scale was completed at 1 (n = 145), 6 (n = 106), 12 (n = 94), and 24 (n = 66) months postdischarge to assess symptoms of PTSD. Heart rate in the ambulance, emergency room, and burn unit were obtained by retrospective medical chart review. RESULTS: Pearson correlations revealed a significant relationship between HR in the ambulance (r = 0.32, P = .016) and burn unit (r = 0.30, P = .001) and ASD scores at baseline. Heart rate in the ambulance was related to PTSD avoidance cluster scores at 1, 6, 12, and 24 months. In women, HR in the ambulance was correlated with PTSD scores at 6 (r = 0.65, P = .005) and 12 (r = 0.78, P = .005) months. When covariates (gender, β-blockers, Brief Symptom Inventory Global Severity Index score) were included in multivariate linear regression analyses, ambulance HR was associated with ASD and PTSD scores at baseline and 1 month, and the interaction of ambulance HR and gender was associated with PTSD scores at 6 and 12 months. Multivariate logistic regression results were similar at baseline and 12 months, which included an HR association yet no interaction at 6 months and a marginal interaction at 1 month. CONCLUSIONS: While peritraumatic HR is most robustly associated with PTSD symptom severity, HR on admission to burn unit also predicts the development of ASD. Gender and avoidance symptoms appear particularly salient in this relationship, and these factors may aid in the identification of subgroups for which HR serves as a biomarker for PTSD. Future work may identify endophenotypic measures of increased risk for PTSD, targeting subgroups for early intervention.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 777,
                "text": "PTSD"
            }
        },
        {
            "context": "The nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in brains of dementia with Lewy bodies. We immunohistochemically investigated the degeneration processes of the nigro-striatal and nigro-amygdaloid pathways and the relationship between the loss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia nigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and TH-positive axonal terminals in the putamen decreased with a specific pattern. The substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that were almost evenly distributed, while the putamen exhibited diffuse or granular alpha-synuclein-immunostaining. Most of the granular stains were positive for anti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were negative. These findings suggest that the axonal terminals in the putamen undergo abnormal alpha-synuclein accumulation, but may not always originate from LB-bearing neurons in the substantia nigra. The central amygdaloid nucleus contained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive dystrophic axonal terminals, the degree of which was greater for cases with granular staining in the putamen, and which was proportional to the number of alpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal terminals in the central amygdaloid nucleus may have originated from LB-bearing neurons in the substantia nigra. The results of the present study indicate that the nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in DLB, and suggest that the degeneration of the nigro-amygdaloid pathway more strongly reflects LB formation in dopaminergic neurons of the substantia nigra than that of the nigro-striatal pathway. In addition, they indicate that there is no direct relationship between the loss of dopaminergic neurons and LB formation in the substantia nigra.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 620,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 154,
                "text": "FBN1"
            }
        },
        {
            "context": "Genetic analysis of oculocutaneous albinism type 1 (OCA1) in Indian families: two novel frameshift mutations in the TYR Gene. PURPOSE: Oculocutaneous albinism type 1 (OCA1) patients demonstrate a partial or total lack of melanin in the skin, hair and eye. OCA1 is an autosomal recessive genetic disorder caused by mutations in the TYR gene located at chromosome band 11q14-q25. The purpose of this study was to carry out genetic analysis of OCA1 in Indian families. METHODS: Genomic DNA was isolated from blood leukocytes of all the individuals in this study. Haplotype analysis was performed at the TYR locus using informative microsatellite markers. Eight sets of primers were used to amplify the entire coding region of the TYR gene for bidirectional direct sequencing mutation analysis. RESULTS: Two novel deletions (c.937del8, c.1379del2) and a previously known nonsense mutation (R278X) in the TYR gene were identified from a total of 8 oculocutaneous albinism patients in India. CONCLUSIONS: Our study reports the distribution of two novel frameshift and a previously reported nonsense mutations in four OCA1 families from the Indian population. These findings will contribute to the development of a diagnostic method for OCA1 carrier status and genetic counseling for OCA1 affected families.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 116,
                "text": "TYR"
            }
        },
        {
            "context": "Inhibition of protein kinase C delta attenuates allergic airway inflammation through suppression of PI3K/Akt/mTOR/HIF-1 alpha/VEGF pathway. Vascular endothelial growth factor (VEGF) is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α). Recently, inhibition of the mammalian target of rapamycin (mTOR) has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K)/Akt or protein kinase C-delta (PKC δ) in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 422,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "Indication for antihypertensive treatment: superiority of ambulatory vs casual blood pressure measurement. The antihypertensive effect of isradipine was studied in 45 patients with mild-to-moderate hypertension (mean age 59 years) using casual and ambulatory 24-h blood pressure measurement. Patients were included into the study according to their casual blood pressure. Isradipine was started at a dose of 1.25 mg twice daily for 4 weeks, and increased to 2.5 mg twice daily if casual blood pressure was not normalized. If necessary, 3 mg of spirapril, a new angiotensin-converting enzyme (ACE) inhibitor, (n = 1) or 5 mg of pindolol (n = 1) was added. The active-treatment period lasted 24 weeks. At the end of the therapy, casual blood pressure was significantly decreased (p < 0.001) from 173/103 to 150/86 mmHg, and mean ambulatory blood pressure, from 146/87 to 140/83 mmHg (p < 0.05). When patients were divided into three groups according to initial whole-day ambulatory blood pressure values (group I: < 140/90 mmHg; group II: > or = 140/90 mmHg; group III: > or = 140/<90 mmHg), no effect of treatment was detected in group I. However, whole-day blood pressure fell significantly (p < 0.001) in group II (155/96 vs 143/88 mmHg) as did systolic blood pressure (p < 0.01) in group III (150/83 vs 142/81 mmHg), whereas diastolic blood pressure remained unchanged. Thus, ambulatory blood pressure measurement may be superior to casual measurement in the decision-making process to treat hypertension, avoiding not only the phenomenon of 'white-coat hypertension', but also ineffective treatment. This conclusion, however, should be confirmed by prospective studies.",
            "question": "What is the indication for isradipine?",
            "answers": {
                "answer_start": 198,
                "text": "hypertension"
            }
        },
        {
            "context": "p53-Based cyclotherapy: exploiting the 'guardian of the genome' to protect normal cells from cytotoxic therapy. Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic effect of p53 can protect normal cells from the toxicity of S- or M-phase poisons. Here, we have reviewed existing cyclotherapy regimens using two well-known p53 activators, nutlin-3 and actinomycin D. We have highlighted an exemplar clinical perspective for cyclotherapy in breast cancer. The recent development of novel stapled peptides as activators of p53 without the corresponding cytotoxicity holds great promise for cyclotherapy to enhance the therapeutic window of existing chemotherapy drugs.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 0,
                "text": "p53"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 453,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Hsp90 is involved in the formation of P-bodies and stress granules. Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.",
            "question": "Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?",
            "answers": {
                "answer_start": 601,
                "text": "Hsp90"
            }
        },
        {
            "context": "Novel strategies in the treatment of castration-resistant prostate cancer       (Review). Prostate cancer is the most common cancer in men in Europe and the United       States, and the third leading cause of death from cancer in Europe. Survival of       prostate cancer cells is dependent on the activation of androgen receptors (AR),       that are overexpressed in this tumor. Furthermore, ~90% of prostate cancer patients       that respond to first-line androgen deprivation therapy (ADT) undergo rapid progression.       This condition is defined as castration-resistant prostate cancer (CRPC). Docetaxel-based       regimens significantly improve overall survival (OS) in patients with CRPC and       represent the only treatment strategy approved by the Food and Drug Administration       (FDA). Recently, abiraterone (second hormonal therapy) and cabazitaxel (new taxane)       have been shown to improve survival in patients with CRPC who progressed following       docetaxel-based chemotherapy. Vaccine therapy has also been demonstrated to improve       OS in patients with asymptomatic or minimally symptomatic metastatic CRPC. Additional       therapeutic targets have been analyzed in prostate cancer, including apoptosis,       angiogenic receptors, vitamin D and Src pathways. Several phase II studies are       ongoing. The high frequency of prostate cancer-related metastatic bone disease       has led to consider this pathway as a therapeutic target. To this end, several       bone-targeted agents have been investigated, most notably zoledronic acid, which       is highly effective at stabilizing the bone and preventing skeletal complications.       More recently, a nuclear factor-β ligand (RANKL) inhibitor, denosumab, has been       developed for the treatment of bone metastases.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1718,
                "text": "RANKL"
            }
        },
        {
            "context": "Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. When a known microimbalance affecting multiple genes is detected in a patient with syndromic intellectual disability, it is usually presumed causative for all observed features. Whole exome sequencing (WES) allows questioning this assumption. In this study of three families with children affected by unexplained syndromic intellectual disability, genome-wide copy number and subsequent analyses revealed a de novo maternal 1.1 Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. In patient 1 carrying the 14q32 microdeletion, tall stature and renal malformation were unexplained by paternal UPD(14), and there was no altered DLK1 expression or unexpected methylation status. By WES and filtering with a mining tool, a novel FBN1 missense variant was found in patient 1 and his mother, who both showed clinical features of Marfan syndrome by thorough anthropometric assessment, and a novel EYA1 missense variant as a probable cause of the renal malformation in the patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- and hyperpigmentation and two malignancies were only partially explained. By WES, compound heterozygous BLM stop founder mutations were detected causing Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited from his unaffected father, WES identified a novel missense variant in the OPHN1 X-linked intellectual disability gene inherited from the unaffected mother as a possible additional cause for developmental delay. Thus, WES seems warranted in patients carrying microdeletions or microduplications, who have unexplained clinical features or microimbalances inherited from an unaffected parent.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 965,
                "text": "FBN1"
            }
        },
        {
            "context": "Efficacy and safety of a phyto-SERM as an alternative to hormone therapy. In this review, we analyze the efficacy and safety of DT56a in the treatment of postmenopausal symptoms. Similar to all selective estrogen receptor modulators (SERMs), DT56a demonstrates dual agonistic and antagonistic effects due to the synergy between its components. DT56a is referred to as a plant-origin SERM (phyto-SERM) and, for this reason, its therapeutic capacity in postmenopausal women differs from other phytoestrogens used independently. Although interesting data on relief of vasomotor symptoms have been reported for DT56a, further clinical studies with a greater number of cases and a longer period of study are required to correctly identify its indications for use as an alternative to hormone therapy, especially in preventing osteoporosis.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 194,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 438,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Paediatric investigation plans for pain: painfully slow! PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.",
            "question": "How many clinical trials for off-label drugs in neonates are cited in the literature.",
            "answers": {
                "answer_start": 472,
                "text": "0"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1612,
                "text": "CO2"
            }
        },
        {
            "context": "CSEQ-SIMULATOR: A DATA SIMULATOR FOR CLIP-SEQ EXPERIMENTS. CLIP-Seq protocols such as PAR-CLIP, HITS-CLIP or iCLIP allow a genome-wide analysis of protein-RNA interactions. For the processing of the resulting short read data, various tools are utilized. Some of these tools were specifically developed for CLIP-Seq data, whereas others were designed for the analysis of RNA-Seq data. To this date, however, it has not been assessed which of the available tools are most appropriate for the analysis of CLIP-Seq data. This is because an experimental gold standard dataset on which methods can be accessed and compared, is still not available. To address this lack of a gold-standard dataset, we here present Cseq-Simulator, a simulator for PAR-CLIP, HITS-CLIP and iCLIP-data. This simulator can be applied to generate realistic datasets that can serve as surrogates for experimental gold standard dataset. In this work, we also show how Cseq-Simulator can be used to perform a comparison of steps of typical CLIP-Seq analysis pipelines, such as the read alignment or the peak calling. These comparisons show which tools are useful in different settings and also allow identifying pitfalls in the data analysis.",
            "question": "Which data simulator is available for CLIP-SEQ experiments?",
            "answers": {
                "answer_start": 0,
                "text": "CSEQ-SIMULATOR"
            }
        },
        {
            "context": "Mutations in MED12 cause X-linked Ohdo syndrome. Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.",
            "question": "What is the genetic basis of Ohdo syndrome?",
            "answers": {
                "answer_start": 0,
                "text": "Mutations in MED12"
            }
        },
        {
            "context": "Isolation and physiochemical properties of protein-rich nematode mitochondrial ribosomes. In the present study, mitochondrial ribosomes of the nematode Ascaris suum were isolated and their physiochemical properties were compared to ribosomes of Escherichia coli. The sedimentation coefficient and buoyant density of A. suum mitochondrial ribosomes were determined. The sedimentation coefficient of the intact monosome was about 55 S. The buoyant density of formaldehyde-fixed ribosomes in cesium chloride was 1.40 g/cm(3), which suggests that the nematode mitoribosomes have a much higher protein composition than other mitoribosomes. The diffusion coefficients obtained from dynamic light scattering measurements were (1.48 +/- 0.04) x 10(-)(7) cm(2) s(-)(1) for 55 S mitoribosomes and (1.74 +/- 0.04) x 10(-)(7) cm(2) s(-)(1) for the 70 S E. coli monosome. The diameter of mitoribosomes was measured by dynamic light-scattering analysis and electron microscopy. Though the nematode mitoribosome has a larger size than the bacterial ribosome, it does not differ significantly in size from mammalian mitoribosomes.",
            "question": "What is the sedimentation coefficient of the mammalian mitoribosome?",
            "answers": {
                "answer_start": 428,
                "text": "55 S"
            }
        },
        {
            "context": "Nucleotide excision repair and its interplay with transcription. Nucleotide excision repair (NER) is a multistep process capable to remove a variety of DNA distorting lesions from prokaryotic and eukaryotic genomes. In eukaryotic cells, the process requires more than 30 proteins to perform the different steps, i.e. recognition of DNA damage, single strand incisions and excision of the lesion-containing DNA fragment and DNA repair synthesis/ligation. NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes. Both in vivo as well as in cultured cells the fast removal of transcription blocking lesions by TCR is crucial to escape from lethal effects of inhibited transcription inhibition The most delicate step in NER is the recognition of the DNA lesions in their different chromatin context and the mechanism of damage recognition in GGR and TCR is principally different and requires specific proteins. In GGR, the XPC-HR23B is essential for the formation of the incision complex. In TCR the Cockayne syndrome (CS) gene products are key players in the recognition of a stalled RNA polymerase the presumed signaling structure for repair of transcribed strands. In this study, we show that the extent of recovery of UV-inhibited transcription and TCR strictly depends on the amount of CSB protein as well as the amount of DNA damage present in the cell. This indicates that the ratio between DNA damage frequency and CSB protein concentration in the cell is rather critical for acute cellular response, i.e. recovery of inhibited transcription upon DNA damage infliction, and hence cellular survival.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 643,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Ancient duplicated conserved noncoding elements in vertebrates: a genomic and functional analysis. Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Although most of these elements share little sequence identity to each other, a small number are remarkably similar and appear to be the product of duplication events. Here, we searched for duplicated conserved noncoding elements in the human genome, using comparisons with Fugu to select putative cis-regulatory sequences. We identified 124 families of duplicated elements, each containing between two and five members, that are highly conserved within and between vertebrate genomes. In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family, thus removing much of the ambiguity in identifying associated genes. We find that duplicate elements have the potential to up-regulate reporter gene expression in a tissue-specific manner and that expression domains often overlap, but are not necessarily identical, between family members. Over two thirds of the families are conserved in duplicate in fish and appear to predate the large-scale duplication events thought to have occurred at the origin of vertebrates. We propose a model whereby gene duplication and the evolution of cis-regulatory elements can be considered in the context of increased morphological diversity and the emergence of the modern vertebrate body plan.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 392,
                "text": "development"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 250,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "5-acetyl-2-arylbenzimidazoles as antiviral agents. Part 4. Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV). Title compounds were also tested against RNA viruses representative of other single-stranded, positive-sense (ssRNA(+)) negative-sense (RNA(-)), or double-stranded (dsRNA) genomes, as well as against representatives of two DNA virus families. Nine compounds showed activity against BVDV (EC(50) = 0.8-8.0 μM), compound 31 being the most potent (EC(50) = 0.80 μM) and selective (SI = CC(50)/EC(50) = >100). When tested in an HCV replicon assay, compound 31 resulted again the most potent, displaying an EC(50) value of 1.11 μM and an SI of 100. Besides inhibiting BVDV, two compounds (35 and 38) showed a moderate activity also against YFV (EC(50) = 13 μM). Interestingly, 35 was moderately active also against RSV (EC(50) = 25 μM).",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 306,
                "text": "three"
            }
        },
        {
            "context": "Epidural blood patch for refractory low CSF pressure headache: a pilot study. Once believed an exceedingly rare disorder, recent evidence suggests that low cerebrospinal fluid (CSF) pressure headache has to be considered an important cause of new daily persistent headaches, particularly among young and middle-aged individuals. Treatment of low CSF pressure headache consists of non-invasive/conservative measures and invasive measures with epidural blood patch providing the cornerstone of the invasive measures. In the present pilot study we therefore aimed to evaluate the treatment efficacy of epidural blood patch (EBP) in treatment-refractory low-pressure headache. Our primary effect parameter was total headache burden defined as area under the curve (AUC: intensity × duration) and as secondary effect parameters we identified: intensity (VAS 0-10), frequency (days per month), duration in hours (total hours/month) and also medication days (days on medication/month). In our primary effect parameter we found a significant reduction in AUC with more than 25% and this is considered to be clinically relevant. We found also a significant and relevant reduction at -22% in intensity. A trend towards reduction in duration was seen. We found no statistically significant reduction in frequency. An increase in days with use of medication was found. Increased awareness of low CSF pressure headache is emphasized and a controlled larger randomized study is needed to confirm the results. However the present results, allows us to conclude that EBP in treatment-refractory low CSF pressure headache can be considered as a treatment option.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 442,
                "text": "epidural blood patch"
            }
        },
        {
            "context": "Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations. Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 197,
                "text": "selective estrogen receptor modulator"
            }
        },
        {
            "context": "Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.",
            "question": "Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?",
            "answers": {
                "answer_start": 1537,
                "text": "SSCprofiler"
            }
        },
        {
            "context": "EFFECT OF THE APOE ε4 ALLELE AND COMBAT EXPOSURE ON PTSD AMONG IRAQ/AFGHANISTAN-ERA VETERANS. BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans. METHOD: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report. RESULTS: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5). CONCLUSIONS: Although preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 1015,
                "text": "PTSD"
            }
        },
        {
            "context": "Brigatinib Effective in ALK+ NSCLC. Results from a phase I/II trial indicate that the investigational ALK inhibitor brigatinib is active in patients with ALK-rearranged non-small cell lung cancer. Patients who had previously received crizotinib-as well as those who hadn't-responded to the drug, which was also active in patients with brain metastases.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 189,
                "text": "cancer"
            }
        },
        {
            "context": "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways. The transition between a unicellular yeast form to multicellular filaments is crucial for budding yeast foraging and the pathogenesis of many fungal pathogens such as Candida albicans. Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation. Overexpression of either ECM22 or UPC2 leads to increased filamentation, whereas cells lacking both ECM22 and UPC2 do not exhibit filamentous growth. Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes. These genes all play a positive role in filamentous growth, and their expression is upregulated during filamentation in an Ecm22/Upc2-dependent manner. Furthermore, ergosterol content increases during filamentous growth. UPC2 expression also increases during filamentation and is inhibited by the transcription factors Sut1 and Sut2. The expression of SUT1 and SUT2 in turn is under negative control of the transcription factor Ste12. We suggest that during filamentation Ste12 becomes activated and reduces SUT1/SUT2 expression levels. This would result in increased UPC2 levels and as a consequence to transcriptional activation of FHN1, NPR1, PRR2 and sterol biosynthesis genes. Higher ergosterol levels in combination with the proteins Fhn1, Npr1 and Prr2 would then mediate the transition to filamentous growth.",
            "question": "Which gene is the paralog of yeast UPC2?",
            "answers": {
                "answer_start": 607,
                "text": "Ecm22"
            }
        },
        {
            "context": "Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 1000,
                "text": "HIV"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8 times"
            }
        },
        {
            "context": "Potent in vitro synergism of fusidic acid (FA) and berberine chloride (BBR) against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). It was found in the present study that combined use of fusidic acid (FA) and berberine chloride (BBR) offered an in vitro synergistic action against 7 of the 30 clinical methicillin-resistant Staphylococcus aureus (MRSA) strains, with a fractional inhibitory concentration (FIC) index ranging from 0.5 to 0.19. This synergistic effect was most pronounced on MRSA 4806, an FA-resistant isolate, with a minimum inhibitory concentration (MIC) value of 1,024 μg/ml. The time-kill curve experiment showed that FA plus BBR yielded a 4.2 log10 c.f.u./ml reduction in the number of MRSA 4806 bacteria after 24-h incubation as compared with BBR alone. Viable count analysis showed that FA plus BBR produced a 3.0 log10 c.f.u./ml decrease in biofilm formation and a 1.5 log10 c.f.u./ml decrease in mature biofilm in viable cell density as compared with BBR alone. In addition, phase contrast micrographs confirmed that biofilm formation was significantly inhibited and mature biofilm was obviously destructed when FA was used in combination with BBR. These results provide evidence that combined use of FA and BBR may prove to be a promising clinical therapeutic strategy against MRSA.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 372,
                "text": "MRSA"
            }
        },
        {
            "context": "Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 55,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1564,
                "text": "factor Xa"
            }
        },
        {
            "context": "Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of γ-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 29,
                "text": "poly(ADP-Ribose) polymerase"
            }
        },
        {
            "context": "Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 215,
                "text": "MITF"
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 2002,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Anesthetic efficacy of the inferior alveolar nerve block in red-haired women. INTRODUCTION: The exact reasons for failure of the inferior alveolar nerve (IAN) block are not completely known, but red hair could play a role. The genetic basis for red hair involves specific mutations, red hair color (RHC) alleles, in the melanocortin-1 receptor (MC1R) gene. The purpose of this prospective randomized study was to investigate a possible link between certain variant alleles of the MC1R gene or its phenotypic expression of red hair and the anesthetic efficacy of the IAN block in women. MATERIALS: One-hundred twenty-four adult female subjects (62 red haired and 62 dark haired) participated in this study. Dental anxiety was determined in each subject using the Corah Dental Anxiety Questionnaire. The subjects were given 2 cartridges of 2% lidocaine with 1:100,000 epinephrine via the IAN block. Pulpal anesthesia was measured in the posterior and anterior teeth in 4-minute cycles for 60 minutes using an electric pulp tester. The MC1R alleles were genotyped for each subject from cheek cells containing DNA collected using buccal swabs. RESULTS: Women with red hair and women with 2 RHC alleles reported significantly higher levels of dental anxiety compared with women with dark hair or women with 0 RHC alleles. No significant differences in anesthetic success were found between any of the groups for any of the teeth. CONCLUSIONS: Red hair and the MC1R gene were significantly linked to higher levels of dental anxiety but were unrelated to success rates of the IAN block in women with healthy pulps.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 345,
                "text": "MC1R"
            }
        },
        {
            "context": "Long-term remission in patients with dermatitis herpetiformis on a normal diet. BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. OBJECTIVES: To investigate the effects on long-term remission of dermatitis herpetiformis in patients who underwent a gluten challenge and subsequently reintroduced dietary gluten. PATIENTS AND METHODS: We studied 38 patients (14 male and 24 female) with biopsy-confirmed dermatitis herpetiformis. They had followed a gluten-free diet for a mean of 8 years, achieving clinical remission and intestinal normalization. The patients were asked to reintroduce gluten in their diet and agreed to undergo skin and intestinal biopsies during the follow-up. RESULTS: Of the 38 patients abandoning a gluten-free diet, 31 reported the onset of rash within an average of 2 months. Seven subjects (three males, mean age 15 years at challenge) experienced no clinical or histological relapses (median follow-up 12 years), and lost IgA immunoglobulin from the skin. The two series of patients differed in terms of age at diagnosis (mean age: 26.6 vs. 6 years), the use of dapsone (one of 31 vs. four of seven) and adherence to the gluten-free diet (strict compliance in 26 of 31 vs. none of seven). CONCLUSIONS: Our data suggest that the ingestion of small doses of gluten in childhood and/or the use of an anti-inflammatory drug may modify the immunological response inducing immune tolerance. We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 1594,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Congenital long QT syndrome in adults. A family with the Romano-Ward syndrome is presented. This family showed typical features of this syndrome with QT prolongation, torsades de pointes ventricular tachycardia, sudden death and an autosomal dominant inheritance pattern. The index case presented with an exacerbation of torsades de pointes ventricular tachycardia from diuretic induced hypokalaemia, and responded to diuretic withdrawal and beta blocker therapy.",
            "question": "What is the mode of inheritance of Romano Ward long QT syndrome?",
            "answers": {
                "answer_start": 232,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "X inactive-specific transcript (Xist) expression and X chromosome inactivation in the preattachment bovine embryo. Expression of the X inactive-specific transcript (Xist) is thought to be essential for the initiation of X chromosome inactivation and dosage compensation during female embryo development. In the present study, we analyzed the patterns of Xist transcription and the onset of X chromosome inactivation in bovine preattachment embryos. Reverse transcription-polymerase chain reaction (RT-PCR) revealed the presence of Xist transcripts in all adult female somatic tissues evaluated. In contrast, among the male tissues examined, Xist expression was detected only in testis. No evidence for Xist transcription was observed after a single round of RT-PCR from pools of in vitro-derived embryos at the 2- to 4-cell stage. Xist transcripts were detected as a faint amplicon at the 8-cell stage initially, and consistently thereafter in all stages examined up to and including the expanded blastocyst stage. Xist transcripts, however, were subsequently detected from the 2-cell stage onward after nested RT-PCR. Preferential [3H]thymidine labeling indicative of late replication of one of the X chromosomes was noted in female embryos of different developmental ages as follows: 2 of 7 (28.5%) early blastocysts, 6 of 13 (46.1%) blastocysts, 8 of 11 (72.1%) expanded blastocysts, and 14 of 17 (77.7%) hatched blastocysts. These results suggest that Xist expression precedes the onset of late replication in the bovine embryo, in a pattern compatible with a possible role of bovine Xist in the initiation of X chromosome inactivation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 32,
                "text": "Xist"
            }
        },
        {
            "context": "A Study to Determine if Addition of Palatal Petechiae to Centor Criteria Adds More Significance to Clinical Diagnosis of Acute Strep Pharyngitis in Children. Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 564,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 0,
                "text": "MARS"
            }
        },
        {
            "context": "Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 1456,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Comparison of the Xpert methicillin-resistant Staphylococcus aureus (MRSA) assay, BD GeneOhm MRSA assay, and culture for detection of nasal and cutaneous groin colonization by MRSA. Detection of methicillin (meticillin)-resistant Staphylococcus aureus colonization was assessed using combined nose and groin swabs in two commercial PCR assays (the Xpert MRSA assay and the BD GeneOhm MRSA assay). Compared to routine culture, both had similar sensitivities (87.0% versus 84.8%, respectively) and specificities (93.8% versus 92.7%, respectively). Combined PCR assays provide a rapid and more-complete assessment of colonization at a cost similar to that of single-site analysis.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 176,
                "text": "MRSA"
            }
        },
        {
            "context": "Prevalence of tuberculosis infection and comparison of multiple-puncture liquid tuberculin test and Mantoux test among drug users. In order to determine the prevalence of latent infection due to Mycobacterium tuberculosis in drug users and to provide centres for drug users with a practical tool for tuberculosis screening, 237 drug users were subjected to the Monotest and, for reference purposes, to the Mantoux test. The overall prevalence of subjects with a tuberculin skin reaction size > or = 5 mm in the Mantoux test was 25.7%; utilizing a cut-off of > or = 10 mm, the prevalence was 11.4%. Irrespective of cut-off, the Monotest showed a sensitivity of > 90% and a specificity of > 80%. At a prevalence of 25.7%, and with cut-offs of > or = 5 or > or = 10 mm, the positive predictive value was 83% or 62.2%, respectively. Irrespective of cut-off, the negative predictive value was > 97%. In conclusion, the Monotest proved satisfactory as a tool for epidemiological screening in a population with a high prevalence for latent tuberculosis, namely drug users.",
            "question": "The Mantoux test detects what latent infection/disease?",
            "answers": {
                "answer_start": 209,
                "text": "tuberculosis"
            }
        },
        {
            "context": "RAPIDR: an analysis package for non-invasive prenatal testing of aneuploidy. UNLABELLED: Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package) is an easy-to-use open-source R package that implements several published NIPT analysis methods. The input to RAPIDR is a set of sequence alignment files in the BAM format, and the outputs are calls for aneuploidy, including trisomies 13, 18, 21 and monosomy X as well as fetal sex. RAPIDR has been extensively tested with a large sample set as part of the RAPID project in the UK. The package contains quality control steps to make it robust for use in the clinical setting. AVAILABILITY AND IMPLEMENTATION: RAPIDR is implemented in R and can be freely downloaded via CRAN from here: http://cran.r-project.org/web/packages/RAPIDR/index.html. CONTACT: kitty.lo@ucl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package has been developed for analyzing Non-invasive prenatal testing (NIPT) data?",
            "answers": {
                "answer_start": 219,
                "text": "RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package)"
            }
        },
        {
            "context": "PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV. On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.",
            "question": "Which is the target protein of the drug nivolumab?",
            "answers": {
                "answer_start": 123,
                "text": "programmed death receptor-1"
            }
        },
        {
            "context": "Development and Characterization of a Vaginal Film Containing Dapivirine, a Non- nucleoside Reverse Transcriptase Inhibitor (NNRTI), for prevention of HIV-1 sexual transmission. Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is a potent and promising anti-HIV molecule. It is currently being investigated for use as a vaginal microbicide in two dosage forms, a semi-solid gel and a silicone elastomer ring. Quick-dissolving films are promising and attractive dosage forms that may provide an alternative platform for the vaginal delivery of microbicide drug candidates. Vaginal films may provide advantages such as discreet use, no product leakage during use, lack of requirement for an applicator for insertion, rapid drug release and minimal packaging and reduced wastage. Within this study the in vitro bioactivity of dapivirine as compared to the NNRTI UC781 was further established and a quick dissolve film was developed for vaginal application of dapivirine for prevention of HIV infection. The developed film was characterized with respect to its physical and chemical attributes including water content, mechanical strength, drug release profile, permeability, compatibility with lactobacilli and bioactivity. The anti-HIV activity of the formulated dapivirine film was confirmed in in vitro and ex vivo models. Importantly the physical and chemical properties of the film as well as its bioactivity were maintained for a period of 18 months. In conclusion, a vaginal film containing dapivirine was developed and characterized. The film was shown to prevent HIV-1 infection in vitro and ex vivo and have acceptable characteristics which make this film a promising candidate for testing as vaginal microbicide.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 998,
                "text": "HIV"
            }
        },
        {
            "context": "[Clinical features and molecular characteristics of methicillin-resistant Staphylococcus aureus in children]. OBJECTIVE: To study the clinical and molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) infection in children. METHOD: A total of 37 MRSA strains were isolated from hospitalized patients in Children's Hospital of Fudan University from March 2009 to November 2011. The clinical characteristics were investigated by a cohort study. Furthermore, the mecA, Panton-Valentine leucocidin (PVL) genes were detected by polymerase chain reaction (PCR), and the genotypes of SCCmec were determined by multiplex PCR. RESULT: (1) Among the 37 MRSA isolates, infections with 21 were acquired from hospital (HA-MRSA), and 16 isolates were acquired from community (CA-MRSA). (2) In the study, MRSA frequently caused respiratory tract infection, and most of the strains were isolated from intensive care unit (ICU). (3) CA-MRSA was most frequently associated with skin and soft tissue infections (SSTI), suppurative tonsillitis, even pneumonia and septicemia. HA-MRSA infection was more aggressive, most frequently associated with pneumonia, septicemia, and central nervous system (CNS) infections, such as meningitis. In children with fever caused by HA-MRSA or CA-MRSA infection, HA-MRSA showed a longer duration of fever, for 10.5 days. C-reactive protein (CRP) level caused by HA-MRSA (63.00 mg/L) was higher than CA-MRSA (9.50 mg/L) , and there were statistically significant differences between the groups (t = 2.5670, P < 0.05). However, there were no statistically significant differences between the groups in white blood cell count (WBC) or procalcitonin (PCT) level. (4) Among 37 MRSA isolates, the whole isolates were mecA gene positive (100%). SCCmec genotyping results showed that the most frequent SCCmec types were type III, 17 isolates, the others including type IV 8 isolates, type II1 isolates, nontypable 11 isolates, type I and type V were not found in this group. Therein, among 21 HA-MRSA isolates, SCCmec III was the most common, 15 isolates, type IV 1 isolates, nontypable 5 isolates; among 16 CA-MRSA isolates, SCCmec type IV was the most common, 7 isolates, type III 2 isolates, type II 1 isolate, nontypable 6 isolates. (5) Among the 37 MRSA isolates, 28 were PVL gene positive; and among 21 HA-MRSA isolates, 17 were PVL gene positive; Among 16 CA-MRSA isolates, 11 were PVL gene positive; There were no statistically significant differences between the groups (χ(2) = 0.735, P > 0.05) . CONCLUSION: Compared with CA-MRSA, HA-MRSA infection was more aggressive, and induced higher C reactive protein; the dominant epidemic strains of CA-MRSA was SCCmec type IV, and HA-MRSA was SCCmec type III; the positive rate of PVL gene was high.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 221,
                "text": "MRSA"
            }
        },
        {
            "context": "Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers. Orthologous human and zebrafish enhancers underwent functional evolution within their sequence and often directed related but non-identical expression patterns. Despite an evolutionary distance of 450 million years, one pax6 HCNE drove expression in identical areas when comparing zebrafish vs. human HCNEs. HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 781,
                "text": "development"
            }
        },
        {
            "context": "JTV519 (K201) reduces sarcoplasmic reticulum Ca²⁺ leak and improves diastolic function in vitro in murine and human non-failing myocardium. BACKGROUND AND PURPOSE: Ca²⁺ leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca²⁺ leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²⁺ leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH: SR Ca²⁺ leak was induced by ouabain in murine cardiomyocytes. [Ca²⁺]-transients, SR Ca²⁺ load and RyR2-mediated Ca²⁺ leak (sparks/waves) were quantified, with or without JTV519 (1 µmol·L⁻¹). Contribution of Ca²⁺ -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY RESULTS: Ouabain increased systolic and diastolic cytosolic [Ca²⁺](i) , SR [Ca²⁺], and SR Ca²⁺ leak (Ca²⁺ spark (SparkF) and Ca²⁺ wave frequency), independently of CaMKII and RyR-Ser(2814) phosphorylation. JTV519 decreased SparkF but also SR Ca²⁺ load. At matched SR [Ca²⁺], Ca²⁺ leak was significantly reduced by JTV519, but it had no effect on fractional Ca²⁺ release or Ca²⁺ wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS: JTV519 was effective in reducing SR Ca²⁺ leak by specifically regulating RyR2 opening at diastolic [Ca²⁺](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca²⁺ overload.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 380,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Diagnosis and management of plantar fasciitis. Plantar fasciitis, a chronic degenerative process that causes medial plantar heel pain, is responsible for approximately 1 million physician visits each year. Individuals with plantar fasciitis experience pain that is most intense during their first few steps of the day or after prolonged standing. The authors provide an overview of the diagnosis and management of a common problem encountered in the primary care setting. Routine imaging is not initially recommended for the evaluation of plantar fasciitis but may be required to rule out other pathologic conditions. Overall, plantar fasciitis carries a good prognosis when patients use a combination of several conservative treatment modalities. Occasionally, referral to a specialist may be necessary.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 124,
                "text": "heel pain"
            }
        },
        {
            "context": "Biological implications of selenium and its role in trypanosomiasis treatment. Selenium (Se) is an essential trace element for several organisms and is present in proteins as selenocysteine (Sec or U), an amino acid that is chemically distinct from serine and cysteine by a single atom (Se instead of O or S, respectively). Sec is incorporated into selenoproteins at an in-frame UGA codon specified by an mRNA stem-loop structure called the selenocysteine incorporating sequence (SECIS) presented in selenoprotein mRNA and specific selenocysteine synthesis and incorporation machinery. Selenoproteins are presented in all domains but are not found in all organisms. Although several functions have been attributed to this class, the majority of the proteins are involved in oxidative stress defense. Here, we discuss the kinetoplastid selenocysteine pathway and how selenium supplementation is able to alter the infection course of trypanosomatids in detail. These organisms possess the canonical elements required for selenoprotein production such as phosphoseryl tRNA kinase (PSTK), selenocysteine synthase (SepSecS), selenophosphase synthase (SelD or SPS), and elongation factor EFSec (SelB), whereas other important factors presented in mammal cells, such as SECIS binding protein 2 (SBP) and SecP 43, are absent. The selenoproteome of trypanosomatids is small, as is the selenoproteome of others parasites, which is in contrast to the large number of selenoproteins found in bacteria, aquatic organisms and higher eukaryotes. Trypanosoma and Leishmania are sensitive to auranofin, a potent selenoprotein inhibitor; however, the probable drug mechanism is not related to selenoproteins in kinetoplastids. Selenium supplementation decreases the parasitemia of various Trypanosome infections and reduces important parameters associated with diseases such as anemia and parasite-induced organ damage. New experiments are necessary to determine how selenium acts, but evidence suggests that immune response modulation and increased host defense against oxidative stress contribute to control of the parasite infection.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 480,
                "text": "SECIS"
            }
        },
        {
            "context": "Upregulation of uc.189 in patients with esophageal squamous cell carcinoma and its clinicopathologic value. Ultraconserved elements (UCEs) encoding noncoding RNAs serve as important regulators in cancer biology. Until now, the role of the UCE uc.189 in human cancers remains undefined and the clinical significance of uc.189 in esophageal cancers remains unknown. This study was to identify the prognostic value of uc.189 expression in esophageal squamous cell carcinomas (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of uc.189 in matched cancerous tissues and adjacent noncancerous tissues from 152 patients with ESCC. The correlation of uc.189 with clinicopathological features and prognosis were also analyzed. The expression of uc.189 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (122/152, 80.3%, p<0.01), and the high level of uc.189 expression was significantly correlated with invasion of the tumor (p=0.009), advanced clinical stage (p=0.000), lymph node metastasis (p=0.000), and poor prognosis. High expression of uc.189 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Uc.189 might be considered as a novel molecule involved in ESCC progression, which provides a potential prognostic biomarker and therapeutic target.",
            "question": "For which type of cancer can uc.189 be used as a potential prognostic biomarker?",
            "answers": {
                "answer_start": 436,
                "text": "esophageal squamous cell carcinomas (ESCC)"
            }
        },
        {
            "context": "Regulating heart development: the role of Nf1. Neurofibromatosis type 1 (NF1) is one of the most common human genetic disorders and is associated with significant morbidity and mortality. The gene responsible for this disorder, NF1, encodes neurofibromin, which can function to down-regulate ras activity. Mutations that inactivate NF7 result in elevated levels of ras signaling and increased cell proliferation in some tissues. NF7 functions as a tumor suppressor gene; patients inherit one mutated copy and are believed to acquire a \"second hit\" in tissues that go on to form benign or malignant tumors. NF7 is expressed widely, yet certain tissues are more susceptible to growth dysregulation in NF1 patients. Cardiovascular defects also contribute to NF1, though the cause remains unclear. In a recent study, we used tissue-specific gene inactivation in mice to study the role of neurofibromin in heart development. A further understanding of neurofibromin function will help to elucidate the pathophysiology of NF1 and will also lead to a better understanding of cell cycle regulation and ras pathways in specific cell types. Finally, we comment on how similar genetic strategies can be used in mice to study the role of additional signaling pathways involved in heart development.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 73,
                "text": "NF1"
            }
        },
        {
            "context": "Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 35,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials ( < 104 weeks' duration; typically 24 weeks' duration) and extension studies (typically  > 76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes.",
            "question": "Which protein does empagliflozin inhibit?",
            "answers": {
                "answer_start": 348,
                "text": "SGLT2"
            }
        },
        {
            "context": "[Detection of fibroblast growth factor receptor 3 gene mutation at nucleotide 1138 site in congenita achondroplasia patients]. OBJECTIVE: [corrected] To investigate the mutation at the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) nucleotide 1138 site for identifying the major pathologic mechanism of achondroplasia (ACH) and to evaluate the efficacy of denaturing gradient gel electrophoresis(DGGE) method for screening the point mutations. METHODS: The genomic DNA from 17 clinically diagnosed ACH patients where analysed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) with Sfc I and Msp I restriction endonucleases and by PCR-DGGE technique for screening. RESULTS: G to A transition mutation at nucleotide 1138 was detected in 14/17 of the ACH patients as heterozygotes by PCR-RFLP with Sfc I digestion. No 1138 G to C transition was detected by Msp I digestion. All of the 14 samples with G to A mutation were also found to be positive for point mutation by PCR-DGGE. No mutation was detected in 3 negative samples by PCR-RFLP, implying that there was actually no point mutation in this amplified region. CONCLUSION: Nucleotide 1138 in transmembrane domain of FGFR3 gene is the hot point for mutation in ACH and hence its major pathologic cause. PCR-DGGE is a sensitive and reliable technique for point mutation screening, especially for the heterozygotes.",
            "question": "Mutation of which gene is associated with Achondroplasia?",
            "answers": {
                "answer_start": 209,
                "text": "fibroblast growth factor receptor 3 (FGFR3)"
            }
        },
        {
            "context": "Davidson Trauma Scale (DTS): normative scores in the general population and effect sizes in placebo-controlled SSRI trials. The Davidson Trauma Scale (DTS) was developed as a self-rating for use in diagnosing and measuring symptom severity and treatment outcome in post-traumatic stress disorder (PTSD); 630 subjects were identified by random digit dialing and evaluated for a history of trauma. Prevalence rates of PTSD and subthreshold PTSD with impairment were 2.2 and 4.1%, respectively. In this general population sample, 438 subjects endorsed at least one trauma, and four groups were generated: A) threshold PTSD (n = 13), B) subthreshold PTSD with impairment (n = 26), C) subthreshold PTSD without impairment (n = 78), and D) no PTSD (n = 321). Mean (SD) DTS score in the entire population was 11.0 +/- 18.1. Differences were found in four of the five pairwise between-group contrasts. In a second sample of 447 clinical trial participants from three SSRI vs. placebo studies, we assessed treatment effect size according to different measures. In all three clinical trials, effect size with the DTS was equal to, or better than, those found for the Impact of Event Scale (IES), Clinician Administered PTSD Scale (CAPS), and Structured Interview for PTSD (SIP). These results further affirm the utility of the DTS as a self-rating measure of PTSD symptom severity and in evaluating treatment response.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 265,
                "text": "post-traumatic stress disorder"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 228,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex. The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 420,
                "text": "SWR1"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 414,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2246,
                "text": "stroke"
            }
        },
        {
            "context": "Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. McLeod syndrome is an X-linked multisystem disorder characterized by abnormalities in the neuromuscular and hematopoietic systems. We have assembled a cosmid contig of 360 kb that encompasses the McLeod gene locus. A 50 kb deletion was detected by screening DNA from patients with radiolabeled whole cosmids, and two transcription units were identified within this deletion. The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype. XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins. Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites. These findings provide direct evidence that XK is responsible for McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 722,
                "text": "XK"
            }
        },
        {
            "context": "Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.",
            "question": "Does dasatinib promote or inhibit T-cell proliferation?",
            "answers": {
                "answer_start": 557,
                "text": "inhibits"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 196,
                "text": "Xa"
            }
        },
        {
            "context": "The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 482,
                "text": "ecallantide"
            }
        },
        {
            "context": "Mortality and longevity of elite athletes. The health benefits of leisure-time physical activity are well known, however the effects of engaging in competitive sports on health are uncertain. This literature review examines mortality and longevity of elite athletes and attempts to understand the association between long-term vigorous exercise training and survival rates. Fourteen articles of epidemiological studies were identified and classified by type of sport. Life expectancy, standardised mortality ratio, standardised proportionate mortality ratio, mortality rate, and mortality odds ratio for all causes of death were used to analyse mortality and longevity of elite athletes. It appears that elite endurance (aerobic) athletes and mixed-sports (aerobic and anaerobic) athletes survive longer than the general population, as indicated by lower mortality and higher longevity. Lower cardiovascular disease mortality is likely the primary reason for their better survival rates. On the other hand, there are inconsistent results among studies of power (anaerobic) athletes. When elite athletes engaging in various sports are analysed together, their mortality is lower than that of the general population. In conclusion, long-term vigorous exercise training is associated with increased survival rates of specific groups of athletes.",
            "question": "What is the life expectancy of professional athletes in respect to the general population?",
            "answers": {
                "answer_start": 797,
                "text": "longer than the general population"
            }
        },
        {
            "context": "K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization. K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74). Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 microg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an alpha1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 147,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Anesthesia for deep brain stimulation in a patient with X-linked dystonia-parkinsonism/Lubag disease. Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men. This disease is characterized by dystonia dominating the first 10-15 years of the disorder, which is associated with or replaced by parkinsonian features in later years of life. A 49-year-old man with Lubag disease underwent general anesthesia for deep brain stimulation (DBS) surgery. Anesthesia was maintained mainly with propofol, remifentanil, rocuronium bromide, and sevoflurane. During magnetic resonance imaging, the patient was anesthetized with midazolam, fentanyl, and rocuronium bromide. The surgery was completed safely using these anesthetic agents. After DBS, some symptoms including involuntary movement improved within 10 days.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 129,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "In vitro modeling of gallbladder-associated Salmonella spp. colonization. The host-pathogen interactions occurring in the gallbladder during Salmonella Typhi colonization contribute to typhoid fever pathogenesis during the acute and chronic stages of disease. The gallbladder is the primary reservoir during chronic typhoid carriage. In this organ, Salmonella encounters host-barriers including bile, immunoglobulins, and mucus. However, the bacterium possesses mechanisms to resist and persist in this environment, in part by its ability to attach to and invade into the gallbladder epithelium. Such persistence in the gallbladder epithelium contributes to chronic carriage. In addition, patients harboring gallstones in their gallbladders have increased risk of becoming carriers because these abnormalities serve as a substrate for Salmonella biofilm formation. Our laboratory has studied the Salmonella interactions in this specific environment by developing in vitro methods that closely mimic the gallbladder and gallstones niches. These methods are reproducible and provide a platform for future studies of acute and chronic bacterial infections in the gallbladder.",
            "question": "Gallbladder carriage is a well recognised means of spread of which bacteria?",
            "answers": {
                "answer_start": 141,
                "text": "Salmonella Typhi"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report. INTRODUCTION: Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor. CASE PRESENTATION: Our patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight. CONCLUSIONS: The rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 1089,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Hematopathologic and cytogenetic findings in imatinib mesylate treated chronic myelogenous leukemia patients: 2.5 years' experience. BACKGROUND/AIM: Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region--Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML). Its hematologic and cytogenetic effects have been evaluated in a series of clinical trials. The aim of this study was to report hematologic and cytogenetic response in CML patients during the treatment with imatinib mesylate. METHODS: A total of 21 patients were treated and observed from July 2006 to December 2008. The median time from CML diagnosis was no more than 12 months, so all the patients received previous treatment with hydroxyurea for which the median time was 3 months. The patients received imatinib mesylate in an effective oral dose of 400 to 800 mg daily, which was followed with peripheral blood counts, bone marrow examination, and cytogenetic studies at 6, 12, 18 and 24 months. RESULTS: Complete hematologic responses were reported for 19 (90.48%) of 21 patients studied. Among 19 patients who had a response, 16 (86%) did so within 3 months. The best cytogenetic response rate at any time during the study treatment with imatinib mesylate, among 14 patients in which cytogenetic response evaluated was: complete cytogenetic response in 7 (50%) patients, partial cytogenetic response in 6 (42.9%) patients and minor cytogenetic response in 1 (7.1%) patient. No patients had progressed to accelerated or blastic phase. The most frequent adverse effects that seemed to be related to treatment with imatinib mesylate were edema and musculoskeletal pain; overall, most were mild. Only one patient discontinued treatment because of hematologic toxic effects. CONCLUSION: The results obtained in this study confirm that imatinib mesylate induces a complete hematological and cytogenetic response in a high percentage of patients with chronic-phase CML.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 283,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Salivary and serum IgA antigliadin antibodies in dermatitis herpetiformis. Serum IgA class antigliadin antibodies (IgA-AGA) are increased in untreated patients with coeliac disease and dermatitis herpetiformis (DH), and it has been suggested that salivary IgA-AGA measurements could be used as a non-invasive screening test for gluten-sensitive enteropathy. In the present study salivary and serum IgA-AGA were measured by an ELISA test in 10 untreated patients with DH. The results were compared to IgA-AGA levels in nine patients with DH on a long-term gluten-free diet (GFD) and in 20 healthy control subjects on an ordinary diet. The mean serum but not salivary IgA-AGA concentrations were significantly higher in the untreated than in the patients with DH on a long-term GFD. When the 10 untreated patients with DH adhered to a GFD for 3 months, the rash disappeared and the mean serum IgA-AGA decreased to normal levels, but no change was found in the mean salivary IgA-AGA concentration. These results show that serum but not salivary IgA-AGA measurements are suitable for monitoring GFD treatment in patients with DH. The discrepancy between the serum and salivary IgA-AGA concentrations suggests that systemic and salivary IgA-AGA responses are controlled separately.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 185,
                "text": "dermatitis herpetiformis"
            }
        },
        {
            "context": "Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 136,
                "text": "NF1"
            }
        },
        {
            "context": "Functional significance of lysine 1423 of neurofibromin and characterization of a second site suppressor which rescues mutations at this residue and suppresses RAS2Val-19-activated phenotypes. Lysine 1423 of neurofibromin (neurofibromatosis type I gene product [NF1]) plays a crucial role in the function of NF1. Mutations of this lysine were detected in samples from a neurofibromatosis patient as well as from cancer patients. To further understand the significance of this residue, we have mutated it to all possible amino acids. Functional assays using yeast ira complementation have revealed that lysine is the only amino acid that produced functional NF1. Quantitative analyses of different mutant proteins have suggested that their GTPase-activating protein (GAP) activity is drastically reduced as a result of a decrease in their Ras affinity. Such a requirement for a specific residue is not observed in the case of other conserved residues within the GAP-related domain. We also report that another residue, phenylalanine 1434, plays an important role in NF1 function. This was first indicated by the finding that defective NF1s due to an alteration of lysine 1423 to other amino acids can be rescued by a second site intragenic mutation at residue 1434. The mutation partially restored GAP activity in the lysine mutant. When the mutation phenylalanine 1434 to serine was introduced into a wild-type NF1 protein, the resulting protein acquired the ability to suppress activated phenotypes of RAS2Val-19 cells. This suppression, however, does not involve Ras interaction, since the phenylalanine mutant does not stimulate the intrinsic GTPase activity of RAS2Val-19 protein and does not have an increased affinity for Ras proteins.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 308,
                "text": "NF1"
            }
        },
        {
            "context": "Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 344,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 1775,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 566,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 351,
                "text": "Genomiser"
            }
        },
        {
            "context": "The Role of Nursing Professionals in the Management of Patients With High-Risk Neuroblastoma Receiving Dinutuximab Therapy. Neuroblastoma, an embryonic cancer of the sympathetic nervous system, is the most common extracranial solid tumor in childhood. Dinutuximab (formerly called ch14.18), a monoclonal antibody targeting the disialoganglioside GD2, has been shown to significantly improve survival rates in patients with high-risk neuroblastoma. However, the safe and effective use of dinutuximab therapy in these high-risk patients requires medical expertise in patient selection, treatment administration, and the monitoring and management of adverse events. Findings of the randomized phase III study (ANBL0032) led to the approval of dinutuximab for the treatment of children with high-risk neuroblastoma. Multi-institutional nursing approaches to implementing standard protocols ensure the effective management of high-risk neuroblastoma patients receiving dinutuximab immunotherapy. Understanding and implementing recommendations for the management of the clinically important and most common adverse events are essential to ensuring patient continuation of therapy and improving patient outcomes.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 433,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease. BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 141,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "ACS chemical neuroscience molecule spotlight on semagacestat (LY450139). Semagacestat (LY450139) is a novel γ-secretase inhibitor currently in late-stage development by Eli Lilly and Company as a potential treatment for Alzheimer's disease (AD). Semagacestat is currently being studied in two phase III clinical trials.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 48,
                "text": "semagacestat"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 105,
                "text": "bicarbonate"
            }
        },
        {
            "context": "In vitro characterization of mutant yeast RNA polymerase II with reduced binding for elongation factor TFIIS. We have reported previously the isolation and genetic characterization of mutations in the gene encoding the largest subunit of yeast RNA polymerase II (RNAPII), which lead to 6-azauracil (6AU)-sensitive growth. It was suggested that these mutations affect the functional interaction between RNAPII and transcription-elongation factor TFIIS because the 6AU-sensitive phenotype of the mutant strains was similar to that of a strain defective in the production of TFIIS and can be suppressed by increasing the dosage of the yeast TFIIS-encoding gene, PPR2, RNAPIIs were purified and characterized from two independent 6AU-sensitive yeast mutants and from wild-type (wt) cells. In vitro, in the absence of TFIIS, the purified wt polymerase and the two mutant polymerases showed similar specific activity in polymerization, readthrough at intrinsic transcriptional arrest sites and nascent RNA cleavage. In contrast to the wt polymerase, both mutant polymerases were not stimulated by the addition of a 3-fold molar excess of TFIIS in assays of promoter-independent transcription, readthrough or cleavage. However, stimulation of the ability of the mutant RNAPIIs to cleave nascent RNA and to read through intrinsic arrest sites was observed at TFIIS:RNAPII molar ratios greater than 600:1. Consistent with these findings, the binding affinity of the mutant polymerases for TFIIS was found to be reduced by more than 50-fold compared with that of the wt enzyme. These studies demonstrate that TFIIS has an important role in the regulation of transcription by yeast RNAPII and identify a possible binding site for TFIIS on RNAPII.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 813,
                "text": "TFIIS"
            }
        },
        {
            "context": "SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 210,
                "text": "NCX"
            }
        },
        {
            "context": "Upper limb function is normal in patients with restless legs syndrome (Willis-Ekbom Disease). OBJECTIVE: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. METHODS: RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy controls (n=17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. RESULTS: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. CONCLUSIONS: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. SIGNIFICANCE: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 47,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 370,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "Targeting the gene in Friedreich ataxia. Pathological expansions of GAA repeats in the first intron of the frataxin gene cause most cases of Friedreich ataxia, a progressively debilitating neurodegenerative disease. The disease is inherited in an autosomal recessive manner and the GAA repeats are suspected to form unusual non B-DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Recent work has shown that GAA repeats induce heterochromatin formation and silencing of the frataxin gene locus. Frataxin plays a crucial role in iron metabolism and detoxification and interacts with electron transport chain proteins. Clinical trials are currently underway to examine the efficacy of antioxidants in the treatment of Friedreich ataxia, but therapeutics designed to increase frataxin message levels are still in the developmental stages. This review will focus on the progress of potential treatment strategies for Friedreich ataxia that target the GAA expanded gene and seek to increase the level of frataxin message and protein.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 1059,
                "text": "frataxin"
            }
        },
        {
            "context": "Assessment of yeast chromosome XII instability: single chromosome comet assay. The tools and techniques used in single-cell analysis of DNA damage in yeast Saccharomyces cerevisiae are limited. In this study, we modified the single cell gel electrophoresis assay, namely, the single chromosome comet assay based on DNA break analysis, at the chromosomal level. We studied the largest yeast chromosome XII, which contains the rDNA locus, and we investigated its instability using cell cycle checkpoint-, DNA damage- and antioxidative defence-deficient, and lifespan-deregulated yeast mutant strains. Moreover, we compared chromosome XII instability with the variability of nucleolar rDNA fluorescence signals. Three single-gene-deletion strains, cells lacking single-stranded DNA endonuclease, Rad1p; NAD(+)-dependent histone deacetylase, Sir2p; and gamma glutamylcysteine synthetase, Gsh1p, were more prone to chromosome XII instability compared to corresponding wildtype strains, indicating that DNA damage repair machinery, chromatin silencing and redox homeostasis may contribute to genome stability. Elevation in the number of DNA breaks was correlated with a high variability in the levels of nucleolar rDNA in the Δrad1 background, while unaffected chromosome XII and low variability in nucleolar rDNA fluorescence signals were observed in the Δtor1 longevity mutant. Taken together, the single chromosome comet assay may be successfully used to study DNA damage at the chromosomal level, which might be overlooked using whole population analysis on DNA breaks with PFGE separation.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 390,
                "text": "chromosome XII"
            }
        },
        {
            "context": "A bivalent chromatin structure marks key developmental genes in embryonic stem cells. The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed \"bivalent domains,\" consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 351,
                "text": "development"
            }
        },
        {
            "context": "Sushi.R: flexible, quantitative and integrative genomic visualizations for publication-quality multi-panel figures. Interpretation and communication of genomic data require flexible and quantitative tools to analyze and visualize diverse data types, and yet, a comprehensive tool to display all common genomic data types in publication quality figures does not exist to date. To address this shortcoming, we present Sushi.R, an R/Bioconductor package that allows flexible integration of genomic visualizations into highly customizable, publication-ready, multi-panel figures from common genomic data formats including Browser Extensible Data (BED), bedGraph and Browser Extensible Data Paired-End (BEDPE). Sushi.R is open source and made publicly available through GitHub (https://github.com/dphansti/Sushi) and Bioconductor (http://bioconductor.org/packages/release/bioc/html/Sushi.html).",
            "question": "Which R/bioconductor package is used for integrative genomics visualizations?",
            "answers": {
                "answer_start": 416,
                "text": "Sushi.R"
            }
        },
        {
            "context": "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.",
            "question": "Which gene is responsible for proper speech development?",
            "answers": {
                "answer_start": 93,
                "text": "FOXP2"
            }
        },
        {
            "context": "PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.",
            "question": "Which gene is mutated in the Karak syndrome?",
            "answers": {
                "answer_start": 446,
                "text": "PLA2G6"
            }
        },
        {
            "context": "Enhancer evolution across 20 mammalian species. The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.",
            "question": "Are human enhancers or promoters evolving faster?",
            "answers": {
                "answer_start": 458,
                "text": "enhancers"
            }
        },
        {
            "context": "emMAW: computing minimal absent words in external memory. Motivation: The biological significance of minimal absent words has been investigated in genomes of organisms from all domains of life. For instance, three minimal absent words of the human genome were found in Ebola virus genomes. There exists an O(n) -time and O(n) -space algorithm for computing all minimal absent words of a sequence of length n on a fixed-sized alphabet based on suffix arrays. A standard implementation of this algorithm, when applied to a large sequence of length n , requires more than 20 n  bytes of RAM. Such memory requirements are a significant hurdle to the computation of minimal absent words in large datasets. Results: We present emMAW, the first external-memory algorithm for computing minimal absent words. A free open-source implementation of our algorithm is made available. This allows for computation of minimal absent words on far bigger data sets than was previously possible. Our implementation requires less than 3 h on a standard workstation to process the full human genome when as little as 1 GB of RAM is made available. We stress that our implementation, despite making use of external memory, is fast; indeed, even on relatively smaller datasets when enough RAM is available to hold all necessary data structures, it is less than two times slower than state-of-the-art internal-memory implementations. Availability and implementation: https://github.com/solonas13/maw (free software under the terms of the GNU GPL). Contact: alice.heliou@lix.polytechnique.fr or solon.pissis@kcl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm is available for computing minimal absent words using external memory?",
            "answers": {
                "answer_start": 721,
                "text": "emMAW"
            }
        },
        {
            "context": "Neurocognitive profile in Turner's syndrome is not affected by growth impairment. Turner's syndrome (TS) is a chromosomal disorder that results from the loss of the entire or a part of the X-chromosome and occurs in 1/2,500 female births. According to the majority of specific reports, intelligence in TS is generally found to be normal and the prevalence of mental retardation does not seem to be increased in TS except for those patients with a small ring X-chromosome. We evaluated 33 girls with TS with chronological age from 6-18 years. Intellectual assessment included the WISC III and the WAIS-R scales. Our results showed: 1) mean full scale intelligence quotient (FSIQ) was significantly lower than expected based on normative data (p < 0.0005); 2) no correlation was present between height and general intellectual ability; 3) mean performance intelligence quotient (PIQ) was significantly lower than both mean verbal intelligence quotient (VIQ) and FSIQ (p < 0.0025 and p < 0.01, respectively), and most patients had a VIQ-PIQ discrepancy; 4) the frequency of mental retardation in our study group was significantly higher than that observed in the general population (15.1% vs 2.3%, p < 0.025); 5) a significant association was found between karyotype and VIQ, and the best score was achieved in the subgroup of patients with structural abnormalities of the X-chromosome. In the light of these findings we conclude that the clinical picture in TS may encompass a slightly reduced FSIQ, VIQ and especially an inadequate PIQ, but this neurocognitive profile is not significantly affected by statural impairment. Since these neurocognitive defects can be responsible for misdiagnosed school difficulties, we suggest that girls with TS should receive specialized educational support and multidisciplinary care.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 189,
                "text": "X"
            }
        },
        {
            "context": "Assessment of allele-specific gene silencing by RNA interference with mutant and wild-type reporter alleles. Allele-specific gene silencing by RNA interference (RNAi) is therapeutically useful for specifically suppressing the expression of alleles associated with disease. To realize such allele-specific RNAi (ASPRNAi), the design and assessment of small interfering RNA (siRNA) duplexes conferring ASP-RNAi is vital, but is also difficult. Here, we show ASP-RNAi against the Swedish- and London-type amyloid precursor protein (APP) variants related to familial Alzheimer's disease using two reporter alleles encoding the Photinus and Renilla luciferase genes and carrying mutant and wild-type allelic sequences in their 3'-untranslated regions. We examined the effects of siRNA duplexes against the mutant alleles in allele-specific gene silencing and off-target silencing against the wild-type allele under heterozygous conditions, which were generated by cotransfecting the reporter alleles and siRNA duplexes into cultured human cells. Consistently, the siRNA duplexes determined to confer ASP-RNAi also inhibited the expression of the bona fide mutant APP and the production of either amyloid beta 40- or 42-peptide in Cos-7 cells expressing both the full-length Swedish- and wild-type APP alleles. The present data suggest that the system with reporter alleles may permit the preclinical assessment of siRNA duplexes conferring ASP-RNAi, and thus contribute to the design and selection of the most suitable of such siRNA duplexes.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 563,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received > 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade > 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade > 3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 1473,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Differential effects of diverse p53 isoforms on TAp73 transcriptional activity and apoptosis. The p53 activities are due, at least in part, to its ability to form oligomers that bind to specific DNA sequences and activate transcription. Since some mutant p53 proteins and ΔNp73 isoforms form heterocomplexes with TAp73, we asked whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73. Moreover, it has already been found that some isoforms form complex with wtp53 and some of them inhibit p53 tumor-suppressor functions. Therefore, we studied the complex formation and co-immunoprecipitation assays show that all six p53 isoforms examined can form complexes with TAp73β, whereas only Δ133p53α/β/γ isoforms form complex with TAp73α. All p53 isoforms counteract TAp73β transactivation function but with different efficiency and in a promoter-dependent manner. Furthermore, apoptotic activity of TAp73β was augmented by coexpression of p53β, whereas Δ133p53α and β inhibit its apoptotic activity most efficiently. We have determined the half-life of different p53 isoforms: p53γ isoform has the shortest half-life, whereas Δ133p53γ has the longest half-life. Inhibitory interactions of two proteins in complex often lead to their stabilization. However, only three isoforms (Δ133p53α, Δ133p53β and Δ40p53α) stabilize TAp73β. We are convinced that defining the interactions between p53/p73 would give a new insight into how the p53 isoforms modulate the p73 functions in tumorigenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 424,
                "text": "7"
            }
        },
        {
            "context": "Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 414,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 887,
                "text": "53BP1"
            }
        },
        {
            "context": "New anticoagulants: focus on venous thromboembolism. Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 885,
                "text": "xa"
            }
        },
        {
            "context": "Mechanisms of activation of NADPH oxidases. The members of the NOX family of enzymes are expressed in a variety of tissues and serve a number of functions. There is a high level of conservation of primary protein sequence, as well as functional features, although specialized responses are beginning to emerge. In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function. Studies of cytosolic co-factors showed that the C-terminal cytoplasmic domain of NOX1 was absolutely required for activation with NOXO1 and NOXA1 and that this activity required interaction of the putative NADPH-binding region of this domain with NOXA1. Finally, we have provided the first example of how alternative splicing of a NOX co-factor may be involved in the regulation of NADPH oxidase function.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 657,
                "text": "NOX1"
            }
        },
        {
            "context": "Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. Polyglutamine diseases, including Huntington's disease, designate a group of nine neurodegenerative disorders characterized by the presence of a toxic polyglutamine expansion in specific target proteins. Using cell and mouse models, we have shown that expanded polyglutamine led to activation of the stress kinase JNK and the transcription factor AP-1, which are implicated in neuronal death. Polyglutamine expansion-induced stress shared common features with protein-damaging stress such as heat shock, because activation of JNK involved inhibition of JNK phosphatase activities. Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6. Aggregation of M3/6 by polyglutamine expansion appeared to be indirect, because M3/6 was not recruited into polyglutamine inclusions. The heat shock protein HSP70, which is known to inhibit JNK during the heat shock response, suppressed polyglutamine-mediated aggregation of M3/6 and activation of JNK. Interestingly, levels of HSP70 were down-regulated by polyglutamine expansion. We suggest that reduction of HSP70 by expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in activation of JNK and AP-1.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 1309,
                "text": "JNK"
            }
        },
        {
            "context": "[Difficult therapeutic decision making in treatment of children with oesophageal atresia and trisomy of chromosome 18 - comments by geneticist, surgeon, neonatologist, paediatrician and anaesthesiologist]. Oesophageal atresia is a congenital defect of alimentary tract concerning the interruption of oesophagus with or without connection with the trachea. Its incidence is 1:3000-3500 of live-born. Associated anomalies including genetic disorders occur in 50% of patients. Edwards syndrome which is trisomy of chromosome 18 with poor prognosis. The incidence of Edwards syndrome is 1:5000 of live-born. About 5% of these children live more than 1 year. The aim of this article is a retrospective analysis of the course of treatment of newborn with oesophageal atresia and Edwards syndrome and making of therapeutic decision. The authors from different medical specializations: clinical genetics, paediatric surgery, paediatrics and neonatology, paediatric intensive care and palliative medicine, have undertaken a discussion regarding surgical treatment of children with oesophageal atresia and chromosomal, lethal syndrome.",
            "question": "What is the incidence of Edwards syndrom in the european population?",
            "answers": {
                "answer_start": 583,
                "text": "1:5000"
            }
        },
        {
            "context": "Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. Lewy bodies, neuropathological hallmarks of Parkinson's disease and dementia with Lewy bodies, comprise alpha-synuclein filaments and other less defined proteins. Characterization of Lewy body proteins that interact with alpha-synuclein may provide insight into the mechanism of Lewy body formation. Double immunofluorescence labeling and confocal microscopy revealed approximately 80% of cortical Lewy bodies contained microtubule-associated protein 1B (MAP-1B) that overlapped with alpha-synuclein. Lewy bodies were isolated using an immunomagnetic technique from brain tissue of patients dying with dementia with Lewy bodies. Lewy body proteins were resolved by polyacrylamide gel electrophoresis. Immunoblotting confirmed the presence of MAP-1B and alpha-synuclein in purified Lewy bodies. Direct binding studies revealed a high affinity interaction (IC(50) approximately 20 nm) between MAP-1B and alpha-synuclein. The MAP-1B-binding sites were mapped to the last 45 amino acids of the alpha-synuclein C terminus. MAP-1B also bound in vitro assembled alpha-synuclein fibrils. Thus, MAP-1B may be involved in the pathogenesis of Lewy bodies via its interaction with monomeric and fibrillar alpha-synuclein.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 83,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 175,
                "text": "MRSA"
            }
        },
        {
            "context": "Gender differences in Latin-American patients with rheumatoid arthritis. BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a large population with unique characteristics, including high admixture. OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in LAC. METHODS: This was a 2-phase study. First we conducted a cross-sectional and analytical study in which 1128 consecutive Colombian patients with RA were assessed. Second, a systematic review of the literature was done to evaluate the effect of gender in LAC patients with RA. RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man. Colombian women with RA are more at risk of having an early age at onset and developing polyautoimmunity and abdominal obesity, and they perform more household duties than their male counterparts. However, male gender was associated with the presence of extra-articular manifestations. Of a total of 641 potentially relevant articles, 38 were considered for final analysis, in which several factors and outcomes related to gender were identified. CONCLUSIONS: RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 712,
                "text": "women"
            }
        },
        {
            "context": "CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package is used for the detection of chromosomal abnormalities from microarray data?",
            "answers": {
                "answer_start": 0,
                "text": "CAFE"
            }
        },
        {
            "context": "Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is neuroprotective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the central nervous system (CNS), when delivered peripherally, is limited due to the blood-brain barrier (BBB). We have developed a means of delivering BDNF into the CNS using genetically engineered bone marrow stem cells (BMSCs) as a vehicle, and have explored the clinical effects of BDNF on outcomes in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). BDNF-engineered-BMSCs were transplanted (i.v.) into irradiated 2-week-old SJL/J female mice. Eight weeks after transplantation, mice were immunized with a peptide of proteolipid protein (PLP(139-151)). Mice, which had received BDNFengineered BMSCs, showed a significant delay in EAE onset and a reduction in overall clinical severity compared to mice receiving BMSC transfected with an empty vector lacking the BDNF gene. In addition, pathological examination showed that BDNF delivery reduced demyelination and increased remyelination. Inhibition of pro-inflammatory cytokines TNF-alpha and IFN-gamma and enhanced expression of the antiinflammatory cytokines IL-4, IL-10, and IL-11 were found in the CNS tissues of the BDNF transplanted group. These results support the use of BMSCs as vehicles to deliver BDNF into the CNS of EAE animals. This is a potentially novel therapeutic approach that might be used to deliver BDNF gene or genes for other therapeutic proteins into the CNS in MS or in other diseases of the CNS in which accessibility of therapeutic proteins is limited due to the BBB.",
            "question": "Which is the most widely used model for the study of multiple sclerosis (MS)?",
            "answers": {
                "answer_start": 640,
                "text": "experimental autoimmune encephalomyelitis (EAE)"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 196,
                "text": "Xa"
            }
        },
        {
            "context": "The 5' → 3' exoribonuclease XRN1/Pacman and its functions in cellular processes and development. XRN1 is a 5' → 3' processive exoribonuclease that degrades mRNAs after they have been decapped. It is highly conserved in all eukaryotes, including homologs in Drosophila melanogaster (Pacman), Caenorhabditis elegans (XRN1), and Saccharomyces cerevisiae (Xrn1p). As well as being a key enzyme in RNA turnover, XRN1 is involved in nonsense-mediated mRNA decay and degradation of mRNAs after they have been targeted by small interfering RNAs or microRNAs. The crystal structure of XRN1 can explain its processivity and also the selectivity of the enzyme for 5' monophosphorylated RNA. In eukaryotic cells, XRN1 is often found in particles known as processing bodies (P bodies) together with other proteins involved in the 5' → 3' degradation pathway, such as DCP2 and the helicase DHH1 (Me31B). Although XRN1 shows little specificity to particular 5' monophosphorylated RNAs in vitro, mutations in XRN1 in vivo have specific phenotypes suggesting that it specifically degrades a subset of RNAs. In Drosophila, mutations in the gene encoding the XRN1 homolog pacman result in defects in wound healing, epithelial closure and stem cell renewal in testes. We propose a model where specific mRNAs are targeted to XRN1 via specific binding of miRNAs and/or RNA-binding proteins to instability elements within the RNA. These guide the RNA to the 5' core degradation apparatus for controlled degradation.",
            "question": "Which is the enzyme that degrades decapped mRNAs?",
            "answers": {
                "answer_start": 97,
                "text": "XRN1"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 639,
                "text": "GBshape"
            }
        },
        {
            "context": "Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Nestin is a unique intermediate filament protein. While it is robustly expressed in developing brain, postnatal expression is limited to the brain's subventricular zone (SVZ) and endothelial cells. Reexpression occurs, however, under several pathological conditions, including injury and neoplasia. We hypothesized that nestin would be a sensitive marker of early neoplasia after transplacental exposure of rats to ethylnitrosourea (ENU). Rats of various ages were administered bromodeoxyuridine (BudR) before sacrifice, and brain sections were examined for proliferative cells and several immunohistochemical markers, including nestin. Additional rats were examined after a stab wound injury to assess the expression of two of these markers, GFAP and nestin, in reactive astrocytes. All ENU-induced brain tumors (n = 9) were classified as gliomas (astrocytomas or oligoastrocytomas) based on their histology and immunophenotype. Nestin expression was noted in all tumors examined and was present in tumor cells as well as endothelial cells. During tumor development, we consistently noted nestin-expressing cells bearing multiple processes distributed throughout brain parenchyma. Both single cells and multiple cell clusters were observed as early as postnatal day 30 in all ENU-exposed brains examined (n = 11). Such distinctive nestin-expressing cells were not seen in nestin-stained control brains or ENU-exposed brains stained for GFAP or vimentin, nor was such a cell seen in a stab wound model used to assess reactive astrocytosis. While the number of these clusters was highly variable among rats, their size increased between 30 and 90 days. The data suggest that these nestin-expressing cells represent an early stage of the neoplastic process. It remains to be determined whether these cells become apparent at 30 days of age due to \"dedifferentiation\" of a local resident astrocyte or astrocyte precursor cell or migration of a relatively undifferentiated precursor/stem cell from the SVZ.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 86,
                "text": "Nestin"
            }
        },
        {
            "context": "Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Many patients with multiple myeloma (MM) are elderly (aged >65 years) or unfit, and therefore ineligible for stem-cell transplantation. The novel agents thalidomide, bortezomib, and lenalidomide have shown improved outcomes in these patients. This article discusses the role of continuous therapy in improving patient outcomes and how novel agents with better tolerability profiles could lead to a change in the treatment paradigm. According to the proposed concept, treatment of transplant-ineligible patients with MM should include achievement of high-quality responses with effective induction combination regimens, as well as maintenance of the response with long-term therapy for optimal sustained efficacy.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 112,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Koebner's phenomenon and necrobiosis lipoidica diabeticorum. In 1877, Dr Heinrich Koebner inflicted an experimental trauma on the uninvolved skin of a psoriatic patient. This resulted in the appearance of a typical psoriatic lesion at the site of trauma. This reaction, known as Koebner's phenomenon (KP), has subsequently been associated with several skin diseases. However, it has not been associated previously with necrobiosis lipoidica diabeticorum (NBL), a rare skin manifestation of diabetes mellitus. This report presents the unusual finding of NBL associated with KP in a patient with diabetes mellitus.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 490,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "A radiopathological classification of dural tail sign of meningiomas. OBJECT: The completeness of meningioma resection depends on the resection of dura mater invaded by the tumor. The pathological changes of the dura around the tumor can be interpreted by evaluating the dural tail sign (DTS) on MRI studies. The goal of this study was to clarify the pathological characteristics of the DTSs, propose a classification based on the histopathological and radiological correlation, and identify the invasive range of tumor cells in different types of DTS. METHODS: The authors retrospectively reviewed 179 patients with convexity meningiomas who underwent Simpson Grade I resection. All patients underwent an enhanced MRI examination preoperatively. The convexity meningiomas were dichotomized into various subtypes in accordance with the 2007 WHO classification of tumors of the CNS, and the DTS was identified based on the Goldsher criteria. The range of resection of the involved dura was 3 cm from the base of the tumor, which corresponded with the length of DTS on MRI studies. Histopathological examination of dura at 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 cm from the base of the tumor was conducted, and the findings were correlated with the preoperative MRI appearance of the DTS. RESULTS: A total of 154 (86%) of 179 convexity meningiomas were classified into WHO Grade I subtype, including transitional (44 [28.6%] of 154), meningothelial (36 [23.4%] of 154), fibrous (23 [14.9%] of 154), psammomatous (22 [14.3%] of 154), secretory (10 [6.5%] of 154), and angiomatous (19 [12.3%] of 154). The other 25 (14%) were non-Grade I (WHO) tumors, including atypical (12 [48%] of 25), anaplastic (5 [20%] of 25), and papillary (8 [32%] of 25). The DTS was classified into 5 types: smooth (16 [8.9%] of 179), nodular (36 [20.1%] of 179), mixed (57 [31.8%] of 179), symmetrical multipolar (15 [8.4%] of 179), and asymmetrical multipolar (55 [30.7%] of 179). There was a significant difference in distribution of DTS type between Grade I and non-Grade I tumors (p = 0.004), whereas the difference was not significant among Grade I tumors (0.841) or among non-Grade I tumors (p = 0.818). All smooth-type DTSs were encountered in Grade I tumors, and the mixed DTS (52 [33.8%] of 154) was the most common type in these tumors. Nodular-type DTS was more commonly seen in non-Grade I tumors (12 [48%] of 25). Tumor invasion was found in 88.3% (158 of 179) of convexity meningiomas, of which the range of invasion in 82.3% (130 of 158) was within 2 cm and that in 94.9% (150 of 158) was within 2.5 cm. The incidence of invasion and the range invaded by tumor cells varied in different types of DTS, and differences were statistically significant (p < 0.001). CONCLUSIONS: Nodular-type DTS on MRI studies might be associated with non-Grade I tumors. The range of dural resection for convexity meningiomas should be 2.5 cm from the tumor base, and if this extent of resection is not feasible, the type of DTS should be considered. However, for skull base meningiomas, in which mostly Simpson Grade II resection is achieved, the use of this classification should be further validated. The classification of DTS enables the surgeon to predict preoperatively and then to achieve the optimal range of dural resection that might significantly reduce the recurrence rate of meningiomas.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 3038,
                "text": "meningioma"
            }
        },
        {
            "context": "Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 466,
                "text": "Restless Legs Syndrome"
            }
        },
        {
            "context": "LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.",
            "question": "Which R / bioconductor package is used for enrichment analysis of genomic regions?",
            "answers": {
                "answer_start": 0,
                "text": "LOLA"
            }
        },
        {
            "context": "Initiation of spectrin dimerization involves complementary electrostatic interactions between paired triple-helical bundles. The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit, each of which comprises largely a series of homologous triple-helical motifs. Initiation of dimer assembly involves strong binding between complementary motifs near the actin-binding end of the dimer. In this study, the mechanism of lateral spectrin association at this dimer nucleation site was investigated using the analytical ultracentrifuge to analyze heterodimers formed from recombinant peptides containing two or four homologous motifs from each subunit (alpha20-21/beta1-2; alpha18-21/beta1-4). Both the two-motif and four-motif dimer associations were weakened substantially with increasing salt concentration, indicating that electrostatic interactions are important for the dimer initiation process. Modeling of the electrostatic potential on the surface of the alpha20 and beta2 motifs showed that the side of the motifs comprising the A and B helices is the most favorable for association, with an area of positive electrostatic potential on the AB face of the beta2 motif opposite negative potential on the AB face of the alpha20 motif and vise versa. Protease protection analysis of the alpha20-21/beta1-2 dimer showed that multiple trypsin and proteinase K sites in the A helices of the beta2 and alpha21 motifs become buried upon dimer formation. Together, these data support a model where complementary long range electrostatic interactions on the AB faces of the triple-helical motifs in the dimer nucleation site initiate the correct pairing of motifs, i.e. alpha21-beta1 and alpha20-beta2. After initial docking of these complementary triple-helical motifs, this association is probably stabilized by subsequent formation of stronger hydrophobic interactions in a complex involving the A helices of both subunits and possibly most of the AB faces. The beta subunit A helix in particular appears to be buried in the dimer interface.",
            "question": "Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?",
            "answers": {
                "answer_start": 167,
                "text": "antiparallel"
            }
        },
        {
            "context": "Population pharmacokinetics of rilotumumab, a fully human monoclonal antibody against hepatocyte growth factor, in cancer patients. Rilotumumab is an investigational, fully human, monoclonal antibody immunoglobulin G2 against hepatocyte growth factor (HGF) that blocks the binding of HGF to its receptor MET and has shown trends toward improved survival in a phase 2 clinical trial in gastric cancer. To characterize rilotumumab pharmacokinetics in patients with cancer and to identify factors affecting the pharmacokinetics, rilotumumab concentration data from seven clinical trials were analyzed with a nonlinear mixed-effect model. We found that rilotumumab exhibited linear and time-invariant kinetics over a dose range of 0.5-20 mg/kg. Typical systemic clearance and central volume of distribution were 0.184 L/day and 3.56 L, respectively. Body weight is the most significant covariate, and sex, cancer type, coadministration of chemotherapeutics, baseline plasma HGF and tumor MET levels, and renal and hepatic functions did not have an effect on rilotumumab pharmacokinetics. The concentration-time profiles for the rilotumumab clinical regimens were projected well with the model.",
            "question": "What is inhibited by a drug rilotumumab?",
            "answers": {
                "answer_start": 226,
                "text": "hepatocyte growth factor"
            }
        },
        {
            "context": "Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called \"neurofibromin.\" It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the \"two hit\" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 220,
                "text": "NF1"
            }
        },
        {
            "context": "Transvaginal ultrasound measurement of bladder wall thickness: a more reliable approach than transperineal and transabdominal approaches. OBJECTIVES To validate transperineal, transabdominal and transvaginal ultrasound (US) techniques to measure bladder wall thickness (BWT). SUBJECTS AND METHODS Women underwent US measurement of BWT at three different anatomical sites: anterior wall, dome and trigone of the bladder by two 'blinded' operators using transabdominal, transperineal and transvaginal approaches at separate visits and by a single operator using transabdominal and transperineal techniques. Bland-Altman analysis was used to determine interobserver reliability for all three techniques and intraobserver reliability for transabdominal and transperineal methods. RESULTS In all, 25 women were scanned. The transperineal US had a high interobserver mean difference when measuring the anterior BWT (-0.34) and a high intraobserver mean difference when measuring the anterior (0.54) and dome BWT (0.33). Transabdominal US had a high interobserver mean difference for all measurements of BWT, and a high intraobserver mean difference when measuring the trigonal thickness (0.56). Transvaginal US had a consistent interobserver mean difference for all three measurements. The transperineal and transabominal approaches had the widest intraobserver and interobserver 95% confidence intervals of the mean difference when compared with the transvaginal approach. CONCLUSIONS Transabdominal and transperineal US for measuring BWT did not have good intraobserver and interobserver reliability for measurement of the three anatomical sites to determine mean BWT. Transvaginal US had good interobserver reliability, thus mean BWT is best measured using the transvaginal approach.",
            "question": "How is bladder wall thickness measured?",
            "answers": {
                "answer_start": 208,
                "text": "ultrasound"
            }
        },
        {
            "context": "Multiple Myeloma Gets Three New Drugs. In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 238,
                "text": "CD38"
            }
        },
        {
            "context": "Genetic Determinants of RNA Editing Levels of ADAR Targets in Drosophila melanogaster. RNA editing usually affects only a fraction of expressed transcripts and there is a vast amount of variation in editing levels of ADAR (adenosine deaminase, RNA-specific) targets. Here we explore natural genetic variation affecting editing levels of particular sites in 81 natural strains of Drosophila melanogaster. The analysis of associations between editing levels and single-nucleotide polymorphisms allows us to map putative cis-regulatory regions affecting editing of 16 A-to-I editing sites (cis-RNA editing quantitative trait loci or cis-edQTLs, P < 10(-8)). The observed changes in editing levels are validated by independent molecular technique. All identified regulatory variants are located in close proximity of modulated editing sites. Moreover, colocalized editing sites are often regulated by same loci. Similar to expression and splicing QTL studies, the characterization of edQTLs will greatly expand our understanding of cis-regulatory evolution of gene expression.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 46,
                "text": "ADAR"
            }
        },
        {
            "context": "The strength and functional performance in patients with facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive myopathy with autosomal dominant inheritance remarkable for its early involvement of facial musculature. The purpose of our study was to assess the rate of strength deterioration, functional condition and performance of activity of daily living of patients with FSHD in Taiwan. Twenty patients diagnosed with FSHD were included in this study. Manual muscle testing (MMT) was used to evaluate muscle strength. The Brooke and Vignos scales were used to assess upper and lower extremity function respectively, and the capability of the activity of daily living was measured by Barthel index. The result of the strength testing was characterized by the presence of a progressive asymmetrical muscular weakness in patients with FSHD. The mean muscular strength of the right extremity was weaker than its left counterparts (p < 0.05) and the shoulder muscle group was the weakest. According to the Brooke functional scale, 20% of our patients were graded as 1, 30% as grade 2, and 50% as grade 3. On the Vignos functional scale, 50% of patients fell into grade 1, 10% in grade 2, and 40% in grades 3-5. Vignos scale was significantly correlated with mean muscle strength (p < 0.05). The average value of Barthel index was 97.8 +/- 4.7. The muscle strength decline in this Taiwanese of FSHD population was more severe in shoulder girdle area. The mean muscle strength of the right extremity was weaker than the left. Most of our patients suffered from mild or moderate physical disability. Finding of these Taiwanese FSHD population is similar to those reported elsewhere in the world.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 181,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Analysis of the intracellular localization of p73 N-terminal protein isoforms TAp73 and ∆Np73 in medulloblastoma cell lines. The protein homologous to the tumor suppressor p53, p73, has essential roles in development and tumorigenesis. This protein exists in a wide range of isoforms with different, even antagonistic, functions. However, there are virtually no detailed morphological studies analyzing the endogenous expression of p73 isoforms at the cellular level in cancer cells. In this study, we investigated the expression and subcellular distribution of two N-terminal isoforms, TAp73 and ΔNp73, in medulloblastoma cells using immunofluorescence microscopy. Both proteins were observed in all cell lines examined, but differences were noted in their intracellular localization between the reference Daoy cell line and four newly established medulloblastoma cell lines (MBL-03, MBL-06, MBL-07 and MBL-10). In the new cell lines, TAp73 and ΔNp73 were located predominantly in cell nuclei. However, there was heterogeneity in TAp73 distribution in the cells of all MBL cell lines, with the protein located in the nucleus and also in a limited non-random area in the cytoplasm. In a small percentage of cells, we detected cytoplasmic localization of TAp73 only, i.e., nuclear exclusion was observed. Our results provide a basis for future studies on the causes and function of distinct intracellular localization of p73 protein isoforms with respect to different protein-protein interactions in medulloblastoma cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 590,
                "text": "7"
            }
        },
        {
            "context": "A cytochrome c methyltransferase from Crithidia oncopelti. The mitochondrial cytochrome c-557 of Crithidia oncopelti contains two lysine residues and an N-terminal proline residue that are methylated in vivo by the methyl group of methionine. The purified cytochrome can act as a methyl acceptor for a methyltransferase activity in the cell extract that uses S-adenosylmethionine as methyl donor. Crithidia cytochrome c-557 is by far the best substrate for this methyltransferase of those tested, in spite of the fact that methylation sites are already almost fully occupied. The radioactive uptake of [14C]methyl groups from S-adenosylmethionine occurred only at a lysine residue (-8) and the N-terminal proline residue. This methyltransferase appears to differ from that of Neurospora and yeast [Durban, Nochumson, Kim, Paik & Chan (1978) J. Biol. Chem. 253, 1427-1435; DiMaria, Polastro, DeLange, Kim & Paik (1979) J. Biol. Chem. 254, 4645-4652] in that lysine-72 of horse cytochrome c is a poor acceptor. Also, the Crithidia methyltransferase appears to be stable to carry lysine methylation much further to completion than do the enzymes from yeast and Neurospora, which produce very low degrees of methylation in native cytochromes c.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 361,
                "text": "adenosylmethionine"
            }
        },
        {
            "context": "Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) and Fatal Pneumonia with Pediatric Deaths in Krasnoyarsk, Siberian Russia: Unique MRSA's Multiple Virulence Factors, Genome, and Stepwise Evolution. Methicillin-resistant Staphylococcus aureus (MRSA) is a common multidrug-resistant (MDR) pathogen. We herein discussed MRSA and its infections in Krasnoyarsk, Siberian Russia between 2007 and 2011. The incidence of MRSA in 3,662 subjects was 22.0% and 2.9% for healthcare- and community-associated MRSA (HA- and CA-MRSA), respectively. The 15-day mortality rates for MRSA hospital- and community-acquired pneumonia (HAP and CAP) were 6.5% and 50%, respectively. MRSA CAP cases included pediatric deaths; of the MRSA pneumonia episodes available, > 27.3% were associated with bacteremia. Most cases of HA-MRSA examined exhibited ST239/spa3(t037)/SCCmecIII.1.1.2 (designated as ST239Kras), while all CA-MRSA cases examined were ST8/spa1(t008)/SCCmecIV.3.1.1(IVc) (designated as ST8Kras). ST239Kras and ST8Kras strongly expressed cytolytic peptide (phenol-soluble modulin α, PSMα; and δ-hemolysin, Hld) genes, similar to CA-MRSA. ST239Kras pneumonia may have been attributed to a unique set of multiple virulence factors (MVFs): toxic shock syndrome toxin-1 (TSST-1), elevated PSMα/Hld expression, α-hemolysin, the staphylococcal enterotoxin SEK/SEQ, the immune evasion factor SCIN/SAK, and collagen adhesin. Regarding ST8Kras, SEA was included in MVFs, some of which were common to ST239Kras. The ST239Kras (strain OC3) genome contained: a completely unique phage, φSa7-like (W), with no att repetition; S. aureus pathogenicity island SaPI2R, the first TSST-1 gene-positive (tst+) SaPI in the ST239 lineage; and a super copy of IS256 ( > 22 copies/genome). ST239Kras carried the Brazilian SCCmecIII.1.1.2 and United Kingdom-type tst. ST239Kras and ST8Kras were MDR, with the same levofloxacin resistance mutations; small, but transmissible chloramphenicol resistance plasmids spread widely enough to not be ignored. These results suggest that novel MDR and MVF+ HA- and CA-MRSA (ST239Kras and ST8Kras) emerged in Siberian Russia (Krasnoyarsk) associated with fatal pneumonia, and also with ST239Kras, a new (Siberian Russian) clade of the ST239 lineage, which was created through stepwise evolution during its potential transmission route of Brazil-Europe-Russia/Krasnoyarsk, thereby selective advantages from unique MVFs and the MDR.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 170,
                "text": "MRSA"
            }
        },
        {
            "context": "Transitional lumbosacral vertebrae and low back pain: diagnostic pitfalls and management of Bertolotti's syndrome. OBJECTIVE: Bertolotti's syndrome is a spine disorder characterized by the occurrence of a congenital lumbar transverse mega-apophysis in a transitional vertebral body that usually articulates with the sacrum or the iliac bone. It has been considered a possible cause of low back pain. METHOD: We analyzed the cases of Bertolotti's syndrome that failed clinical treatment and reviewed the literature concerning this subject. RESULTS: Five patients in our series had severe low back pain due to the neo-articulation and two of them were successfully submitted to surgical resection of the transverse mega-apophysis. Taking into account the clinical and surgical experience acquired with these cases, we propose a diagnostic-therapeutic algorithm. CONCLUSION: There is still no consensus about the most appropriate therapy for Bertolotti's syndrome. In patients in whom the mega-apophysis itself may be the source of back pain, surgical resection may be a safe and effective procedure.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 13,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival. Previous studies have shown that DNA methyltransferase (Dnmt) 1 is required for maintenance of bulk DNA methylation and is essential for mouse development. However, somatic disruption of DNMT1 in the human cancer cell line HCT116 was not lethal and caused only minor decreases in methylation. Here, we report the identification of a truncated DNMT1 protein, which was generated by the disruption of DNMT1 in HCT116 cells. The truncated protein, which had parts of the regulatory N-terminal domain deleted but preserved the catalytic C-terminal domain, was present at different levels in all DNMT1 single-knockout and DNMT1/DNMT3b double-knockout cell lines tested and retained hemimethylase activity. DNMT1 RNAi resulted in decreased cell viability in WT and knockout cells and further loss of DNA methylation in DNMT1 knockout cells. Furthermore, we observed a delay in methylation after replication and an increase in hemimethylation of specific CpG sites in cells expressing the truncated protein. Remethylation studies after drug-induced hypomethylation suggest a putative role of DNMT1 in the de novo methylation of a subtelomeric repeat, D4Z4, which is lost in cells lacking full-length DNMT1. Our data suggest that DNMT1 might be essential for maintenance of DNA methylation, proliferation, and survival of cancer cells.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1359,
                "text": "DNMT1"
            }
        },
        {
            "context": "Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. BACKGROUND: The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort). INTERPRETATION: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 49,
                "text": "malaria"
            }
        },
        {
            "context": "Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.",
            "question": "Which is the E3 ubiquitin ligase which ubiquitinates IkB leading to its proteasomal degradation?",
            "answers": {
                "answer_start": 2076,
                "text": "beta-TrCP"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 584,
                "text": "xa"
            }
        },
        {
            "context": "Early discharge of patients with presumed opioid overdose: development of a clinical prediction rule. OBJECTIVE: To develop a clinical prediction rule to identify patients who can be safely discharged one hour after the administration of naloxone for presumed opioid overdose. METHODS: Patients who received naloxone for known or presumed opioid overdose were formally evaluated one hour later for multiple potential predictor variables. Patients were classified into two groups: those with adverse events within 24 hours and those without. Using classification and regression tree methodology, a decision rule was developed to predict safe discharge. RESULTS: Clinical findings from 573 patients allowed us to develop a clinical prediction rule with a sensitivity of 99% (95% CI = 96% to 100%) and a specificity of 40% (95% CI = 36% to 45%). Patients with presumed opioid overdose can be safely discharged one hour after naloxone administration if they: 1) can mobilize as usual; 2) have oxygen saturation on room air of >92%; 3) have a respiratory rate >10 breaths/min and <20 breaths/min; 4) have a temperature of >35.0 degrees C and <37.5 degrees C; 5) have a heart rate >50 beats/min and <100 beats/min; and 6) have a Glasgow Coma Scale score of 15. CONCLUSIONS: This prediction rule for safe early discharge of patients with presumed opioid overdose performs well in this derivation set but requires validation followed by confirmation of safe implementation.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 308,
                "text": "naloxone"
            }
        },
        {
            "context": "Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 251,
                "text": "Xa"
            }
        },
        {
            "context": "A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.",
            "question": "Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?",
            "answers": {
                "answer_start": 542,
                "text": "Genomiser"
            }
        },
        {
            "context": "Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate. Oxidative stress activates the c-Jun N-terminal kinase (JNK) pathway. However, the exact mechanisms by which reactive oxygen species (ROS) activate JNK are unclear. We found that the ability of hydrogen peroxide (H(2)O(2)) to induce JNK activation varied in different cell types. Pyrrolidine dithiocarbamate (PDTC), a presumed antioxidant, induced JNK activation on its own and enhanced JNK activation by H(2)O(2) in many cell types, including Jurkat, HEK293, and LNCaP and Tsu-Pr1 prostate cancer cells. The activation of JNK by PDTC, in the presence or absence of exogenous H(2)O(2), was dependent on its chelating ability to metal ions, most likely copper ions. Despite the strong JNK-activating ability, H(2)O(2) plus PDTC did not induce significant activation of the upstream kinases, SEK1/MKK4 and MKK7. However, the JNK inactivation rate was slower in cells treated with H(2)O(2) plus PDTC compared with the rate in cells treated with ultraviolet C (UV-C). Treatment of H(2)O(2) plus PDTC significantly decreased the expression levels of a JNK phosphatase, M3/6 (also named hVH-5), but not the levels of other phosphatases (PP2A and PP4). In contrast, UV-C irradiation did not cause the down-regulation of M3/6. These results suggest that JNK activation by H(2)O(2) plus PDTC resulted from the down-regulation of JNK phosphatases. Our data also reveal a necessity to carefully evaluate the pharmacological and biochemical properties of PDTC.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 1466,
                "text": "JNK"
            }
        },
        {
            "context": "Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure. BACKGROUND: Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia. OBJECTIVE: To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF). METHODS AND RESULTS: CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups. CONCLUSIONS: In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 1217,
                "text": "NCX"
            }
        },
        {
            "context": "Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. Specific outcomes upon activation of the c-Jun N-terminal kinase (JNK) pathway critically depend on the intensity and duration of signal transmission. Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. It has been shown that M3/6 itself is phosphorylated by JNK upon stimulation with arsenite, but the role of this phosphorylation has not been investigated. In this study, we mapped JNK-induced phosphorylation sites on M3/6 using mass spectrometry. Phosphorylated residues Ser 515, Thr 518 and Ser 520 were identified and site-directed mutagenesis was employed to investigate their role. Upon arsenite stimulation, M3/6 mutated at these sites exhibited decreased phosphorylation compared to the wild-type protein. No difference was observed in terms of the enzyme's in vitro phosphatase activity, its substrate specificity towards JNK isoforms, its interactions with JNK and the scaffold family of JNK-interacting proteins (JIPs), its stability or its subcellular localization. Interestingly, expression of M3/6 phosphorylation mutants delayed the time-course of JNK phosphorylation and activation by arsenite. We propose that phosphorylation of the M3/6 phosphatase by JNK in response to stress stimuli results in attenuation of phosphatase activity and acceleration of JNK activation.",
            "question": "Which protein is affected by dusp8 activation?",
            "answers": {
                "answer_start": 84,
                "text": "JNK"
            }
        },
        {
            "context": "mpMoRFsDB: a database of molecular recognition features in membrane proteins. SUMMARY: Molecular recognition features (MoRFs) are small, intrinsically disordered regions in proteins that undergo a disorder-to-order transition on binding to their partners. MoRFs are involved in protein-protein interactions and may function as the initial step in molecular recognition. The aim of this work was to collect, organize and store all membrane proteins that contain MoRFs. Membrane proteins constitute ∼30% of fully sequenced proteomes and are responsible for a wide variety of cellular functions. MoRFs were classified according to their secondary structure, after interacting with their partners. We identified MoRFs in transmembrane and peripheral membrane proteins. The position of transmembrane protein MoRFs was determined in relation to a protein's topology. All information was stored in a publicly available mySQL database with a user-friendly web interface. A Jmol applet is integrated for visualization of the structures. mpMoRFsDB provides valuable information related to disorder-based protein-protein interactions in membrane proteins. AVAILABILITY: http://bioinformatics.biol.uoa.gr/mpMoRFsDB",
            "question": "Which is the database of molecular recognition features in membrane proteins?",
            "answers": {
                "answer_start": 0,
                "text": "mpMoRFsDB"
            }
        },
        {
            "context": "SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts. Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 110,
                "text": "Phospholamban"
            }
        },
        {
            "context": "Direct comparison of [(18) F]MH.MZ and [(18) F] altanserin for 5-HT2A receptor imaging with PET. Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 132,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 119,
                "text": "TYR"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 707,
                "text": "IL-1β"
            }
        },
        {
            "context": "Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay. We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 214,
                "text": "HEXA"
            }
        },
        {
            "context": "Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas. PURPOSE: Deregulation of mammalian Polycomb group (PcG) members may contribute to human carcinogenesis. p16INK4a and p14ARF tumor suppressors, human telomerase reverse transcriptase (h-TERT), and oncoprotein c-Myc have been implicated in the regulation of the cell cycle and proliferation mediated by PcG proteins, mainly Bmi-1, in mice and in cell culture experiments. Here, we examine whether these in vitro findings can be extrapolated to the in vivo situation. EXPERIMENTAL DESIGN: We measure the expression of PcG members Bmi-1, Mel-18, and Hpc-2 and their potential targets by reverse transcription-PCR, immunostaining, and Western blotting in a series of 134 breast carcinomas and correlate the data with several clinical-pathologic variables of the tumors. RESULTS: Expression of PcG genes was variably detected, but overexpression of Bmi-1 was the most frequent PcG alteration observed. In addition, statistical direct correlation in expression level of the three PcG members was detected. A correlation between c-Myc and Bmi-1 expression levels was observed; however, there was no correlation between expression of Bmi-1 and p16INK4a, p14ARF, or h-TERT. However, expression of the other PcG members Mel-18 and Hpc-2 correlated with the cell cycle regulators. Moreover, PcG mRNA-altered expression correlated significantly with certain clinical-pathologic variables associated with poor prognosis. CONCLUSIONS: Our data suggest that the oncogenic role of Bmi-1 in human primary breast carcinomas is not determined by its capacity to inhibit INK4a/ARF proteins or to induce telomerase activity.",
            "question": "Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?",
            "answers": {
                "answer_start": 259,
                "text": "p16INK4"
            }
        },
        {
            "context": "FullSSR: Microsatellite Finder and Primer Designer. Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. The software was tested with 2000 sequences of Oryza sativa shotgun sequencing project from the National Center of Biotechnology Information Trace Archive and with partial genome sequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla platensis, and Zilchiopsis collastinensis. FullSSR performance was compared against other similar SSR search programs. The results of the use of this kind of approach depend on the parameters set by the user. In addition, results can be affected by the analyzed sequences because of differences among the genomes. FullSSR simplifies the detection of SSRs and primer design on a big data set. The command line interface of FullSSR was intended to be used as part of genomic analysis tools pipeline; however, it can be used as a stand-alone program because the results are easily interpreted for a nonexpert user.",
            "question": "Which tool exists for microsatellite (SSR) loci detection and primer design?",
            "answers": {
                "answer_start": 901,
                "text": "FullSSR"
            }
        },
        {
            "context": "Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 938,
                "text": "Xa"
            }
        },
        {
            "context": "Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 985,
                "text": "telomerase"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 189,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Inter-observer reproducibility of diagnosis of diabetic foot osteomyelitis based on a combination of probe-to-bone test and simple radiography. Probe-to-bone test and simple X-rays are both standard tests for the diagnosis of diabetic foot osteomyelitis. This study demonstrates the importance of considering jointly clinical information (probe-to-bone test) and diagnostic tests (simple radiography) to increase agreement among clinicians on diagnosis of diabetic foot osteomyelitis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 456,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 102,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.",
            "question": "What is Contrave prescribed for?",
            "answers": {
                "answer_start": 88,
                "text": "obesity"
            }
        },
        {
            "context": "Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790: implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8%. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 242,
                "text": "epidermal growth factor receptor"
            }
        },
        {
            "context": "Idarucizumab for Dabigatran Reversal. BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).",
            "question": "Idarucizumab is an antidote of which drug?",
            "answers": {
                "answer_start": 227,
                "text": "dabigatran"
            }
        },
        {
            "context": "MethPed: an R package for the identification of pediatric brain tumor subtypes. BACKGROUND: DNA methylation profiling of pediatric brain tumors offers a new way of diagnosing and subgrouping these tumors which improves current clinical diagnostics based on histopathology. We have therefore developed the MethPed classifier, which is a multiclass random forest algorithm, based on DNA methylation profiles from many subgroups of pediatric brain tumors. RESULTS: We developed an R package that implements the MethPed classifier, making it easily available and accessible. The package can be used for estimating the probability that an unknown sample belongs to each of nine pediatric brain tumor diagnoses/subgroups. CONCLUSIONS: The MethPed R package efficiently classifies pediatric brain tumors using the developed MethPed classifier. MethPed is available via Bioconductor: http://bioconductor.org/packages/MethPed/.",
            "question": "Which R package could be used for the identification of pediatric brain tumors?",
            "answers": {
                "answer_start": 0,
                "text": "MethPed"
            }
        },
        {
            "context": "Imetelstat (a telomerase antagonist) exerts off - target effects on the cytoskeleton. Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non - small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 535,
                "text": "telomerase"
            }
        },
        {
            "context": "Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency. Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 1341,
                "text": "DNMT1"
            }
        },
        {
            "context": "Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila, many messenger RNAs involved in neuro-transmission are re-coded at the RNA level by the RNA-editing enzyme, dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto-regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto-editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviours. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re-coding events in fine-tuning brain function and organismal behaviour.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 313,
                "text": "ADAR"
            }
        },
        {
            "context": "Antigenotoxic effects of p53 on spontaneous and ultraviolet light B--induced deletions in the epidermis of gpt delta transgenic mice. Tumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as \"the guardian of the genome.\" To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to A:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(+/+) mice. However, no increase of such large deletions was observed in irradiated p53(-/-) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 524,
                "text": "p53"
            }
        },
        {
            "context": "Upper limb function is normal in patients with restless legs syndrome (Willis-Ekbom Disease). OBJECTIVE: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. METHODS: RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy controls (n=17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. RESULTS: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. CONCLUSIONS: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. SIGNIFICANCE: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 105,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 570,
                "text": "FSHD"
            }
        },
        {
            "context": "Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 52,
                "text": "MITF"
            }
        },
        {
            "context": "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score < 2.5; probability of 12-week disability progression < 0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 186,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. PURPOSE: The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. METHODS: In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. FINDINGS: Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in > 2% of patients and > 2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. IMPLICATIONS: Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 173,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 449,
                "text": "Xist"
            }
        },
        {
            "context": "Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis in mammals. Mutations at a single N-glycosylation sequon of tyrosinase have been reported to be responsible for oculocutaneous albinism type IA in humans, characterized by inactive tyrosinase and the total absence of pigmentation. To probe the role that each N-glycosylation site plays in the synthesis of biologically active tyrosinase, we analyzed the calnexin mediated folding of tyrosinase N-glycosylation mutants. We have determined that four of the six potential N-glycosylation sites, including that associated with albinism, are occupied. Analysis of the folding pathway and activity of 15 tyrosinase mutants lacking one or more of the occupied N-glycosylation sites shows that glycans at any two N-glycosylation sites are sufficient to interact with calnexin and give partial activity, but a specific pair of sites (Asn(86) and Asn(371)) is required for full activity. The mutants with less than two N-glycosylation sites do not interact with calnexin and show a complete absence of enzyme activity. Copper analysis of selected mutants suggests that the observed partial activity is due to two populations with differential copper content. By correlating the degree of folding with the activity of tyrosinase, we propose a local folding mechanism for tyrosinase that can explain the mechanism of inactivation of tyrosinase N-glycosylation mutants found in certain pigmentation disorders.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 370,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Small heat shock protein 20 interacts with protein phosphatase-1 and enhances sarcoplasmic reticulum calcium cycling. BACKGROUND: Heat shock proteins (Hsp) are known to enhance cell survival under various stress conditions. In the heart, the small Hsp20 has emerged as a key mediator of protection against apoptosis, remodeling, and ischemia/reperfusion injury. Moreover, Hsp20 has been implicated in modulation of cardiac contractility ex vivo. The objective of this study was to determine the in vivo role of Hsp20 in the heart and the mechanisms underlying its regulatory effects in calcium (Ca) cycling. METHODS AND RESULTS: Hsp20 overexpression in intact animals resulted in significant enhancement of cardiac function, coupled with augmented Ca cycling and sarcoplasmic reticulum Ca load in isolated cardiomyocytes. This was associated with specific increases in phosphorylation of phospholamban (PLN) at both Ser16 and Thr17, relieving its inhibition of the apparent Ca affinity of SERCA2a. Accordingly, the inotropic effects of Hsp20 were abrogated in cardiomyocytes expressing nonphosphorylatable PLN (S16A/T17A). Interestingly, the activity of type 1 protein phosphatase (PP1), a known regulator of PLN signaling, was significantly reduced by Hsp20 overexpression, suggesting that the Hsp20 stimulatory effects are partially mediated through the PP1-PLN axis. This hypothesis was supported by cell fractionation, coimmunoprecipitation, and coimmunolocalization studies, which revealed an association between Hsp20, PP1, and PLN. Furthermore, recombinant protein studies confirmed a physical interaction between AA 73 to 160 in Hsp20 and AA 163 to 330 in PP1. CONCLUSIONS: Hsp20 is a novel regulator of sarcoplasmic reticulum Ca cycling by targeting the PP1-PLN axis. These findings, coupled with the well-recognized cardioprotective role of Hsp20, suggest a dual benefit of targeting Hsp20 in heart disease.",
            "question": "Which protein phosphatase has been found to interact with the heat shock protein, HSP20?",
            "answers": {
                "answer_start": 1182,
                "text": "PP1"
            }
        },
        {
            "context": "The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 118,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 227,
                "text": "tyr"
            }
        },
        {
            "context": "Acute Stroke Despite Dabigatran Anticoagulation Treated with Idarucizumab and Intravenous Tissue Plasminogen Activator. Dabigatran is a direct thrombin inhibitor used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. For patients who present with an acute stroke despite dabigatran therapy, clinical data on the use of intravenous tissue plasminogen activator (IV-tPA) is limited. There is an anticipated increased risk of symptomatic intracranial hemorrhage (sICH) when using IV-tPA in patients on dabigatran therapy. In 2015, the humanized monoclonal antibody fragment idarucizumab was approved for rapid (minutes) reversal of anticoagulant effects of dabigatran. Dabigatran reversal with idarucizumab before administration of IV-tPA might reduce the risk of sICH. We report a case of a 69-year-old stroke patient on dabigatran for paroxysmal atrial fibrillation who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 12. There was no early evidence of ischemic stroke or hemorrhage on head computed tomography, and coagulation studies implied therapeutic dabigatran levels. After controlling blood pressure, dabigatran was reversed with idarucizumab, and IV-tPA was administrated beginning 197 minutes after he was last seen at his baseline. Subsequent brain magnetic resonance imaging showed 2 punctate infarcts in the left temporal lobe and occipital lobe with no evidence of hemorrhage. The patient was discharged with an NIHSS of 1. Telephone follow-up 2 months later indicated that he was at his prestroke baseline, except for a complaint of worsened short-term memory. Idarucizumab reversal of dabigatran may reduce the risk of sICH and should be considered for acute stroke patients arriving in the IV-tPA time window.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 683,
                "text": "dabigatran"
            }
        },
        {
            "context": "No effect of anti-interleukin-5 therapy (mepolizumab) on the atopy patch test in atopic dermatitis patients. BACKGROUND: The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens in atopic dermatitis (AD) patients. Mepolizumab is a monoclonal antibody to interleukin-5, which reduces peripheral blood eosinophils. Previously, we reported that mepolizumab treatment did not result in clinical improvement in AD. The current study investigates the effect of mepolizumab therapy on the APT in the same patients. METHODS: Mepolizumab treatment was given at days 0 and 7 in a double-blind placebo-controlled design. The APT was applied at days -2, 0, 14 and 28. Clinical evaluation of each APT was conducted 48 h after application at days 0, 2, 16 and 30. Skin biopsies were taken at days 0, 2 and 16 for eosinophil counts. RESULTS: The mepolizumab-treated group showed no significant reduction in macroscopic outcome of the APT. Tissue eosinophils were reduced in the mepolizumab-treated group at day 16 compared with placebo; however, this was not significant. CONCLUSION: Mepolizumab therapy cannot prevent the eczematous reaction induced by the APT. Furthermore, the influx of tissue eosinophil numbers in the APT is not significantly inhibited after mepolizumab treatment compared with placebo, despite a significant reduction in peripheral blood eosinophils.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 18,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Oxytocin receptor gene sequences in owl monkeys and other primates show remarkable interspecific regulatory and protein coding variation. The oxytocin (OT) hormone pathway is involved in numerous physiological processes, and one of its receptor genes (OXTR) has been implicated in pair bonding behavior in mammalian lineages. This observation is important for understanding social monogamy in primates, which occurs in only a small subset of taxa, including Azara's owl monkey (Aotus azarae). To examine the potential relationship between social monogamy and OXTR variation, we sequenced its 5' regulatory (4936bp) and coding (1167bp) regions in 25 owl monkeys from the Argentinean Gran Chaco, and examined OXTR sequences from 1092 humans from the 1000 Genomes Project. We also assessed interspecific variation of OXTR in 25 primate and rodent species that represent a set of phylogenetically and behaviorally disparate taxa. Our analysis revealed substantial variation in the putative 5' regulatory region of OXTR, with marked structural differences across primate taxa, particularly for humans and chimpanzees, which exhibited unique patterns of large motifs of dinucleotide A+T repeats upstream of the OXTR 5' UTR. In addition, we observed a large number of amino acid substitutions in the OXTR CDS region among New World primate taxa that distinguish them from Old World primates. Furthermore, primate taxa traditionally defined as socially monogamous (e.g., gibbons, owl monkeys, titi monkeys, and saki monkeys) all exhibited different amino acid motifs for their respective OXTR protein coding sequences. These findings support the notion that monogamy has evolved independently in Old World and New World primates, and that it has done so through different molecular mechanisms, not exclusively through the oxytocin pathway.",
            "question": "Which is the \"bonding hormone\"?",
            "answers": {
                "answer_start": 142,
                "text": "oxytocin"
            }
        },
        {
            "context": "A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia. Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 999,
                "text": "Ibrutinib"
            }
        },
        {
            "context": "Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage. OBJECTIVES: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. METHODS: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activity was measured, along with that of other LCP initiators (mannose-binding lectin, ficolin-2, and ficolin-1), C3 activation products, and soluble C5b-9 terminal complex, in a prospective cohort of 39 patients with SAH and 20 healthy controls. The following parameters were recorded: SAH severity, assessed using the World Federation of Neurosurgical Societies grading scale; vasospasm, defined as neuro-worsening with angiographic confirmation of vessel narrowing; cerebral ischemia, defined as hypodense lesion on CT scan performed before discharge; and 6-month outcome, assessed using the Glasgow Outcome Scale. RESULTS: In patients, no changes were detected for ficolin-3 compared with controls. Notably, however, ficolin-3-mediated functional LCP activity was reduced. Low levels of plasma ficolin-3 and ficolin-3-mediated functional LCP activity were related to SAH severity, vasospasm, and cerebral ischemia. Moreover, ficolin-3 functional LCP activity was decreased in patients with unfavorable outcome. CONCLUSION: Our data provide evidence that LCP is activated after SAH and that the actual plasma concentrations of ficolin-3 reflect the severity of brain injury as evaluated by clinical and structural parameters. These results support the idea that ficolin-3-mediated functional LCP activity may be targeted to control injury progression in SAH.",
            "question": "Which pathway is activated by ficolin-3?",
            "answers": {
                "answer_start": 176,
                "text": "lectin complement pathway"
            }
        },
        {
            "context": "Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with \"other type I fibrillinopathy.\" In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete \"clinical\" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 223,
                "text": "FBN1"
            }
        },
        {
            "context": "Dyke-Davidoff-Masson syndrome: case report of fetal unilateral ventriculomegaly and hypoplastic left middle cerebral artery. Prenatal ultrasonographic detection of unilateral cerebral ventriculomegaly arises suspicion of pathological condition related to cerebrospinal fluid flow obstruction or cerebral parenchimal pathology. Dyke-Davidoff-Masson syndrome is a rare condition characterized by cerebral hemiatrophy, calvarial thickening, skull and facial asymmetry, contralateral hemiparesis, cognitive impairment and seizures. Congenital and acquired types are recognized and have been described, mainly in late childhood, adolescence and adult ages. We describe a female infant with prenatal diagnosis of unilateral left ventriculomegaly in which early brain MRI and contrast enhanced-MRI angiography, showed cerebral left hemiatrophy associated with reduced caliber of the left middle cerebral artery revealing the characteristic findings of the Dyke-Davidoff-Masson syndrome. Prenatal imaging, cerebral vascular anomaly responsible for the cerebral hemiatrophy and the early clinical evolution have never been described before in such a young child and complete the acquired clinical descriptions in older children. Differential diagnosis, genetic investigations, neurophysiologic assessments, short term clinical and developmental follow up are described. Dyke-Davidoff-Masson syndrome must be ruled out in differential diagnosis of fetal unilateral ventriculomegaly. Early clinical assessment, differential diagnosis and cerebral imaging including cerebral MRI angiography allow the clinicians to diagnose also in early infancy this rare condition.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 394,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.",
            "question": "Which syndrome is NHE6 associated with?",
            "answers": {
                "answer_start": 54,
                "text": "Christianson syndrome"
            }
        },
        {
            "context": "Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene. Sotos syndrome is a well-known overgrowth syndrome caused by haploinsufficiency of NSD1 gene located at 5q35. There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). We investigated detailed craniofacial, dental, and oral findings in five patients with deletion type, and three patients with mutation type Sotos syndrome. All eight patients had a high palate, excessive tooth wear, crowding, and all but one patient had hypodontia and deep bite. Hypodontia was exclusively observed in the second premolars, and there were no differences between the deletion and mutation types in the number of missing teeth. Another feature frequently seen in common with both types was maxillary recession. Findings seen more frequently and more pronounced in deletion-type than in mutation-type included mandibular recession, scissors or posterior cross bite, and small dental arch with labioclination of the maxillary central incisors. It is noteworthy that although either scissors bite or cross bite was present in all of the deletion-type patients, neither of these was observed in mutation-type patients. Other features seen in a few patients include enamel hypoplasia (two deletion patients), and ectopic tooth eruption (one deletion and one mutation patients). Our study suggests that Sotos syndrome patients should be observed closely for possible dental and oral complications especially for malocculusion in the deletion-type patients.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 119,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 1509,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Familial isolated pituitary adenoma: evidence for genetic heterogeneity. The identification of mutations in the Aryl hydrocarbon receptor interacting protein (AIP) gene in a subset of familial isolated pituitary adenoma (FIPA) cases has recently expanded our understanding of the pathophysiology of inherited pituitary adenoma disorders. However, a genetic cause of has not yet been determined in the majority (85%) of FIPA families and half of the families with isolated familial somatotropinoma. Several studies and reviews have assessed the genetic and clinical features of AIP-mutated FIPA patients, which range from a complete lack of symptoms in adult/elderly individuals to large, aggressive early-onset pituitary tumors. In this study, we aimed to briefly revise the data available for the 11q13 locus and other additional loci that have been implicated in genetic susceptibility to FIPA: 2p16-12; 3q28; 4q32.3-4q33; chr 5, 8q12.1, chr 14, 19q13.4 and 21q22.1. These candidate regions may contain unidentified gene(s) that can be potentially disrupted in AIP-negative FIPA families. A better knowledge of these susceptibility loci may disclose modifier genes that are likely to play exacerbating or protective roles in the phenotypic diversity of AIP-mutated families.",
            "question": "Mutation of which gene is implicated in the familial isolated pituitary adenoma?",
            "answers": {
                "answer_start": 112,
                "text": "Aryl hydrocarbon receptor interacting protein"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.",
            "question": "Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?",
            "answers": {
                "answer_start": 233,
                "text": "thyroid transcription factor 1"
            }
        },
        {
            "context": "Novel anticoagulants for stroke prevention in atrial fibrillation: current clinical evidence and future developments. Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 712,
                "text": "xa"
            }
        },
        {
            "context": "Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and > 10 years) and baseline mobility testing passing level (pass at > 125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 10 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.",
            "question": "Which retinal dystrophy related gene is targeted by the AAV2-hRPE65v2 drug?",
            "answers": {
                "answer_start": 52,
                "text": "RPE65"
            }
        },
        {
            "context": "The emerging role of p53 in exercise metabolism. The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-α protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53(Ser15) is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5'adenosine monophosphate-activated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guidelines to strategically target p53 signalling. The emerging role of p53 in skeletal muscle metabolism therefore represents a novel and exciting research area for exercise and muscle physiologists.",
            "question": "Which tumor suppressor is referred to as \"the guardian of the genome\"?",
            "answers": {
                "answer_start": 86,
                "text": "p53"
            }
        },
        {
            "context": "The tyrosinase gene and oculocutaneous albinism type 1 (OCA1): A model for understanding the molecular biology of melanin formation. Through the last century there has been a steady progression in our understanding of the biology of melanin biosynthesis. Much of this work includes the analysis of coat color mutations of the mouse and albinism in man. Our understanding has been greatly enhanced in the last 10 years, as the molecular pathogenesis of albinism has been better understood. Different mutations of the tyrosinase gene (TYR) , and their association with oculocutaneous albinism type 1 (OCA1) has provided insight into the biology of tyrosinase, including protein trafficking and structure/function analysis. Several questions still remain, including cryptic mutations that affect tyrosinase activity and the minimum amount of pigment required for normal optic development. The next 10 years should prove just as exciting as the last.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 4,
                "text": "tyr"
            }
        },
        {
            "context": "[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 288,
                "text": "xa"
            }
        },
        {
            "context": "Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon. Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene. Several gene silencing approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower ataxin-3 protein levels, but since this protein is involved in deubiquitination and proteasomal protein degradation, its long-term silencing might not be desirable. Here, we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein. In vitro studies showed that exon skipping did not negatively impact the ubiquitin binding capacity of ataxin-3. Our in vivo studies showed no toxic properties of the novel truncated ataxin-3 protein. These results suggest that exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 201,
                "text": "ataxin-3"
            }
        },
        {
            "context": "Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. Alzheimer's disease (AD) is associated with deposition of amyloid-β (Aβ) in the brain, which is reflected by low concentration of the Aβ(1-42) peptide in the cerebrospinal fluid (CSF). The γ-secretase inhibitor LY450139 (semagacestat) lowers plasma Aβ(1-40) and Aβ(1-42) in a dose-dependent manner but has no clear effect on the CSF level of these isoforms. Less is known about the potent γ-secretase modulator E2012. Using targeted proteomics techniques, we recently identified several shorter Aβ isoforms in CSF, such as Aβ(1-16), which is produced by a novel pathway. In a Phase II clinical trial on AD patients, Aβ(1-14), Aβ(1-15) and Aβ(1-16) increased several-fold during γ-secretase inhibitor treatment. In the present study, 9 dogs were treated with a single dose of the γ-secretase modulator E2012, the γ-secretase inhibitor LY450139, or vehicle with a dosing interval of 1 week. The CSF Aβ isoform pattern was analyzed by immunoprecipitation combined with MALDI-TOF mass spectrometry. We show here that Aβ(1-15) and Aβ(1-16) increase while Aβ(1-34) decreases in response to treatment with the γ-secretase inhibitor LY450139, which is in agreement with previous studies. The isoform Aβ(1-37) was significantly increased in a dose-dependent manner in response to treatment with E2012, while Aβ(1-39), Aβ(1-40) and A(1-42) decreased. The data presented suggests that the γ-secretase modulator E-2012 alters the cleavage site preference of γ-secretase. The increase in Aβ(1-37) may inhibit Aβ(1-42) oligomerization and toxicity.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 337,
                "text": "semagacestat"
            }
        },
        {
            "context": "\"Mowat-Wilson\" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with \"syndromic Hirschsprung disease\" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations. In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had \"syndromic Hirschsprung disease\" two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the \"Mowat-Wilson syndrome.\"",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 237,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 352,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis. Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 101,
                "text": "CO2"
            }
        },
        {
            "context": "Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, <20% represent C-->T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 227,
                "text": "NF1"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 1010,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 874,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Pain-mediated affect regulation is reduced after dialectical behavior therapy in borderline personality disorder: a longitudinal fMRI study. Borderline Personality Disorder (BPD) is characterized by affective instability, but self-injurious behavior appears to have an emotion-regulating effect. We investigated whether pain-mediated affect regulation can be altered at the neural level by residential Dialectical Behavior Therapy (DBT), providing adaptive emotion regulation techniques. Likewise, we investigated whether pain thresholds or the appraisal of pain change after psychotherapy. We investigated 28 patients with BPD undergoing DBT (self-referral), 15 patients with treatment as usual and 23 healthy control subjects at two time points 12 weeks apart. We conducted an fMRI experiment eliciting negative emotions with picture stimuli and induced heat pain to investigate the role of pain in emotion regulation. Additionally, we assessed heat and cold pain thresholds.At first measurement, patients with BPD showed amygdala deactivation in response to painful stimulation, as well as altered connectivity between left amygdala and dorsal anterior cingulate cortex. These effects were reduced after DBT, as compared with patients with treatment as usual. Pain thresholds did not differ between the patient groups. We replicated the role of pain as a means of affect regulation in BPD, indicated by increased amygdala coupling. For the first time, we could demonstrate that pain-mediated affect regulation can be changed by DBT.",
            "question": "Which personality disorder is treated using dialectical behavior therapy?",
            "answers": {
                "answer_start": 81,
                "text": "borderline personality disorder"
            }
        },
        {
            "context": "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).",
            "question": "Which disease is treated with semaglutide?",
            "answers": {
                "answer_start": 57,
                "text": "Type 2 Diabetes"
            }
        },
        {
            "context": "Riociguat: first global approval. Riociguat (Adempas(®)), an oral first-in-class soluble guanylate cyclase (sGC) stimulator, is under global development by Bayer Healthcare Pharmaceuticals Inc. for the treatment of adult patients with inoperable or chronic/persistent chronic thromboembolic pulmonary hypertension (CTEPH) and for the treatment of adult patients with pulmonary arterial hypertension (PAH). The drug directly stimulates sGC in a nitric oxide independent manner, thereby increasing the sensitivity of sGC to nitric oxide, leading to increased cyclic guanosine monophosphate generation (a key signalling molecule involved in regulating vascular tone, proliferation, fibrosis and inflammation). Riociguat is the world's first approved pharmacotherapy for CTEPH, with its first global approval in this indication occurring in Canada. It has subsequently been approved in the USA for the treatment of patients with CTEPH and also received its first global approval in patients with PAH in the USA. It is undergoing regulatory review for these indications in Europe and for use in patients with CTEPH in Japan. This article summarizes the milestones in the development of riociguat, leading to its first global approvals in patients with CTEPH and PAH.",
            "question": "What is generic name of drug Adempas?",
            "answers": {
                "answer_start": 34,
                "text": "Riociguat"
            }
        },
        {
            "context": "A new database for ribosomal protein genes which are mutated in Diamond-Blackfan Anemia. Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in Diamond-Blackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locus-specific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.",
            "question": "Which class of genes are mutated in Diamond Blackfan Anemia patients?",
            "answers": {
                "answer_start": 19,
                "text": "ribosomal protein genes"
            }
        },
        {
            "context": "The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis. The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 57,
                "text": "CO2"
            }
        },
        {
            "context": "Nestin reporter transgene labels multiple central nervous system precursor cells. Embryonic neuroepithelia and adult subventricular zone (SVZ) stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP) specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telencephalon contained many and the ventral telencephalon few eGFP+ cells. eGFP+ cells were found in postnatal and adult neurogenic regions. eGFP+ cells in the SVZ expressed multiple phenotype markers, glial fibrillary acidic protein, Dlx, and neuroblast-specific molecules suggesting the transgene is expressed through the lineage. eGFP+ cell numbers increased in the SVZ after cortical injury, suggesting this line will be useful in probing postinjury neurogenesis. In non-neurogenic regions, eGFP was strongly expressed in oligodendrocyte progenitors, but not in astrocytes, even when they were reactive. This eGFP+ mouse will facilitate studies of proliferative neuroepithelia and adult neurogenesis, as well as of parenchymal oligodendrocytes.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 177,
                "text": "nestin"
            }
        },
        {
            "context": "Inhibition by SEA0400, a selective inhibitor of Na+/Ca2+ exchanger, of Na+ -dependent Ca2+ uptake and catecholamine release in bovine adrenal chromaffin cells. The effects of SEA0400, a selective inhibitor of the Na(+)/Ca(2+) exchanger (NCX), on Na(+)-dependent Ca(2+) uptake and catecholamine (CA) release were examined in bovine adrenal chromaffin cells that were loaded with Na(+) by treatment with ouabain and veratridine. SEA0400 inhibited Na(+)-dependent (45)Ca(2+) uptake and CA release, with the IC(50) values of 40 and 100 nM, respectively. The IC(50) values of another NCX inhibitor KB-R7943 were 1.8 and 3.7 microM, respectively. These results indicate that SEA0400 is about 40 times more potent than KB-R7943 in inhibiting NCX working in the reverse mode. In intact cells, SEA0400 and KB-R7943 inhibited CA release induced by acetylcholine and DMPP. The IC(50) values of SEA0400 were 5.1 and 4.5 microM and the values of KB-R7943 were 2.6 and 2.1 microM against the release induced by acetylcholine and DMPP, respectively, indicating that the potency of SEA0400 is about a half of that of KB-R7943 in inhibiting the nicotinic receptor-mediated CA release. The binding of [(3)H]nicotine with nicotinic receptors was inhibited by SEA0400 (IC(50) = 90 microM) and KB-R7943 (IC(50) = 12 microM). From these results, it is concluded that unlike KB-R7943, SEA0400 has a potent and selective action on NCX in bovine adrenal chromaffin cells.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 213,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. OBJECTIVE: To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine. METHODS: Migraine patients were randomized 2:1 to double-blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2-24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with > 1 triptan-related adverse events in the 14-day period post dose. RESULTS: Of 1068 patients randomized, 641 (90%) patients treated > 1 attack with telcagepant and 313 (88%) treated > 1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan-related adverse events (difference: -6.2%; 95% CI -10.4, -2.6; P < .001) and drug-related adverse events (difference: -15.6%; 95% CI -22.2, -9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence > 5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%). CONCLUSIONS: Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan-related and drug-related adverse events favored telcagepant over rizatriptan.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 242,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "One-year safety and tolerability profile of pridopidine in patients with Huntington disease. OBJECTIVE: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease. METHODS: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day). RESULTS: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported > 1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and > 1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported > 1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified. CONCLUSION: Pridopidine ( < 90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that pridopidine ( < 90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year.",
            "question": "Pridopidine has been tested for treatment of which disorder?",
            "answers": {
                "answer_start": 200,
                "text": "Huntington disease"
            }
        },
        {
            "context": "Upregulation of amyloid precursor protein isoforms containing Kunitz protease inhibitor in dementia with Lewy bodies. Amyloid precursor protein (APP) is involved in the accumulation of alpha-synuclein, the main component of Lewy bodies. It is currently unknown, however, whether any of the APP isoforms is instrumental in alpha-synuclein deposition in dementia with Lewy bodies (DLB). Using real-time RT-PCR, we have studied relative mRNA expression levels of APP isoforms in frozen postmortem frontal cortices of DLB patients, Alzheimer disease (AD) patients, and control subjects. Of the three main APP isoforms, the two with a Kunitz protease inhibitory (KPI) motif (APP770 and APP751) were found to be specifically overexpressed in the frontal cortices of DLB patients when compared with controls and AD patients. These findings suggest a specific role of APP isoforms containing Kunitz protease inhibitor in DLB pathogenesis.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 185,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Vaccination of cattle with a recombinant bivalent toxoid against botulism serotypes C and D. Cattle botulism is a fatal intoxication caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum serotypes C and D resulting in economic losses. Vaccination is the most effective way to control botulism. However, the commercially available vaccines are difficult and hazardous to produce. Neutralizing antibodies against the C-terminal fragment of the BoNT heavy chain (HC) are known to protect against lethal doses of BoNTs. We report the vaccination of cattle with a previously tested recombinant chimera consisting of Escherichia coli heat-labile enterotoxin B subunit and the HC of BoNTs C and D. Vaccinated animals produced neutralizing antibodies against serotypes C and D averaging 5±0 and 6.14±1.06IU/mL, respectively. For BoNT D, the titers were greater than those measured for the commercial vaccine, which induced titers of 5±0 and 2.85±1.35 against the respective serotypes, suggesting that this chimera is effective against cattle botulism.",
            "question": "Which is the most known bacterium responsible for botulism (sausage-poisoning)?",
            "answers": {
                "answer_start": 185,
                "text": "Clostridium botulinum"
            }
        },
        {
            "context": "Coilin, more than a molecular marker of the cajal (coiled) body. The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 0,
                "text": "Coilin"
            }
        },
        {
            "context": "The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes. Nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase (JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured astrocytes. In view of the previous observation that NO stimulates the activity of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 651,
                "text": "NCX"
            }
        },
        {
            "context": "Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 65,
                "text": "IL-1β"
            }
        },
        {
            "context": "Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model. OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. METHODS: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. RESULTS: Gait deficiency in untreated rats was present 3-7 days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. CONCLUSIONS: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 0,
                "text": "Nerve growth factor"
            }
        },
        {
            "context": "Deformed wing virus associated with Tropilaelaps mercedesae infesting European honey bees (Apis mellifera). Mites in the genus Tropilaelaps (Acari: Laelapidae) are ectoparasites of the brood of honey bees (Apis spp.). Different Tropilaelaps subspecies were originally described from Apis dorsata, but a host switch occurred to the Western honey bee, Apis mellifera, for which infestations can rapidly lead to colony death. Tropilaelaps is hence considered more dangerous to A. mellifera than the parasitic mite Varroa destructor. Honey bees are also infected by many different viruses, some of them associated with and vectored by V. destructor. In recent years, deformed wing virus (DWV) has become the most prevalent virus infection in honey bees associated with V. destructor. DWV is distributed world-wide, and found wherever the Varroa mite is found, although low levels of the virus can also be found in Varroa free colonies. The Varroa mite transmits viral particles when feeding on the haemolymph of pupae or adult bees. Both the Tropilaelaps mite and the Varroa mite feed on honey bee brood, but no observations of DWV in Tropilaelaps have so far been reported. In this study, quantitative real-time RT-PCR was used to show the presence of DWV in infested brood and Tropilaelaps mercedesae mites collected in China, and to demonstrate a close quantitative association between mite-infested pupae of A. mellifera and DWV infections. Phylogenetic analysis of the DWV sequences recovered from matching pupae and mites revealed considerable DWV sequence heterogeneity and polymorphism. These polymorphisms appeared to be associated with the individual brood cell, rather than with a particular host.",
            "question": "What is the genus for the common European honey bee?",
            "answers": {
                "answer_start": 91,
                "text": "Apis"
            }
        },
        {
            "context": "Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 175,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on human non-small cell lung cancer cells. The antitumor effect of CGP41251 (4'-N-benzoyl staurosporine), a selective protein kinase C (PKC) inhibitor, was examined on two kinds of human non-small cell lung cancer (NSCLC) cell lines (adenocarcinoma: A549 and squamous cell carcinoma: NCI-H520). CGP41251 at 0.5 or 1.0 microM inhibited the proliferation of these tumor cell lines significantly; However, at 0.1 microM, it did not show any significant inhibition. Cell cycle analysis indicated that CGP41251 at 0.5 or 1.0 microM arrested the cell cycle progression at the G2/M phase up to 24 hr, but 0.1 microM did not. It seems that the antiproliferative action of CGP41251 against human NSCLC is related to G2/M accumulation. In NCI-H520, CGP41251 caused DNA re-replication without mitosis. In a nude mice xenograft, CGP41251 at a dose of 200 mg/kg showed antitumor activity against these cell lines. Histopathologically, expansion of central necrosis was observed, although no destruction of tumor nests was seen by CGP41251 administration. In both tumor tissues, the PKC activity of the particulate fraction was significantly decreased by CGP41251 treatment. From these results, it is thought that the antitumor activity of CGP41251 against human NSCLS is accompanied by the decrease of PKC activity in the particulate fraction. Moreover, the G2/M arrest of the cell cycle induced by CGP41251 might be important for the growth inhibitory action of this compound.",
            "question": "From which tissue was the NCI-H520 cell-line derived?",
            "answers": {
                "answer_start": 333,
                "text": "squamous cell carcinoma"
            }
        },
        {
            "context": "Inhibitors of anaplastic lymphoma kinase: a patent review. IMPORTANCE OF THE FIELD: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. Aberrant ALK activity has been implicated in the oncogenesis of human cancers as a fusion protein in anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, systemic histiocytosis and NSCLC or through mutations in the full length protein in hereditary familial neuroblastoma. Thus, abrogation of ALK signaling through direct kinase inhibition has become an attractive therapeutic intervention point for a subset of genetically defined human cancers. AREAS COVERED IN THIS REVIEW: This manuscript provides a comprehensive review of the patent literature pertaining to ALK inhibitors and outlines their potential as anticancer therapeutic agents. WHAT THE READER WILL GAIN: The reader will gain an understanding of the major structural classes of ALK inhibitors and insights into the future of this class of drugs. TAKE HOME MESSAGE: Multiple small-molecule ALK inhibitors have been reported with diverse chemical architecture, potency, kinase selectivity profiles and activity against potential resistance. The breadth of inhibitors combined with the recent discoveries of the involvement of ALK in lung, breast and colorectal cancers has kept the field advancing at a rapid pace.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 267,
                "text": "cancer"
            }
        },
        {
            "context": "Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-tyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib.",
            "question": "Mutations in which gene determine response to both erlotinib and gefitinib?",
            "answers": {
                "answer_start": 114,
                "text": "epidermal growth factor receptor (EGFR) gene"
            }
        },
        {
            "context": "Genetic Determinants of RNA Editing Levels of ADAR Targets in Drosophila melanogaster. RNA editing usually affects only a fraction of expressed transcripts and there is a vast amount of variation in editing levels of ADAR (adenosine deaminase, RNA-specific) targets. Here we explore natural genetic variation affecting editing levels of particular sites in 81 natural strains of Drosophila melanogaster. The analysis of associations between editing levels and single-nucleotide polymorphisms allows us to map putative cis-regulatory regions affecting editing of 16 A-to-I editing sites (cis-RNA editing quantitative trait loci or cis-edQTLs, P < 10(-8)). The observed changes in editing levels are validated by independent molecular technique. All identified regulatory variants are located in close proximity of modulated editing sites. Moreover, colocalized editing sites are often regulated by same loci. Similar to expression and splicing QTL studies, the characterization of edQTLs will greatly expand our understanding of cis-regulatory evolution of gene expression.",
            "question": "Which is the major RNA editing enzyme in Drosophila melanogaster?",
            "answers": {
                "answer_start": 223,
                "text": "adenosine deaminase, RNA-specific"
            }
        },
        {
            "context": "[Puffy hand syndrome in drug addiction treated by low-stretch bandages]. BACKGROUND: Puffy hand syndrome is a complication of intravenous drug abuse, which has no current available treatment. Arm and forearm edema are voluminous and cause functional and aesthetic disturbances. We report two cases successfully treated by low-stretch bandages. OBSERVATIONS: A 40-year-old man and a 34-year-old woman, both intravenous drug users, with puffy hand syndrome were hospitalized for 11 days. Treatment included daily multilayer bandaging. Lymphedema volumes calculated by utilizing the formula for a truncated cone decreased by 16% on the left side and 12% on the right side for the first patient and 31 and 17% for the second. Hand circumference decreased 4.3 cm on the left side and 3.2 cm on the right side in case 1, and 2.5 cm and 1.9 cm respectively for case 2. The patients were taught self-bandaging techniques during their hospital stays. Elastic gloves were fitted at the end of treatment. Reduction of lymphedema volume remained stable after 18 months in one patient while for the second patient further treatment and hospitalization were required due to poor compliance. DISCUSSION: The pathogenesis of this edema is probably multifactorial: venous, lymphatic insufficiency and the direct toxicity of injected drugs. Lymphedema treatment currently consists of low-stretch bandaging and wearing elastic garments, which is effective in decreasing the volume of puffy hand syndrome.",
            "question": "What causes \"Puffy hand syndrome\"?",
            "answers": {
                "answer_start": 126,
                "text": "intravenous drug abuse"
            }
        },
        {
            "context": "The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review. INTRODUCTION: Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. AREAS COVERED: SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. EXPERT OPINION: A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1491,
                "text": "xa"
            }
        },
        {
            "context": "The evolutionary basis for the feeding behavior of domestic dogs (Canis familiaris) and cats (Felis catus). The dentition, sense of taste and meal patterning of domestic dogs and cats can be interpreted in terms of their descent from members of the order Carnivora. The dog is typical of its genus, Canis, in its relatively unspecialized dentition, and a taste system that is rather insensitive to salt. The preference of many dogs for large infrequent meals reflects the competitive feeding behavior of its pack-hunting ancestor, the wolf Canis lupus. However, its long history of domestication, possibly 100,000 years, has resulted in great intraspecific diversity of conformation and behavior, including feeding. Morphologically and physiologically domestic cats are highly specialized carnivores, as indicated by their dentition, nutritional requirements, and sense of taste, which is insensitive to both salt and sugars. Their preference for several small meals each day reflects a daily pattern of multiple kills of small prey items in their ancestor, the solitary territorial predator Felis silvestris. Although in the wild much of their food selection behavior must focus on what to hunt, rather than what to eat, cats do modify their food preferences based on experience. For example, the \"monotony effect\" reduces the perceived palatability of foods that have recently formed a large proportion of the diet, in favor of foods with contrasting sensory characteristics, thereby tending to compensate for any incipient nutritional deficiencies. Food preferences in kittens during weaning are strongly influenced by those of their mother, but can change considerably during at least the first year of life.",
            "question": "The common house cat, Felis silvestris catus and the domestic dog, Canis familiaris both belong to what taxonomic order?",
            "answers": {
                "answer_start": 255,
                "text": "Carnivora"
            }
        },
        {
            "context": "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 127,
                "text": "MC1R"
            }
        },
        {
            "context": "SeqArray-a storage-efficient high-performance data format for WGS variant calls. Motivation: Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Results: Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. Availability and Implementation: http://www.bioconductor.org/packages/SeqArray. Contact: zhengx@u.washington.edu. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which algorithm has been proposed for efficient storage of WGS variant calls?",
            "answers": {
                "answer_start": 1291,
                "text": "SeqArray"
            }
        },
        {
            "context": "Dermatitis herpetiformis: coeliac disease of the skin. Dermatitis herpetiformis (DH) is a lifelong, gluten-sensitive, blistering skin disease with pathognomonic immunoglobulin (Ig)A deposits in the papillary dermis. Less than 10% of patients with DH have gastrointestinal symptoms suggestive of coeliac disease, yet they all have gluten-sensitive enteropathy. The rash, too, responds to gluten withdrawal. Therefore, DH provides a unique example of the frequent existence of gastroenterologically 'silent' but dermatologically active coeliac disease. DH and coeliac disease are strictly associated with class II HLA alleles A1*0501 and B1*02 encoding the HLA-DQ2 heterodimer. Coeliac disease segregates in the families of patients with DH, also supporting a shared genetic background. Monozygotic twins, one with DH and the other with coeliac disease, show that environmental, not genetic, factors seem to be responsible for the development of the rash in DH. A clinically silent but immunologically active coeliac disease in the gut could well produce IgA autoantibodies which react also with the connective tissue in the skin. The antigen for deposited IgA and its role, if any, in the blister formation in DH remains, however, to be elucidated.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 55,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. BACKGROUND: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder resulting in the growth of a variety of tumours, and is inherited in an autosomal dominant pattern. Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that commonly harbour oncogenic mutations in KIT or PDGFRA and are thought to arise from the interstitial cells of Cajal (ICC; the pacemaker cells of the gut). AIM: To characterise two patients with NF1 and GISTs. METHODS: Two patients were genotyped for germline mutations in NF1. GISTs from both patients were genotyped for somatic mutations in KIT and PDGFRA. Loss of heterozygosity (LOH) of NF1 in one GIST was assessed by genotyping seven microsatellite markers spanning 2.39 Mb of the NF1 locus in the tumour and in genomic DNA. The known germline mutation in NF1 was confirmed in GIST DNA by sequencing. The copy number of the mutated NF1 allele was determined by multiplex ligand-dependent probe amplification. RESULTS: GISTs from both patients were of wild type for mutations in KIT and PDGFRA. In the GIST with adequate DNA, all seven markers were informative and showed LOH at the NF1 locus; sequencing of NF1 from that GIST showed no wild-type sequence, suggesting that it was lost in the tumour. Multiplex ligand-dependent probe amplification analysis showed that two copies of all NF1 exons were present. CONCLUSIONS: This is the first evidence of mitotic recombination resulting in a reduction to homozygosity of a germline NF1 mutation in an NF1-associated GIST. We hypothesise that the LOH of NF1 and lack of KIT and PDGFRA mutations are evidence of an alternative pathogenesis in NF1-associated GISTs.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 165,
                "text": "NF1"
            }
        },
        {
            "context": "Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 841,
                "text": "orbit"
            }
        },
        {
            "context": "Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine. Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r > 0.99. The assay demonstrated accuracy > 80% and precision < 20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.",
            "question": "What fruit causes Jamaican vomiting sickness?",
            "answers": {
                "answer_start": 427,
                "text": "ackee fruit"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment. AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.",
            "question": "Which enzyme is inhibited by ixazomib?",
            "answers": {
                "answer_start": 216,
                "text": "proteasome"
            }
        },
        {
            "context": "Serum protein fingerprinting by PEA immunoassay coupled with a pattern-recognition algorithms distinguishes MGUS and multiple myeloma. Serum protein fingerprints associated with MGUS and MM and their changes in MM after autologous stem cell transplantation (MM-ASCT, day 100) remain unexplored. Using highly-sensitive Proximity Extension ImmunoAssay on 92 cancer biomarkers (Proseek Multiplex, Olink), enhanced serum levels of Adrenomedullin (ADM, P= .0004), Growth differentiation factor 15 (GDF15, P= .003), and soluble Major histocompatibility complex class I-related chain A (sMICA, P= .023), all prosurvival and chemoprotective factors for myeloma cells, were detected in MM comparing to MGUS. Comparison of MGUS and healthy subjects revealed elevation of angiogenic and antia-poptotic midkine (P= .0007) and downregulation of Transforming growth factor beta 1 (TGFB1, P= .005) in MGUS. Importantly, altered serum pattern was associated with MM-ASCT compared to paired MM at the diagnosis as well as to healthy controls, namely by upregulated B-Cell Activating Factor (sBAFF) (P< .006) and sustained elevation of other pro-tumorigenic factors. In conclusion, the serum fingerprints of MM and MM-ASCT were characteristic by elevated levels of prosurvival and chemoprotective factors for myeloma cells.",
            "question": "Which method is Proseek based on?",
            "answers": {
                "answer_start": 318,
                "text": "Proximity Extension ImmunoAssay"
            }
        },
        {
            "context": "Inactivation of a histone methyltransferase by mutations in human cancers. Histone methyltransferase (HMT)(1) class enzymes that methylate lysine residues of histones or proteins contain a conserved catalytic core termed the SET domain, which shares sequence homology with an independently described sequence motif, the PR domain. Intact PR or SET sequence is required for tumor suppression functions, but it remains unclear whether it is histone methyltransferase activity that underlies tumor suppression. We now show that tumor suppressor RIZ1 (PRDM2) methylates histone H3 on lysine 9, and this activity is reduced by mutations in the PR domain found in human cancers. Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities. These results support the hypothesis that H3 lysine 9 methylation activities of a PR/SET domain have tumor suppression functions and may underlie carcinogenesis associated with dietary methyl donor deficiency.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 225,
                "text": "SET domain"
            }
        },
        {
            "context": "Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 227,
                "text": "tyr"
            }
        },
        {
            "context": "Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study. BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.",
            "question": "Aleglitazar is agonist of which receptor?",
            "answers": {
                "answer_start": 20,
                "text": "peroxisome proliferator-activated receptor-α/γ"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which is the genome browser database for DNA shape annotations?",
            "answers": {
                "answer_start": 0,
                "text": "GBshape"
            }
        },
        {
            "context": "Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers. Orthologous human and zebrafish enhancers underwent functional evolution within their sequence and often directed related but non-identical expression patterns. Despite an evolutionary distance of 450 million years, one pax6 HCNE drove expression in identical areas when comparing zebrafish vs. human HCNEs. HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 1512,
                "text": "development"
            }
        },
        {
            "context": "Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1843,
                "text": "xa"
            }
        },
        {
            "context": "Shprintzen-Goldberg syndrome: case report. The Shprintzen-Goldberg syndrome is an extremely rare syndrome with a characteristic face. This is one of a group of disorders characterized by craniosynostosis and marfanoid features. The aim of this study was to present a new sporadic case of the syndrome and describe in detail the findings at the maxillofacial region.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 187,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 91,
                "text": "DBA"
            }
        },
        {
            "context": "Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 497,
                "text": "7"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 1885,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Controlled-release oxycodone for the treatment of bortezomib-induced neuropathic pain in patients with multiple myeloma. PURPOSE: Bortezomib, a proteasome inhibitor drug very effective against multiple myeloma, may induce the so-called bortezomib-induced peripheral neuropathy (BIPN), hardly manageable with common analgesic drugs. This study assessed the effectiveness of controlled-release (CR) oral oxycodone in controlling pain and its interference on daily functions of patients with hematologic malignancies affected by BIPN. METHODS: Forty-six patients (median age, 62 years) affected by myeloma and lymphoma, complaining of BIPN-related pain of moderate-to-severe intensity and unresponsive to previous analgesic treatments, were treated with CR oxycodone. The intensity of continuous and brief pain (BP) along with interference of pain with the common daily dimensions of feeling and function were evaluated by using an 11-point numerical rating scale (NRS); a global patient evaluation of efficacy was also performed. RESULTS: The daily average dose of CR oxycodone administered was 28.46 mg (range, 20-80 mg). The pain intensity decreased from a mean NRS value of 7.6 at baseline to 1.3 on day 14. The frequency of BP was reduced from 61 to 47% of patients and its intensity from 7.4 to 3.1 NRS score. A similar trend to decreasing values was observed for all the daily life functions. Slight- or mild-intensity side effects were observed in 23 patients (51%). At the end of the study, 75% of patients found the treatment effective or very effective. CONCLUSION: CR oxycodone for relief of BIPN-related pain was effective and well tolerated. The pain control significantly improved also the quality of the daily life functions, which are usually compromised in these suffering patients.",
            "question": "What disease is Velcade (bortezomib) mainly used for?",
            "answers": {
                "answer_start": 193,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 395,
                "text": "CD38"
            }
        },
        {
            "context": "The iron-binding CyaY and IscX proteins assist the ISC-catalyzed Fe-S biogenesis in Escherichia coli. In eukaryotes, frataxin deficiency (FXN) causes severe phenotypes including loss of iron-sulfur (Fe-S) cluster protein activity, accumulation of mitochondrial iron and leads to the neurodegenerative disease Friedreich's ataxia. In contrast, in prokaryotes, deficiency in the FXN homolog, CyaY, was reported not to cause any significant phenotype, questioning both its importance and its actual contribution to Fe-S cluster biogenesis. Because FXN is conserved between eukaryotes and prokaryotes, this surprising discrepancy prompted us to reinvestigate the role of CyaY in Escherichia coli. We report that CyaY (i) potentiates E. coli fitness, (ii) belongs to the ISC pathway catalyzing the maturation of Fe-S cluster-containing proteins and (iii) requires iron-rich conditions for its contribution to be significant. A genetic interaction was discovered between cyaY and iscX, the last gene of the isc operon. Deletion of both genes showed an additive effect on Fe-S cluster protein maturation, which led, among others, to increased resistance to aminoglycosides and increased sensitivity to lambda phage infection. Together, these in vivo results establish the importance of CyaY as a member of the ISC-mediated Fe-S cluster biogenesis pathway in E. coli, like it does in eukaryotes, and validate IscX as a new bona fide Fe-S cluster biogenesis factor.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 117,
                "text": "frataxin"
            }
        },
        {
            "context": "Two cases of Sotos syndrome with novel mutations of the NSD1 gene. Mutations and deletions of the NSD1 gene, located on chromosome 5q35, are responsible for over 90% of cases of Sotos syndrome. Fluorescent in situ hybridization analysis (FISH), MLPA or multiplex quantitative PCR allow detection of total/partial NSD1 deletions and direct sequencing allows detection of NSD1 mutations. We describe two boys with Sotos syndrome in whom PCR amplification and direct sequencing of the NSD1 gene identified two novel mutations not previously described: c.4736dupG in exon 12 and c.3938_3939insT in exon 7. In addition to the cardinal and major features of the syndrome (abnormal facial appearance, overgrowth, cardiac anomalies, renal anomalies, hypotonia, neonatal jaundice, seizures and brain MRI abnormalities) in both patients, one boy also had cryptorchidism and vertebral anomalies, features considered not common. Despite the wide range of possible combinations of phenotypic features, molecular analysis can correctly identify Sotos syndrome.",
            "question": "Which gene is responsible for the development of Sotos syndrome?",
            "answers": {
                "answer_start": 98,
                "text": "NSD1 gene"
            }
        },
        {
            "context": "Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. INTRODUCTION: To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile. RESULTS: Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2 h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related. CONCLUSIONS: In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).",
            "question": "For which type of diabetes can empagliflozin be used?",
            "answers": {
                "answer_start": 127,
                "text": "type 2 diabetes mellitus"
            }
        },
        {
            "context": "Kell and XK immunohistochemistry in McLeod myopathy. The McLeod syndrome is an X-linked neuroacanthocytosis manifesting with myopathy and progressive chorea. It is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein of yet unknown function. In erythroid tissues, XK forms a functional complex with the Kell glycoprotein. Here, we present an immunohistochemical study in skeletal muscle of normal controls and a McLeod patient with a XK gene point mutation (C977T) using affinity-purified antibodies against XK and Kell proteins. Histological examination of the affected muscle revealed the typical pattern of McLeod myopathy including type 2 fiber atrophy. In control muscles, Kell immunohistochemistry stained sarcoplasmic membranes. XK immunohistochemistry resulted in a type 2 fiber-specific intracellular staining that was most probably confined to the sarcoplasmic reticulum. In contrast, there was only a weak background signal without a specific staining pattern for XK and Kell in the McLeod muscle. Our results demonstrate that the lack of physiological XK expression correlates to the type 2 fiber atrophy in McLeod myopathy, and suggest that the XK protein represents a crucial factor for the maintenance of normal muscle structure and function.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 212,
                "text": "XK"
            }
        },
        {
            "context": "[Cellular pathology of neurodegenerative disorders]. Common cellular and molecular mechanisms including protein aggregation and inclusion body formation are involved in many neurodegenerative diseases. α-Synuclein is a major component of Lewy bodies in Parkinson's disease (PD) as well as in glial cytoplasmic inclusions in multiple system atrophy (MSA). Tau is a principal component of neurofibrillary and glial tangles in tauopathies. Recently, TDP-43 was identified as a component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PD is traditionally considered a movement disorder with hallmark lesions in the brainstem pigmented nuclei. However, pathological changes occur in widespread regions of the central and peripheral nervous systems in this disease. Furthermore, primary glial involvement (\"gliodegeneration\") can be observed in PD and MSA as well as in tauopathy. The present article reviews abnormal protein accumulation and inclusion body formation inside and outside the central nervous system.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 202,
                "text": "α-Synuclein"
            }
        },
        {
            "context": "NOXO1 phosphorylation on serine 154 is critical for optimal NADPH oxidase 1 assembly and activation. Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 162,
                "text": "NOX1"
            }
        },
        {
            "context": "Lucinactant for the treatment of respiratory distress syndrome in neonates. Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in premature neonates. This syndrome is caused by a lack of endogenous surfactant production in the lungs. Surfactant replacement was established as a safe and effective treatment in the 1990s and has become the standard of care for these infants. Surfactant products are either protein-free synthetic phospholipid compounds or animal-derived lung preparations. Currently, about 90,000 infants a year receive treatment with one of the commercially available animal-derived surfactants. Lucinactant (Surfaxin®) is a new synthetic surfactant with a pulmonary surfactant-associated protein B mimic that recently received FDA approval. The clinical trials that have been performed, although underpowered, may indicate that lucinactant is superior to phospholipid synthetic surfactant preparations and at least as effective as animal-derived surfactants in reducing morbidity and mortality from RDS. This review summarizes the current clinical knowledge about lucinactant.",
            "question": "Which disease is treated with lucinactant?",
            "answers": {
                "answer_start": 33,
                "text": "respiratory distress syndrome"
            }
        },
        {
            "context": "Jellyfish collagen stimulates production of TNF-α and IL-6 by J774.1 cells through activation of NF-κB and JNK via TLR4 signaling pathway. We previously reported that jellyfish collagen stimulates both the acquired and innate immune responses. In the acquired immune response, jellyfish collagen enhanced immunoglobulin production by lymphocytes in vitro and in vivo. Meanwhile, in the innate immune response jellyfish collagen promoted cytokine production and phagocytotic activity of macrophages. The facts that jellyfish collagen plays several potential roles in stimulating cytokine production by macrophages have further attracted us to uncover its mechanisms. We herein describe that the cytokine production-stimulating activity of jellyfish collagen was canceled by a Toll-like receptor 4 (TLR4) inhibitor. Moreover, jellyfish collagen stimulated phosphorylation of inhibitor of κBα (IκBα), promoted the translocation of nucleus factor-κB (NF-κB), and activated c-Jun N-terminal kinase (JNK). A JNK inhibitor also abrogated the cytokine production-stimulating activity of jellyfish collagen. These results suggest that jellyfish collagen may facilitate cytokine production by macrophages through activation of NF-κB and JNK via the TLR4 signaling pathways.",
            "question": "Which MAP kinase phosphorylates the transcription factor c-jun?",
            "answers": {
                "answer_start": 994,
                "text": "JNK"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 1010,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 215,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.",
            "question": "Which fusion protein is involved in the development of Ewing sarcoma?",
            "answers": {
                "answer_start": 56,
                "text": "EWS/FLI1"
            }
        },
        {
            "context": "Dynamin-related protein Drp1 and mitochondria are important for Shigella flexneri infection. Shigella infection in epithelial cells induces cell death which is accompanied by mitochondrial dysfunction. In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined. Significant lactate dehydrogenase (LDH) release was detected in the culture supernatant when HeLa cells were infected with Shigella at a high multiplicity of infection. Drp1 inhibition with Mdivi-1 and siRNA knockdown significantly reduced LDH release. HeLa cell death was also accompanied by mitochondrial fragmentation. Tubular mitochondrial networks were partially restored when Drp1 was depleted with either siRNA or inhibited with Mdivi-1. Surprisingly either Mdivi-1 treatment or Drp1 siRNA-depletion of HeLa cells also reduced Shigella plaque formation. The effect of Mdivi-1 on Shigella infection was assessed using the murine Sereny model, however it had no impact on ocular inflammation. Overall our results suggest that Drp1 and the mitochondria play important roles during Shigella infection.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 232,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family? AIM: to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. METHODS: this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. RESULTS: during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. CONCLUSION: the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 41,
                "text": "MRSA"
            }
        },
        {
            "context": "Chromatin structure characteristics of pre-miRNA genomic sequences. BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs with important roles in regulating gene expression. Recent studies indicate that transcription and cleavage of miRNA are coupled, and that chromatin structure may influence miRNA transcription. However, little is known about the relationship between the chromatin structure and cleavage of pre-miRNA from pri-miRNA. RESULTS: By analysis of genome-wide nucleosome positioning data sets from human and Caenorhabditis elegans (C. elegans), we found an enrichment of positioned nucleosome on pre-miRNA genomic sequences, which is highly correlated with GC content within pre-miRNA. In addition, obvious enrichments of three histone modifications (H2BK5me1, H3K36me3 and H4K20me1) as well as RNA Polymerase II (RNAPII) were observed on pre-miRNA genomic sequences corresponding to the active-promoter miRNAs and expressed miRNAs. CONCLUSION: Our results revealed the chromatin structure characteristics of pre-miRNA genomic sequences, and implied potential mechanisms that can recognize these characteristics, thus improving pre-miRNA cleavage.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 825,
                "text": "RNAPII"
            }
        },
        {
            "context": "The McLeod syndrome without acanthocytes. A 45-year-old man developed chorea, behavioural changes, moderate amyotrophy and polyneuropathy. Hypertrophic cardiomyopathy and increased serum lactate dehydrogenase and creatine kinase (CK) were found. Acanthocytes were not detected. The absence of XK protein and faintly expressed Kell antigens on erythrocytes were found. Genetic test revealed a R133X mutation of the XK gene, confirming the McLeod syndrome. After 7 years he suddenly developed delirium followed by severe hypoglycaemia, hyperthermia, rhabdomyolysis, hepatic and renal failure. Malignant arrhythmia caused death.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 414,
                "text": "XK"
            }
        },
        {
            "context": "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 35,
                "text": "Factor Xa"
            }
        },
        {
            "context": "Spinal hematoma: a literature survey with meta-analysis of 613 patients. Spinal hematoma has been described in autopsies since 1682 and as a clinical diagnosis since 1867. It is a rare and usually severe neurological disorder that, without adequate treatment, often leads to death or permanent neurological deficit. Epidural as well as subdural and subarachnoid hematomas have been investigated. Some cases of subarachnoid spinal hematoma may present with symptoms similar to those of cerebral hemorrhage. The literature offers no reliable estimates of the incidence of spinal hematoma, perhaps due to the rarity of this disorder. In the present work, 613 case studies published between 1826 and 1996 have been evaluated, which represents the largest review on this topic to date. Most cases of spinal hematoma have a multifactorial etiology whose individual components are not all understood in detail. In up to a third of cases (29.7%) of spinal hematoma, no etiological factor can be identified as the cause of the bleeding. Following idiopathic spinal hematoma, cases related to anticoagulant therapy and vascular malformations represent the second and third most common categories. Spinal and epidural anesthetic procedures in combination with anticoagulant therapy represent the fifth most common etiological group and spinal and epidural anesthetic procedures alone represent the tenth most common cause of spinal hematoma. Anticoagulant therapy alone probably does not trigger spinal hemorrhage. It is likely that there must additionally be a \"locus minoris resistentiae\" together with increased pressure in the interior vertebral venous plexus in order to cause spinal hemorrhage. The latter two factors are thought to be sufficient to cause spontaneous spinal hematoma. Physicians should require strict indications for the use of spinal anesthetic procedures in patients receiving anticoagulant therapy, even if the incidence of spinal hematoma following this combination is low. If spinal anesthetic procedures are performed before, during, or after anticoagulant treatment, close monitoring of the neurological status of the patient is warranted. Time limits regarding the use of anticoagulant therapy before or after spinal anesthetic procedures have been proposed and are thought to be safe for patients. Investigation of the coagulation status alone does not necessarily provide an accurate estimate of the risk of hemorrhage. The most important measure for recognizing patients at high risk is a thorough clinical history. Most spinal hematomas are localized dorsally to the spinal cord at the level of the cervicothoracic and thoracolumbar regions. Subarachnoid hematomas can extend along the entire length of the subarachnoid space. Epidural and subdural spinal hematoma present with intense, knife-like pain at the location of the hemorrhage (\"coup de poignard\") that may be followed in some cases by a pain-free interval of minutes to days, after which there is progressive paralysis below the affected spinal level. Subarachnoid hematoma can be associated with meningitis symptoms, disturbances of consciousness, and epileptic seizures and is often misdiagnosed as cerebral hemorrhage based on these symptoms. Most patients are between 55 and 70 years old. Of all patients with spinal hemorrhage, 63.9% are men. The examination of first choice is magnetic resonance imaging. The treatment of choice is surgical decompression. Of the patients investigated in the present work, 39.6% experienced complete recovery. The less severe the preoperative symptoms are and the more quickly surgical decompression can be performed, the better are the chances for complete recovery. It is therefore essential to recognize the relatively typical clinical presentation of spinal hematoma in a timely manner to allow correct diagnostic and therapeutic measures to be taken to maximize the patient's chance of complete recovery.",
            "question": "What drug treatment can cause a spinal epidural hematoma?",
            "answers": {
                "answer_start": 1083,
                "text": "anticoagulant therapy"
            }
        },
        {
            "context": "Chicken trunk neural crest migration visualized with HNK1. The development of the nervous system involves cells remaining within the neural tube (CNS) and a group of cells that delaminate from the dorsal neural tube and migrate extensively throughout the developing embryo called neural crest cells (NCC). These cells are a mesenchymal highly migratory group of cells that give rise to a wide variety of cell derivatives: melanocytes, sensory neurons, bone, Schwann cells, etc. But not all NCC can give rise to all derivatives, they have fate restrictions based on their axial level of origin: cranial, vagal, trunk and sacral. Our aim was to provide a thorough presentation on how does trunk neural crest cell migration looks in the chicken embryo, in wholemount and in sections using the unique chicken marker HNK1. The description presented here makes a good guideline for those interested in viewing trunk NCC migration patterns. We show how before HH14 there are few trunk NCC delaminating and migrating, but between HH15 through HH19 trunk NCC delaminate in large numbers. Melanocytes precursors begin to enter the dorsolateral pathway by HH17. We found that by HH20 HNK1 is not a valid good marker for NCC and that HNK1 is a better marker than Sox10 when looking at neural crest cells morphology and migration details.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 300,
                "text": "NCC"
            }
        },
        {
            "context": "Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I. The classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown. We investigated whether cEDS affected the protein synthesis rate in skin and tendon, and whether this could be stimulated in tendon tissue with insulin-like growth factor-I (IGF-I). Five patients with cEDS and 10 healthy, matched controls (CTRL) were included. One patellar tendon of each participant was injected with 0.1 ml IGF-I (Increlex, Ipsen, 10 mg/ml) and the contralateral tendon with 0.1 ml isotonic saline as control. The injections were performed at both 24 and 6 h prior to tissue sampling. The fractional synthesis rate (FSR) of proteins in skin and tendon was measured with the stable isotope technique using a flood-primed continuous infusion over 6 h. After the infusion one skin biopsy and two tendon biopsies (one from each patellar tendon) were obtained. We found similar baseline FSR values in skin and tendon in the cEDS patients and controls [skin: 0.005 ± 0.002 (cEDS) and 0.007 ± 0.002 (CTRL); tendon: 0.008 ± 0.001 (cEDS) and 0.009 ± 0.002 (CTRL) %/h, mean ± SE]. IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0.007 ± 0.002, CTRL 0.001 ± 0.001%/h). In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 403,
                "text": "connective tissue"
            }
        },
        {
            "context": "Adjusting for background mutation frequency biases improves the identification of cancer driver genes. A common goal of tumor sequencing projects is finding genes whose mutations are selected for during tumor development. This is accomplished by choosing genes that have more non-synonymous mutations than expected from an estimated background mutation frequency. While this background frequency is unknown, it can be estimated using both the observed synonymous mutation frequency and the non-synonymous to synonymous mutation ratio. The synonymous mutation frequency can be determined across all genes or in a gene-specific manner. This choice introduces an interesting trade-off. A gene-specific frequency adjusts for an underlying mutation bias, but is difficult to estimate given missing synonymous mutation counts. Using a genome-wide synonymous frequency is more robust, but is less suited for adjusting biases. Studying four evaluation criteria for identifying genes with high non-synonymous mutation burden (reflecting preferential selection of expressed genes, genes with mutations in conserved bases, genes with many protein interactions, and genes that show loss of heterozygosity), we find that the gene-specific synonymous frequency is superior in the gene expression and protein interaction tests. In conclusion, the use of the gene-specific synonymous mutation frequency is well suited for assessing a gene's non-synonymous mutation burden.",
            "question": "Are most driver gene mutations synonymous or non-synonymous?",
            "answers": {
                "answer_start": 276,
                "text": "non-synonymous"
            }
        },
        {
            "context": "Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 165,
                "text": "tyr"
            }
        },
        {
            "context": "Intracranial artery dissection in an adolescent with Marfan syndrome. Marfan syndrome is an autosomal dominant connective tissue disorder commonly due to mutation of the fibrillin-1 (FBN-1) gene that causes disruption of elastic fibers in large- and medium-size arteries and predisposes to aneurysm formation and arterial dissection. Cardiovascular complications occur in most patients with Marfan syndrome, but interestingly, neurovascular complications of Marfan syndrome are rare. We present a novel case of an adolescent with Marfan syndrome with spontaneous intracranial cerebral artery dissection and ischemic stroke with hemorrhagic transformation. This case is novel in that it reports spontaneous intracranial dissection in a young patient with Marfan syndrome and highlights the rare intrinsic neurovascular complications that can occur in these patients.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 111,
                "text": "connective tissue"
            }
        },
        {
            "context": "Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. DESIGN: A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. SETTING: An 800-bed, teaching, university-affiliated hospital. PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant \"waking\" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 2138,
                "text": "flumazenil"
            }
        },
        {
            "context": "Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 24,
                "text": "LPIN2"
            }
        },
        {
            "context": "Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of γ-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation.",
            "question": "Which enzyme is inhibited by niraparib?",
            "answers": {
                "answer_start": 185,
                "text": "poly(ADP-Ribose) polymerase"
            }
        },
        {
            "context": "Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B). MWS has been reported in association with Hirschsprung disease (HSCR). MWS is sometimes difficult to diagnose clinically, especially when HSCR is absent. Thus, it is necessary to detect gene abnormalities at the molecular level. Here we report two Japanese girls with MWS, who showed a distinct facial phenotype, severe intellectual disability and epileptic seizures. Major congenital anomalies of the patients were very different. Patient 1 suffered from severe congenital heart disease, but did not show apparent HSCR. Patient 2 suffered from typical HSCR and underwent surgical treatment, but did not have congenital heart disease. According to the gene analysis using white blood cells, they had nonsense mutations in ZFHX1B, R695X and Q433X, respectively. In conclusion, molecular genetic analysis of ZFHX1B is important for a definite diagnosis of MWS which has a wide phenotypic spectrum of congenital anomalies.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 1049,
                "text": "ZFHX1B"
            }
        },
        {
            "context": "Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus. RATIONALE: Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. OBJECTIVE: The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. METHODS AND RESULTS: Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. CONCLUSIONS: Mitochondrial fission is an obligatory, early step in mammalian O2 sensing and offers a promising target for modulating DA patency.",
            "question": "What is the functional role of the protein Drp1?",
            "answers": {
                "answer_start": 50,
                "text": "mitochondrial fission"
            }
        },
        {
            "context": "Mitosis-specific phosphorylation of PML at T409 regulates spindle checkpoint. During mitosis, Promyelocytic leukemia nuclear bodies (PML NBs) change dramatically in morphology and composition, but little is known about function of PML in mitosis. Here, we show that PML is phosphorylated at T409 (PML p409) in a mitosis-specific manner. More importantly, PML p409 contributes to maintain the duration of pro-metaphase and regulates spindle checkpoint. Deficient PML p409 caused a shortening of pro-metaphase and challenged the nocodazole-triggered mitotic arrest. T409A mutation led to a higher frequency of misaligned chromosomes on metaphase plate, and subsequently death in late mitosis. In addition, inhibition of PML p409 repressed growth of tumor cells, suggesting that PML p409 is a potential target for cancer therapy. Collectively, our study demonstrated an important phosphorylated site of PML, which contributed to explore the role of PML in mitosis.",
            "question": "What is the effect of nocodazole cell treatment?",
            "answers": {
                "answer_start": 548,
                "text": "mitotic arrest"
            }
        },
        {
            "context": "Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. PURPOSE: While the selective 5-hydroxytryptamine type 2a receptor (5-HT2AR) radiotracer [18F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT2ARs with positron emission tomography (PET) in albino rats. PROCEDURES: Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals. RESULT: Overall brain uptake of [18F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals. CONCLUSION: [18F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 1278,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 432,
                "text": "CD38"
            }
        },
        {
            "context": "Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 175,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1010,
                "text": "xa"
            }
        },
        {
            "context": "Differential molecular response of the transcripts B2A2 and B3A2 to imatinib mesylate in chronic myeloid leukemia. Chronic myeloid leukemia (CML) originates from the hematopoietic stem cell and is characterized by the reciprocal translocation t(9;22)(q34;q11), which results in the BCR-ABL fusion gene on chromosome 22q-, also known as the Philadelphia chromosome. This chimeric gene codes for a cytoplasmic protein with constitutive tyrosine-kinase activity, responsible for cellular transformation and leukemogenesis in CML. The aim of this observational cohort study was to discriminate and quantify BCR-ABL transcripts in the peripheral blood of patients with CML who were treated with imatinib mesylate (Glivec, Novartis). Twenty-two patients were followed for six months during treatment. Quantitative real time polymerase chain reaction was performed before treatment and after 3 and 6 months from treatment initiation. As compared with the third month, there was a significant decrease in BCR-ABL expression in the sixth month of treatment (P = 0.0002). At the sixth month, there was a significant difference in the levels of the two major transcripts of BCR-ABL, B2A2 and B3A2 (P = 0.0347), indicating that B2A2 may be more sensitive to imatinib. The results of our study indicate that imatinib is able to modify the natural history of CML, and raise the hypothesis that patients who express the B2A2 transcript may have a better prognosis.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 603,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. p53 is a sequence specific transcription factor that is activated in response to various forms of genotoxic stress to induce cell cycle arrest and apoptosis. Induction of p53 is subjected to complex and strict control through several pathways, as it will often determine cellular fate. The p73 protein shares strong structural and functional similarities with p53 such as the potential to activate p53 responsive genes and the ability to induce apoptosis. In addition to alternative splicing at the carboxyl terminus which yields several p73 isoforms, a p73 variant lacking the N-terminal transactivation domain (Delta Np73) was described in mice. In this study, we report the cloning and characterisation of the human Delta Np73 isoforms, their regulation by p53 and their possible role in carcinogenesis. As in mice, human Delta Np73 lacks the transactivation domain and starts with an alternative exon (exon 3'). Its expression is driven by a second promoter located in a genomic region upstream of this exon, supporting the idea of two independently regulated proteins, derived from the same gene. As anticipated, Delta Np73 is capable of regulating TAp73 and p53 function since it is able to block their transactivation activity and their ability to induce apoptosis. Interestingly, expression of the Delta Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. The regulation of Delta Np73 is exerted through a p53 responsive element located on the Delta N promoter. Expression of Delta Np73 not only regulates the function of p53 and TAp73 but also shuts off its own expression, once again finely regulating the whole system. Our data also suggest that increased expression of Delta Np73, functionally inactivating p53, could be involved in tumorogenesis. An extensive analysis of the expression pattern of Delta Np73 in primary tumours would clarify this issue.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 1610,
                "text": "7"
            }
        },
        {
            "context": "Inducible and transmissible genetic events and pediatric tumors of the nervous system. Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 689,
                "text": "NF1"
            }
        },
        {
            "context": "Crosslinking-MS analysis reveals RNA polymerase I domain architecture and basis of rRNA cleavage. RNA polymerase (Pol) I contains a 10-subunit catalytic core that is related to the core of Pol II and includes subunit A12.2. In addition, Pol I contains the heterodimeric subcomplexes A14/43 and A49/34.5, which are related to the Pol II subcomplex Rpb4/7 and the Pol II initiation factor TFIIF, respectively. Here we used lysine-lysine crosslinking, mass spectrometry (MS) and modeling based on five crystal structures, to extend the previous homology model of the Pol I core, to confirm the location of A14/43 and to position A12.2 and A49/34.5 on the core. In the resulting model of Pol I, the C-terminal ribbon (C-ribbon) domain of A12.2 reaches the active site via the polymerase pore, like the C-ribbon of the Pol II cleavage factor TFIIS, explaining why the intrinsic RNA cleavage activity of Pol I is strong, in contrast to the weak cleavage activity of Pol II. The A49/34.5 dimerization module resides on the polymerase lobe, like TFIIF, whereas the A49 tWH domain resides above the cleft, resembling parts of TFIIE. This indicates that Pol I and also Pol III are distantly related to a Pol II-TFIIS-TFIIF-TFIIE complex.",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 837,
                "text": "TFIIS"
            }
        },
        {
            "context": "The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy. Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p=0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot-Marie-Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot-Marie-Tooth Disease type 2.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 205,
                "text": "GAN gene"
            }
        },
        {
            "context": "Interaction of Cep135 with a p50 dynactin subunit in mammalian centrosomes. Cep135 is a 135-kDa, coiled-coil centrosome protein important for microtubule organization in mammalian cells [Ohta et al., 2002: J. Cell Biol. 156:87-99]. To identify Cep135-interacting molecules, we screened yeast two-hybrid libraries. One clone encoded dynamitin, a p50 dynactin subunit, which localized at the centrosome and has been shown to be involved in anchoring microtubules to centrosomes. The central domain of p50 binds to the C-terminal sequence of Cep135; this was further confirmed by immunoprecipitation and immunostaining of CHO cells co-expressing the binding domains for Cep135 and p50. Exogenous p50 lacking the Cep 135-binding domain failed to locate at the centrosome, suggesting that Cep135 is required for initial targeting of the centrosome. Altered levels of Cep135 and p50 by RNAi and protein overexpression caused the release of endogenous partner molecules from centrosomes. This also resulted in dislocation of other centrosomal molecules, such as gamma-tubulin and pericentrin, ultimately leading to disorganization of microtubule patterns. These results suggest that Cep135 and p50 play an important role in assembly and maintenance of functional microtubule-organizing centers.",
            "question": "Where in the cell do we find the protein Cep135?",
            "answers": {
                "answer_start": 109,
                "text": "centrosome"
            }
        },
        {
            "context": "LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.",
            "question": "Which database is available for the identification of chorion proteins in Lepidopteran proteomes?",
            "answers": {
                "answer_start": 0,
                "text": "LepChorionDB"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 609,
                "text": "xa"
            }
        },
        {
            "context": "Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS: An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.",
            "question": "Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?",
            "answers": {
                "answer_start": 254,
                "text": "diabetes mellitus"
            }
        },
        {
            "context": "Validation of the use of the ROSIER scale in prehospital assessment of stroke. AIM: To determine the utility of the Recognition of Stroke in the Emergency Room (ROSIER) scale as a stroke recognition tool among Chinese patients in the prehospital setting. MATERIALS AND METHODS: Compared with the Cincinnati Prehospital Stroke Scale (CPSS), emergency physicians prospectively used the ROSIER as a stroke recognition tool on suspected patients in the prehospital setting. And, the final discharge diagnosis of stroke or transient ischemic attack made by neurologists, after assessment and review of clinical symptomatology and brain imaging findings, was used as the reference standard for diagnosis in the study. Then, the ROSIER and the CPSS like sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), related coefficient (r) and Kappa value were calculated. RESULTS: In this study, 540 of 582 suspected stroke patients met the study criteria. The CPSS showed a diagnostic Se of 88.77% (95% confidence intervals [CI] 86.11-91.43%), Sp of 68.79% (95% CI 64.88-72.70%), PPV of 87.40% (95% CI 85.97-88.83%), NPV of 71.52% (95% CI 67.71-75.33%) and r of 0.503. Relatively, the ROSIER showed a diagnostic Se of 89.97% (95% CI 87.44-92.64%), Sp of 83.23% (95% CI 80.08-86.38%), PPV of 92.66% (95% CI 90.46-94.86%), NPV of 77.91% (95% CI 74.41-81.41%) and r of 0.584. According to the final discharge diagnosis, both the ROSIER and the CPSS were associated with the final discharge diagnosis (P < 0.05).The Kappa statistic value of the ROSIER and the CPSS were 0.718 and 0.582, respectively. However, there was no statistical significance of the positive rate between the ROSIER and the CPSS in this study (P > 0.05). CONCLUSIONS: The ROSIER is a sensitive and specific stroke recognition tool for health providers' use among Chinese patients in the prehospital setting. However, it cannot be used to confidently rule out or identify stroke as a diagnosis. Comprehensive clinical assessment and further examination on potential stroke patients are still important and cannot be replaced. When it is difficult to objectively complete the ROSIER for patients, the CPSS could replace it in the prehospital setting.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 71,
                "text": "stroke"
            }
        },
        {
            "context": "[Intergenerational study of the mutation that causes Myotonic Dystrophy Type 1 in Costa Rica]. INTRODUCTION: Myotonic dystrophy type 1 is a neuromuscular, degenerative and progressive disease, with an autosomal dominant pattern of inheritance, variable expressivity and incomplete penetrance. The genetic defect is an unstable mutation due to the expansion of the triplet CTG in the 3 unstranslated region at the DMPK gene on chromosome 19q13.3. OBJECTIVE: The main objective was to study the intergenerational behavior of the DM1 mutation in order to evaluate the importance of this disease as a neurological problem that could be manageable by genetic counseling. PATIENTS AND METHODS: The study involved 84 patients with clinical diagnosis of DM1 and their relatives, which were confirmed through molecular diagnosis using Southern blot and PCR. RESULTS: Data analysis reveals the size of the mutation presents a positive correlation with the severity of the symptoms and a negative correlation with the age of onset. Transmission of the DM1 mutation is sex and size dependent among the Costa Rican patients. There is an important increment in the size of the mutation between generations and there are no differences in mutation size respect to the transmitting sex. CONCLUSION: The worldwide intergenerational behavior of the DM1 mutation is similar in Costa Rica",
            "question": "How is myotonic dystrophy inherited?",
            "answers": {
                "answer_start": 201,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. BACKGROUND AND OBJECTIVES: Iron depletion is common in regular blood donors. The objective of the study was to investigate the frequency and severity of iron depletion in regular blood donors and whether IV iron is more effective than oral to avoid iron depletion and symptoms thereof, especially restless legs syndrome (RLS). METHOD: One hundred and twenty blood donors with at least five previous whole blood donations were randomized to receive either IV iron sucrose (Venofer(®), RenaPharma/Vifor, Uppsala, Sweden), 200 mg, or to 20×100 mg of oral iron sulphate (Duroferon(®), GlaxoSmithKline, Stockholm, Sweden), after each blood donation during 1 year. Iron status and RLS incidence and severity were investigated. RESULTS: Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). The IV iron group increased storage iron to a greater extent than the oral iron group after 12 months (P=0·0043). Female donors were more responsive to IV iron sucrose compared to oral iron sulphate, particularly female donors below 50 years of age. RLS severity scores were significantly lower in the IV iron group. The two treatments were safe. CONCLUSION: Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. IV iron sucrose substitutes iron loss in blood donors more efficiently compared with oral iron sulphate, especially in women. Iron substitution to blood donors should be individualized and based on P-ferritin monitoring.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 1390,
                "text": "Iron"
            }
        },
        {
            "context": "Transcriptome analysis of the zebrafish model of Diamond-Blackfan anemia from RPS19 deficiency via p53-dependent and -independent pathways. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO), RPS19 and p53 morpholino simultaneously (RPS19+p53 MO) and control morpholino (control). We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.",
            "question": "In which syndrome is the RPS19 gene most frequently mutated?",
            "answers": {
                "answer_start": 140,
                "text": "Diamond-Blackfan anemia"
            }
        },
        {
            "context": "Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 403,
                "text": "calcineurin"
            }
        },
        {
            "context": "Rapid detection of Methicillin-Resistant Staphylococcus aureus MRSA in nose, groin, and axilla swabs by the BD GeneOhm MRSA achromopeptidase assay and comparison with culture. OBJECTIVES: To compare the BD GeneOhm Methicillin Resistant Staphylococcus aureus (MRSA) Achromopeptidase (ACP) polymerase chain reaction (PCR) assay with the culture method for the detection of MRSA colonization. METHODS: One hundred and two patients were admitted to the Intensive Care Unit in King Khalid Hospital, Najran, Kingdom of Saudi Arabia from July 2010 to February 2011. Separate swabs from the nose, axilla, and groin of each patient were processed by the culture method (sheep blood agar plate and mannitol salt agar plate) and BD GeneOhm MRSA ACP assay. RESULTS: Of the 287 samples, 62 (21.6%) were MRSA positive by the PCR assay and 26 (9%) were MRSA positive by the culture method. The PCR method showed 88.4% sensitivity and 98.6% negative predictive value. The number of MRSA-PCR positive groin specimens was nearly the same as nasal specimens. The PCR method gave positive results in 22.5% of patients by nasal specimens, 27.5% of patients by nasal and groin specimens, and 30.4% of patients by nasal, groin, and axilla specimens. The PCR method detected 30.4% of patients as MRSA positive while the culture method detected 19.6% of patients as positive for MRSA. CONCLUSION: The BD GeneOhm MRSA ACP assay has high sensitivity and NPV and hence is a useful screening method to exclude patients who are not colonized with MRSA.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 63,
                "text": "MRSA"
            }
        },
        {
            "context": "First example of anti-Kx in a person with the McLeod phenotype and without chronic granulomatous disease. BACKGROUND: Kx is lacking in the RBCs of patients with the McLeod syndrome. This condition is sometimes associated with chronic granulomatous disease (CGD). If given allogeneic RBCs, CGD patients with the McLeod phenotype may produce anti-Kx and anti-Km, and only phenotypically matched McLeod blood would be compatible. McLeod phenotype persons without CGD have made anti-Km but not anti-Kx (2 examples), and thus both McLeod and K(O) blood would be compatible. CASE REPORT: RBCs from a transfused patient with the McLeod phenotype but not with CGD (non-CGD McLeod) were typed for the Kell blood group antigens, and the plasma was analyzed for the presence of antibody by agglutination. The molecular basis was determined by analyzing for XK protein on RBC membranes by Western immunoblotting, by sequencing the XK gene, and by RFLP. RESULTS: The RBCs did not react with anti-Kx + anti-Km and showed weakening of Kell system antigens. The patient's plasma reacted moderately (2+) with RBCs of common Kell type and strongly (4+) with K(O) RBCs and RBCs of common Kell type treated with dithiothreitol, and did not react with McLeod RBCs. XK protein was absent from the RBC membranes. The XK gene had a point mutation in the donor splice site of intron 1 (G>C). CONCLUSION: This is the first report describing the molecular alteration in a non-CGD McLeod patient who has made anti-Kx. The immune response of people with the McLeod phenotype can vary, and K(O) blood may not always be compatible.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1294,
                "text": "XK"
            }
        },
        {
            "context": "Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease. X-Linked Dystonia-Parkinsonism (XDP or \"Lubag\") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 120,
                "text": "X-Linked Dystonia-Parkinsonism"
            }
        },
        {
            "context": "Three periods of regulatory innovation during vertebrate evolution. The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.",
            "question": "How many periods of regulatory innovation led to the evolution of vertebrates?",
            "answers": {
                "answer_start": 0,
                "text": "Three"
            }
        },
        {
            "context": "Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 651,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "A flexible and high throughput liquid chromatography-tandem mass spectrometric assay for the quantitation of telcagepant in human plasma. Telcagepant (MK-0974) is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist and is currently under clinical development. Results from phases II and III clinical trials have suggested that telcagepant is effective for migraine treatment. A reliable and high throughput protein precipitation (PPT) method for determination of telcagepant in human plasma using liquid chromatography coupled with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry has been developed. Clinical samples, internal standard (IS) and acetonitrile are transferred into 96-well plates using a robotic liquid handling system. An aliquot of 10 microL supernatant is directly injected into the LC-MS/MS system where separation is performed on a FluoPhase RP (150 x 2.1mm, 5 microm) column with an isocratic mobile phase (60% acetonitrile with 0.1% formic acid and 40% water with 0.1% formic acid) at 0.2 mL/min. The interfering 3S-diastereomer of telcagepant, which is observed in clinical samples, is chromatographically resolved from telcagepant. The PPT procedure significantly reduces the time required for sample processing and the assay is sufficiently sensitive for detection using both API 4000 and API 3000 mass spectrometers. The linear calibration range is 5-5000 nM using 200 microL of plasma. Assay intraday validation was conducted using six calibration curves derived from six lots of human control plasma. Calibration standard accuracy did not deviate by more than 3% and 6% of nominal values, and precision did not exceed 4% coefficient of variation (CV) and 10% CV, respectively on the API 4000 and API 3000. Several clinical phases IIb and III studies have been successfully supported with this assay.",
            "question": "Which receptor is targeted by telcagepant?",
            "answers": {
                "answer_start": 176,
                "text": "calcitonin gene-related peptide"
            }
        },
        {
            "context": "Understanding the role of the Josephin domain in the PolyUb binding and cleavage properties of ataxin-3. Ataxin-3, the disease protein in the neurodegenerative disorder Spinocerebellar Ataxia Type 3 or Machado Joseph disease, is a cysteine protease implicated in the ubiquitin proteasome pathway. It contains multiple ubiquitin binding sites through which it anchors polyubiquitin chains of different linkages that are then cleaved by the N-terminal catalytic (Josephin) domain. The properties of the ubiquitin interacting motifs (UIMs) in the C-terminus of ataxin-3 are well established. Very little is known, however, about how two recently identified ubiquitin-binding sites in the Josephin domain contribute to ubiquitin chain binding and cleavage. In the current study, we sought to define the specific contribution of the Josephin domain to the catalytic properties of ataxin-3 and assess how the topology and affinity of these binding sites modulate ataxin-3 activity. Using NMR we modeled the structure of diUb/Josephin complexes and showed that linkage preferences are imposed by the topology of the two binding sites. Enzymatic studies further helped us to determine a precise hierarchy between the sites. We establish that the structure of Josephin dictates specificity for K48-linked chains. Site 1, which is close to the active site, is indispensable for cleavage. Our studies open the way to understand better the cellular function of ataxin-3 and its link to pathology.",
            "question": "Which is the protein implicated in Spinocerebellar ataxia type 3?",
            "answers": {
                "answer_start": 105,
                "text": "Ataxin-3"
            }
        },
        {
            "context": "Radiofrequency sensory ablation as a treatment for symptomatic unilateral lumbosacral junction pseudarticulation (Bertolotti's syndrome): a case report. OBJECTIVE: Describe the clinical presentation, diagnostic evaluation, and successful treatment of a case of symptomatic unilateral lumbosacral junction pseudarticulation using a novel radiofrequency nerve ablation technique. CASE: A 56-year-old female patient who had suffered with low back and right upper buttock pain for 16 years experienced incomplete relief with L4/5 facet joint radiofrequency ablation. She was found to have an elongated right L5 transverse process that articulated with the sacral ala (Bertolotti's syndrome). Fluoroscopically guided local anesthetic/corticosteroid injection into the pseudarthrosis eliminated her residual right buttock pain for the duration of the local anesthetic only. Complete pain relief was achieved by injecting local anesthetic circumferentially around the posterior pseudarthrosis articular margin. Accordingly, bipolar radiofrequency strip thermal lesions were created at the same locations. Complete pain relief and full restoration of function was achieved for 16 months postprocedure. CONCLUSION: This case report describes a novel radiofrequency technique for treating symptomatic lumbosacral junction pseudarticulation that warrants further evaluation.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 74,
                "text": "lumbosacral"
            }
        },
        {
            "context": "New anticoagulants: focus on venous thromboembolism. Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 1006,
                "text": "Xa"
            }
        },
        {
            "context": "Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 569,
                "text": "ret"
            }
        },
        {
            "context": "Mepolizumab: 240563, anti-IL-5 monoclonal antibody - GlaxoSmithKline, anti-interleukin-5 monoclonal antibody - GlaxoSmithKline, SB 240563. Mepolizumab is an anti-interleukin-5 monoclonal antibody that is in clinical trials with GlaxoSmithKline (GSK) for the treatment of severe asthma, nasal polyposis and hypereosinophilic syndrome and eosinophilic oesophagitis (the latter two indications are classed as eosinophilia in the phase table). Interleukin-5 stimulates the production, activation and maturation of eosinophils. Since mepolizumab inhibits interleukin-5 and has a long terminal half-life, treatment with mepolizumab causes a sustained reduction in the numbers of circulating eosinophils. Thus, mepolizumab may be a useful therapeutic agent for the treatment of conditions characterized by increased levels of eosinophils. Hypereosinophilic syndrome is a rare idiopathic disease with broad clinical signs and symptoms that is diagnosed based on a persistent blood eosinophil count of >1500 cells, various end-organ damages (including skin, heart, lung, nervous system and digestive system), and with exclusion of known secondary causes of hypereosinophilia. Mepolizumab is in clinical trials for the treatment of hypereosinophilic syndrome, eosinophilc oesophagitis, severe asthma (in patients with airway eosinophilia) and nasal polyposis. GlaxoSmithKline (GSK) has completed enrolment in a phase II study of mepolizumab in 20 patients with symptomatic eosinophilic bronchitis with or without asthma in Canada. The randomized, double-blind, placebo-controlled study is evaluating the effects of intravenous mepolizumab on asthma control, airway eosinophilia and the degree to which concomitant corticosteroid treatment can be reduced (NCT00292877). In previous clinical studies, including trials in the EU and US, mepolizumab has shown a lack of effect on allergen-induced airway responses and inflammation despite a significant reduction in blood and sputum eosinophil levels.A randomized, double-blind, placebo-controlled, multicentre, phase III study of mepolizumab over 9 months in 85 patients with hypereosinophilic syndrome was completed in 2006. All patients have been offered, and continued in, a phase III, open-label, long-term extension study of mepolizumab. Enrolment in this study was completed in September 2006.A phase III, compassionate use trial of mepalizumab (NCT00244686) in patients with hypereosinophilic syndrome was ongoing in October 2007 in the US. Patients who have significant clinical disease but are unresponsive to traditional treatment and those who have demonstrated clinical benefit from previous anti-IL-5 treatment are eligible to take part in the trial. Mepolizumab received orphan drug status for first-line treatment in patients with hypereosinophilic syndrome in the US and the EU in 2004. Mepolizumab is also in phase I/II clinical development for the treatment of eosinophilic oesophagitis. A phase I/II trial (NCT00358449) began in August 2006 in the US, Australia, the UK and Canada, and will enrol approximately 72 paediatric patients with eosinophilic oesophagitis. The randomized, parallel-group clinical trial will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous mepolizumab for 12 weeks. In September 2006, GSK completed enrolment in a phase I/II study of mepolizumab for the treatment of eosinophilic oesophagitis in ten adult patients in Switzerland (NCT00274703). The randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of IV mepolizumab.A phase I/II trial of mepolizumab in four patients with eosinophilic oesophagitis conducted by Cincinnati Children's hospital found the monoclonal antibody was safe and effective. Brigham and Women's Hospital in association with GSK is conducting a phase I/II trial of mepolizumab in patients with Churg-Strauss Syndrome (CSS) in the US. The trial, which started in September 2007, will evaluate the potential of mepolizumab to reduce the need for corticosteroid therapy in patients with CSS (NCT00527566). CSS, otherwise known as allergic granulomatosis, is defined by patients with asthma, eosinophilia and vasculitis.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 75,
                "text": "interleukin-5"
            }
        },
        {
            "context": "New antibodies recognizing p73: comparison with commercial antibodies. p73, unlike p53, is expressed as a number of isomeric forms. Alternative splicing at the 3' end of p73 transcript, together with the usage of a second promoter downstream of exon 3, can generate up to 24 p73 isoforms. Variants lacking the TA domain (DeltaN isoforms) are induced by TAp73 and by p53, and inhibit their transcriptional activity. However, understanding the complex biology of p73 has been handicapped by the lack of high affinity specific antibodies for the different isoforms. Here, we report the characterization, by Western blotting and immunoprecipitation, of three new polyclonal antisera recognizing all p73 isoforms, only DeltaN isoforms or only p73alpha, and which have advantages of affinity and specificity over previously available antibodies.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 356,
                "text": "7"
            }
        },
        {
            "context": "Hypertrophic cardiomyopathy: electrocardiographic manifestations and other important considerations for the emergency physician. Hypertrophic cardiomyopathy (HCM) is one of the most common inherited primary cardiac disorders and the most common cause of sudden cardiac death in young athletes. With advances in technology, it is now recognized that HCM affects individuals of all ages. Many patients with HCM will have a benign course with few symptoms. Some patients, however, possess risk factors that greatly increase the likelihood of sudden death if their disease remains undiagnosed. Therefore, it is imperative that emergency physicians be familiar with the symptoms and typical electrocardiogram manifestations of HCM. Three illustrative cases are presented with a review of the disease.",
            "question": "Which is the most common cause of sudden cardiac death in young athletes?",
            "answers": {
                "answer_start": 129,
                "text": "Hypertrophic cardiomyopathy"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 1064,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R package is used for the detection of chromosomal abnormalities from microarray data?",
            "answers": {
                "answer_start": 0,
                "text": "CAFE"
            }
        },
        {
            "context": "A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade > 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed > 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 215,
                "text": "interleukin-6"
            }
        },
        {
            "context": "Inappropriate use of naloxone in cancer patients with pain. Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 392,
                "text": "naloxone"
            }
        },
        {
            "context": "[Mechanism and strategy for treatment of cancer metastasis to bone]. Bone, as well as the lung and liver, is among the sites of predilection for cancer metastasis. The bone stores large amounts of growth factors such as insulin-like growth factors and transforming growth factor-b, and provides fertile soil for metastatic cancer cells by continuously releasing these bone-stored growth factors, which are a consequence of osteoclastic bone resorption. Metastatic cancer cells in turn produce osteoclast-stimulating cytokines such as parathyroid hormone-related protein( PTH-rP), prostaglandin E2.(PGE2), and various interleukins(ILs). These cancer-produced osteoclast-stimulating cytokines bind to their cognitive receptors and promote the expression of ligands for the receptor activators of nuclear factor kB (RANKL)in osteoblasts. RANKL then binds to its receptor RANK, expressed in pre-osteoclasts, stimulates mature osteoclast formation, and subsequently, osteoclastic bone resorption. This vicious cycle between metastatic cancer cells and osteoclasts is critical to the development and progression of bone metastases. In addition, it is likely that metastatic cancer cells are influenced by bone environments(or niche)and acquire additional capacities such as an epithelial-mesenchymal transition(EMT), allowing them to be resistant to chemotherapy or apoptosis, to survive in a dormant state, or to aggressively spread to distant organs including lung and liver. Thus, the bone can serve as transit port. Disrupting this cycle by inhibiting osteoclastic bone resorption, antagonizing bone-derived growth factors, and neutralizing RANKL or PTH-rP, should be a promising therapeutic intervention for bone metastases. Bisphosphonates(BP)are specific inhibitors of osteoclasts, and have been shown to significantly reduce skeletal-related events(SRE)associated with bone metastasis. Denosumab is a neutralizing monoclonal antibody to RANKL and has recently been found to inhibit SRE more effectively than BP. Further understanding of the crosstalk communication between metastatic cancer cells and bone at the molecular level should lead us to design novel, more effective and specific treatments for cancer patients with bone metastases.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 1939,
                "text": "RANKL"
            }
        },
        {
            "context": "Clonal size-variation of rDNA cluster region on chromosome XII of Saccharomyces cerevisiae. Using pulsed-field gel electrophoresis (PFGE), we have demonstrated clonal variation in the size of chromosome XII in a diploid strain of Saccharomyces cerevisiae X2180-2D. The sizes of the two chromosome XII homologues were very different: 2600 (L-type) and 1450 kb (S-type). The frequency with which we detected clonal size variation in the diploid, compared to that of the parental clones, was about 15-50% of the progeny clones and the range of the size variation of the homologues was 2580-2680 kb (L-type) and 1340-1500 kb (S-type), respectively. The homologue of the L-type appeared to be more frequently variable than that of the S-type. The size variation was shown to be derived from size changes in the rDNA cluster region, which is present in chromosome XII, by digesting the chromosome with XhoI, whose cutting site is not present in a rDNA repeat unit, and hybridizing to rDNA probes. The clonal size variation was also investigated in haploids from spores after meiosis. The L-type and S-type chromosomes segregated 2:2 in an ascus and the sizes of all the S-type chromosomes were shifted up, compared to the original diploid, though the L-type ones were stable. The S-type sizes of 1340, 1450 and 1780 kb in the original diploids changed into the ranges of 1475-1610 kb, 1520-1680 kb and 1820-2010 kb, respectively, in the segregants. Furthermore, we observed that the size of S-type chromosomes in haploid cells was gradually increasing in mitosis during successive subcultures.(ABSTRACT TRUNCATED AT 250 WORDS)",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 847,
                "text": "chromosome XII"
            }
        },
        {
            "context": "Functional expression of a Drosophila gene in yeast: genetic complementation of DNA topoisomerase II. Since DNA topoisomerase II (EC 5.99.1.3) is an essential enzyme in yeast, heterologous topoisomerase II gene expression in yeast cells can provide a system for analyzing the structure and function of topoisomerase II genes from other species. A series of yeast expression plasmids was constructed in which segments of the cDNA sequences encoding Drosophila DNA topoisomerase II were inserted under the transcriptional control of yeast GAL1 promoter. Expression of the functional form of Drosophila topoisomerase II cDNA can complement conditionally lethal, temperature-sensitive mutations in the yeast topoisomerase II gene (TOP2), as well as mutations in which the TOP2 locus was disrupted. The survival of these yeast cells depends upon the continuous expression of Drosophila topoisomerase II. Repression of Drosophila gene expression by glucose causes these yeast cells to cease dividing after a few generations. In addition to these genetic complementation data, the expression of the Drosophila topoisomerase II gene in yeast cells with a disruption in TOP2 can also be detected by immunochemical methods with an antibody specific for Drosophila topoisomerase II.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 189,
                "text": "topoisomerase II"
            }
        },
        {
            "context": "Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. BACKGROUND: Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. These three mutations are valuable companion diagnostic biomarkers for guiding personalized treatment. Quantitative polymerase chain reaction (qPCR)-based methods have been widely used in the clinic by physicians to guide treatment decisions. The aim of this study was to evaluate the technical and clinical sensitivity and specificity of the droplet digital polymerase chain reaction (ddPCR) method in detecting the three EGFR mutations in patients with lung cancer. METHODS: Genomic DNA from H1975 and PC-9 cells, as well as 92 normal human blood specimens, was used to determine the technical sensitivity and specificity of the ddPCR assays. Genomic DNA of formalin-fixed, paraffin-embedded specimens from 78 Chinese patients with lung adenocarcinoma were assayed using both qPCR and ddPCR. RESULTS: The three ddPCR assays had a limit of detection of 0.02% and a wide dynamic range from 1 to 20,000 copies measurement. The L858R and ex19del assays had a 0% background level in the technical and clinical settings. The T790M assay appeared to have a 0.03% technical background. The ddPCR assays were robust for correct determination of EGFR mutation status in patients, and the dynamic range appeared to be better than qPCR methods. The ddPCR assay for T790M could detect patient samples that the qPCR method failed to detect. About 49% of this patient cohort had EGFR mutations (L858R, 15.4%; ex19del, 29.5%; T790M, 6.4%). Two patients with the ex19del mutation also had a naïve T790M mutation. CONCLUSION: These data suggest that the ddPCR method could be useful in the personalized treatment of patients with lung cancer.",
            "question": "Which gene harbors the mutation T790M?",
            "answers": {
                "answer_start": 141,
                "text": "epidermal growth factor receptor"
            }
        },
        {
            "context": "Recent developments in the diagnosis of Marfan syndrome and related disorders. Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.",
            "question": "Which gene mutations cause the Marfan syndrome?",
            "answers": {
                "answer_start": 668,
                "text": "FBN1"
            }
        },
        {
            "context": "Sequential fluctuating paraneoplastic ocular flutter-opsoclonus-myoclonus syndrome and Lambert-Eaton myasthenic syndrome in small-cell lung cancer. Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.",
            "question": "Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?",
            "answers": {
                "answer_start": 837,
                "text": "small-cell lung cancer"
            }
        },
        {
            "context": "A highly sensitive genetic protocol to detect NF1 mutations. Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene. Detecting mutation in NF1 is hindered by the gene's large size, the lack of mutation hotspots, the presence of pseudogenes, and the wide variety of possible lesions. We developed a method for detecting germline mutations by combining an original RNA-based cDNA-PCR mutation detection method and denaturing high-performance liquid chromatography (DHPLC) with multiplex ligation-dependent probe amplification (MLPA). The protocol was validated in a cohort of 56 blood samples from NF1 patients who fulfilled NIH diagnostic criteria, identifying the germline mutation in 53 cases (95% sensitivity). The efficiency and reliability of this approach facilitated detection of different types of mutations, including single-base substitutions, deletions or insertions of one to several nucleotides, microdeletions, and changes in intragenic copy number. Because mutational screening for minor lesions was performed using cDNA and the characterization of mutated alleles was performed at both the RNA and genomic DNA level, the analysis provided insight into the nature of the different mutations and their effect on NF1 mRNA splicing. After validation, we implemented the protocol as a routine test. Here we present the overall unbiased spectrum of NF1 mutations identified in 93 patients in a cohort of 105. The results indicate that this protocol is a powerful new tool for the molecular diagnosis of NF1.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 87,
                "text": "NF1"
            }
        },
        {
            "context": "Transcription domain-associated repair in human cells. Nucleotide excision repair (NER), which is arguably the most versatile DNA repair system, is strongly attenuated in human cells of the monocytic lineage when they differentiate into macrophages. Within active genes, however, both DNA strands continue to be proficiently repaired. The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes. We now report that the previously termed differentiation-associated repair (DAR) depends upon transcription, but not simply upon RNA polymerase II (RNAPII) encountering a lesion: proficient repair of both DNA strands can occur in a part of a gene that the polymerase never reaches, and even if the translocation of RNAPII is blocked with transcription inhibitors. This suggests that DAR may be a subset of global NER, restricted to the subnuclear compartments or chromatin domains within which transcription occurs. Downregulation of selected NER genes with small interfering RNA has confirmed that DAR relies upon the same genes as global genome repair, rather than upon TCR-specific genes. Our findings support the general view that the genomic domains within which transcription is active are more accessible than the bulk of the genome to the recognition and repair of lesions through the global pathway and that TCR is superimposed upon that pathway of NER.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 494,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Unsuspected reason for sciatica in Bertolotti's syndrome. Patients with Bertolotti's syndrome have characteristic lumbosacral anomalies and often have severe sciatica. We describe a patient with this syndrome in whom standard decompression of the affected nerve root failed, but endoscopic lumbosacral extraforaminal decompression relieved the symptoms. We suggest that the intractable sciatica in this syndrome could arise from impingement of the nerve root extraforaminally by compression caused by the enlarged transverse process.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 114,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Pre-pregnancy restless legs syndrome (Willis-Ekbom Disease) is associated with perinatal depression. OBJECTIVES: Both restless legs syndrome ([RLS], also known as Willis-Ekbom Disease [WED]) and depression are common during pregnancy. However, no prior studies have assessed if pregnant women with RLS have an elevated risk of depression during and/or after pregnancy. METHODS: 1,428 women who were pregnant in gestational week 16-17 were asked to participate in a longitudinal survey. They were followed by web-based questionnaires in gestational week 17 and 32, and 6 weeks after delivery. Data were also retrieved from prenatal and birth records. Two different sets of criteria were used to examine the prevalence of RLS in the cohort (International Restless Legs Syndrome Society Group standard criteria and the later developed CH-RLSQ11 questionnaire). The latter questionnaire attempts to exclude those with common \"mimics\" of RLS. RESULTS: Adjusted odds ratio for depression in gestational week 17, 32, and postpartum week 6 in relation to pre-pregnancy RLS onset and moderate to severe symptom severity were 4.74 (2.30 - 9.76), 3.67 (1.85 - 7.28), and 2.58 (1.28 - 5.21), respectively. No significant associations were seen in pregnant women with de novo RLS during pregnancy. When using the standard diagnostic RLS criteria and frequency of symptoms more than 2-3 days per week, the prevalence of RLS was 12.3%. With the CH-RLSQ11 questionnaire and the same threshold for frequency of symptoms the prevalence was 6.5%. CONCLUSION: Women with RLS onset before pregnancy with moderate or severe symptoms had an increased risk of both antenatal and postnatal depression. The self-reported prevalence of RLS during pregnancy is lower when a questionnaire dealing with \"mimics\" is used.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 118,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Osteoporosis and several other bone disorders occur when there is an imbalance between the resorption and formation components of bone remodeling activity. Therapies available for some of these conditions modulate the activity of osteoclasts and/or osteoblasts. The recent discoveries of receptor activator of NF-kappaB ligand (RANKL), an endogenous activator of osteoclastogenenesis and osteoclast activity and its inhibitor, osteoprotegerin (OPG) as pivotal regulatory factors in the pathogenesis of bone diseases like osteoporosis provide unique targets for therapeutic agents. In laboratory animals and now in humans, administering forms of OPG markedly inhibits osteoclast activity and improves bone strength, documenting that the strategy of inhibiting RANKL activity has therapeutic promise. A highly specific, fully human antibody against RANKL has been produced (denosumab) that in early studies in humans reduces bone turnover and improves bone density. Attributes of denosumab in these clinical studies include a very rapid onset of action, sustained effects for several months after a single injection, and good tolerability. These results provide the basis for studies evaluating the effectiveness of denosumab in several clinical conditions characterized by increased osteoclastic activity.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 940,
                "text": "RANKL"
            }
        },
        {
            "context": "[Daratumumab--breakthrough drug in multiple myeloma therapy]. Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 181,
                "text": "CD38"
            }
        },
        {
            "context": "The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31 degrees C than at 37 degrees C, and their degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 255,
                "text": "tyr"
            }
        },
        {
            "context": "webSDA: a web server to simulate macromolecular diffusional association. Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.",
            "question": "Which server is used for simulation of macromolecular diffusional association?",
            "answers": {
                "answer_start": 339,
                "text": "webSDA"
            }
        },
        {
            "context": "Rapid detection of Methicillin-Resistant Staphylococcus aureus MRSA in nose, groin, and axilla swabs by the BD GeneOhm MRSA achromopeptidase assay and comparison with culture. OBJECTIVES: To compare the BD GeneOhm Methicillin Resistant Staphylococcus aureus (MRSA) Achromopeptidase (ACP) polymerase chain reaction (PCR) assay with the culture method for the detection of MRSA colonization. METHODS: One hundred and two patients were admitted to the Intensive Care Unit in King Khalid Hospital, Najran, Kingdom of Saudi Arabia from July 2010 to February 2011. Separate swabs from the nose, axilla, and groin of each patient were processed by the culture method (sheep blood agar plate and mannitol salt agar plate) and BD GeneOhm MRSA ACP assay. RESULTS: Of the 287 samples, 62 (21.6%) were MRSA positive by the PCR assay and 26 (9%) were MRSA positive by the culture method. The PCR method showed 88.4% sensitivity and 98.6% negative predictive value. The number of MRSA-PCR positive groin specimens was nearly the same as nasal specimens. The PCR method gave positive results in 22.5% of patients by nasal specimens, 27.5% of patients by nasal and groin specimens, and 30.4% of patients by nasal, groin, and axilla specimens. The PCR method detected 30.4% of patients as MRSA positive while the culture method detected 19.6% of patients as positive for MRSA. CONCLUSION: The BD GeneOhm MRSA ACP assay has high sensitivity and NPV and hence is a useful screening method to exclude patients who are not colonized with MRSA.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 119,
                "text": "MRSA"
            }
        },
        {
            "context": "Characterization and functional expression of cDNAs encoding methionine-sensitive and -insensitive homocysteine S-methyltransferases from Arabidopsis. Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy). These reactions comprise the SMM cycle. Two Arabidopsis cDNAs specifying enzymes that mediate the SMM --> Met reaction (SMM:Hcy S-methyltransferase, HMT) were identified by homology and authenticated by complementing an Escherichia coli yagD mutant and by detecting HMT activity in complemented cells. Gel blot analyses indicate that these enzymes, AtHMT-1 and -2, are encoded by single copy genes. The deduced polypeptides are similar in size (36 kDa), share a zinc-binding motif, lack obvious targeting sequences, and are 55% identical to each other. The recombinant enzymes exist as monomers. AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM. Both enzymes also use either methyl donor in vivo because both restore the ability to utilize AdoMet or SMM to a yeast HMT mutant. However, AtHMT-1 is strongly inhibited by Met, whereas AtHMT-2 is not, a difference that could be crucial to the control of flux through the HMT reaction and the SMM cycle. Plant HMT is known to transfer the pro-R methyl group of SMM. This enabled us to use recombinant AtHMT-1 to establish that the other enzyme of the SMM cycle, AdoMet:Met S-methyltransferase, introduces the pro-S methyl group. These opposing stereoselectivities suggest a way to measure in vivo flux through the SMM cycle.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 221,
                "text": "AdoMet"
            }
        },
        {
            "context": "α-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 315,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 117,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Light-induced isomerization of the LHCII-bound xanthophyll neoxanthin: possible implications for photoprotection in plants. Light-harvesting pigment-protein complex of Photosystem II (LHCII) is the largest photosynthetic antenna complex of plants and the most abundant membrane protein in the biosphere. Plant fitness and productivity depend directly on a balance between excitations in the photosynthetic apparatus, generated by captured light quanta, and the rate of photochemical processes. Excess excitation energy leads to oxidative damage of the photosynthetic apparatus and entire organism and therefore the balance between the excitation density and photosynthesis requires precise and efficient regulation, operating also at the level of antenna complexes. We show that illumination of the isolated LHCII leads to isomerization of the protein-bound neoxanthin from conformation 9'-cis to 9',13- and 9',13'-dicis forms. At the same time light-driven excitation quenching is observed, manifested by a decrease in chlorophyll a fluorescence intensity and shortened fluorescence lifetimes. Both processes, the neoxanthin isomerization and the chlorophyll excitation quenching, are reversible in dim light. The results of the 77K florescence measurements of LHCII show that illumination is associated with appearance of the low-energy states, which can serve as energy traps in the pigment-protein complex subjected to excess excitation. Possible sequence of the molecular events is proposed, leading to a protective excess excitation energy quenching: neoxanthin photo-isomerization→formation of LHCII supramolecular structures which potentiate creation of energy traps→excitation quenching.",
            "question": "Which is the most abundant membrane protein on Earth?",
            "answers": {
                "answer_start": 184,
                "text": "LHCII"
            }
        },
        {
            "context": "A population-based post mortem study of sudden unexpected death in epilepsy. The aim of this study was to review population autopsy data on epilepsy-related deaths (ERD) in Queensland, Australia, to establish the incidence of autopsy-confirmed sudden unexpected death in epilepsy (SUDEP), explore factors associated with SUDEP, and determine if complete autopsy examinations of SUDEP were performed. All autopsy reports for a 5year period in Queensland were electronically searched for the terms 'epilepsy' or 'seizure'. The identified reports were reviewed, and data were extracted for all ERD. In the study period, 175 ERD were identified from autopsy records (123 SUDEP, 34 accident-related, 3 due to status epilepticus). From data available on the prevalence of epilepsy in Queensland (National Health Survey), the incidence of autopsy-confirmed SUDEP was 0.7 per 1000 person years (95% confidence interval 0.5-1.2 per 1000 person years). The factors associated with SUDEP were male sex (for those >18 years) and subtherapeutic anticonvulsant medication levels (found in 55%). Where recorded, the majority of deaths happened in the person's usual residence (90%), were overnight (70%) and unwitnessed (87%), with the person found prone (74%), in or adjacent to their bed (49%) and with signs of proximate seizure (60%). A complete autopsy was undertaken for only 59% of cases, the majority in urban locations. This study provides support for an unwitnessed overnight seizure being a key factor in autopsy-confirmed SUDEP in Queensland.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 244,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.",
            "question": "Which is the histone residue methylated by MLL1?",
            "answers": {
                "answer_start": 1576,
                "text": "H3K4"
            }
        },
        {
            "context": "Defining the sequence requirements for the positioning of base J in DNA using SMRT sequencing. Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. This highly restricted distribution must be co-determined by the thymidine hydroxylases (JBP1 and JBP2) that catalyze the initial step in J synthesis. To determine the DNA sequences recognized by JBP1/2, we used SMRT sequencing of DNA segments inserted into plasmids grown in Leishmania tarentolae. We show that SMRT sequencing recognizes base J in DNA. Leishmania DNA segments that normally contain J also picked up J when present in the plasmid, whereas control sequences did not. Even a segment of only 10 telomeric (GGGTTA) repeats was modified in the plasmid. We show that J modification usually occurs at pairs of Ts on opposite DNA strands, separated by 12 nucleotides. Modifications occur near G-rich sequences capable of forming G-quadruplexes and JBP2 is needed, as it does not occur in JBP2-null cells. We propose a model whereby de novo J insertion is mediated by JBP2. JBP1 then binds to J and hydroxylates another T 13 bp downstream (but not upstream) on the complementary strand, allowing JBP1 to maintain existing J following DNA replication.",
            "question": "Where is base J found in the genome of Leishmania tarentolae?",
            "answers": {
                "answer_start": 200,
                "text": "telomeric repeats"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 914,
                "text": "thyroid"
            }
        },
        {
            "context": "Heme and FLVCR-related transporter families SLC48 and SLC49. Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.",
            "question": "Which SLC family is FLVCR1 a member of?",
            "answers": {
                "answer_start": 265,
                "text": "SLC49"
            }
        },
        {
            "context": "Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. BACKGROUND: Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. METHODOLOGY/PRINCIPAL FINDINGS: The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. CONCLUSIONS/SIGNIFICANCE: The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 119,
                "text": "TYR"
            }
        },
        {
            "context": "[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1986,
                "text": "CD38"
            }
        },
        {
            "context": "The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 909,
                "text": "53BP1"
            }
        },
        {
            "context": "Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.",
            "question": "Which hormone abnormalities are common in Williams syndrome ?",
            "answers": {
                "answer_start": 437,
                "text": "thyroid"
            }
        },
        {
            "context": "RNAi-mediated knockdown of Xist can rescue the impaired postimplantation development of cloned mouse embryos. Cloning mammals by somatic cell nuclear transfer (SCNT) is highly inefficient. Most SCNT-generated embryos die after implantation because of unidentified, complex epigenetic errors in the process of postimplantation embryonic development. Here we identify the most upstream level of dysfunction leading to impaired development of clones by using RNAi against Xist, a gene responsible for X chromosome inactivation (XCI). A prior injection of Xist-specific siRNA into reconstructed oocytes efficiently corrected SCNT-specific aberrant Xist expression at the morula stage, but failed to do so thereafter at the blastocyst stage. However, we found that shortly after implantation, this aberrant XCI status in cloned embryos had been corrected autonomously in both embryonic and extraembryonic tissues, probably through a newly established XCI control for postimplantation embryos. Embryo transfer experiments revealed that siRNA-treated embryos showed 10 times higher survival than controls as early as embryonic day 5.5 and this high survival persisted until term, resulting in a remarkable improvement in cloning efficiency (12% vs. 1% in controls). Importantly, unlike control clones, these Xist-siRNA clones at birth showed only a limited dysregulation of their gene expression, indicating that correction of Xist expression in preimplantation embryos had a long-term effect on their postnatal normality. Thus, contrary to the general assumption, our results suggest that the fate of cloned embryos is determined almost exclusively before implantation by their XCI status. Furthermore, our strategy provides a promising breakthrough for mammalian SCNT cloning, because RNAi treatment of oocytes is readily applicable to most mammal species.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 469,
                "text": "Xist"
            }
        },
        {
            "context": "Inter-observer reproducibility of diagnosis of diabetic foot osteomyelitis based on a combination of probe-to-bone test and simple radiography. Probe-to-bone test and simple X-rays are both standard tests for the diagnosis of diabetic foot osteomyelitis. This study demonstrates the importance of considering jointly clinical information (probe-to-bone test) and diagnostic tests (simple radiography) to increase agreement among clinicians on diagnosis of diabetic foot osteomyelitis.",
            "question": "Which disease can be diagnosed with the \"probe to bone\" test?",
            "answers": {
                "answer_start": 226,
                "text": "diabetic foot osteomyelitis"
            }
        },
        {
            "context": "The physiological target for LeuRS translational quality control is norvaline. The fidelity of protein synthesis depends on the capacity of aminoacyl-tRNA synthetases (AARSs) to couple only cognate amino acid-tRNA pairs. If amino acid selectivity is compromised, fidelity can be ensured by an inherent AARS editing activity that hydrolyses mischarged tRNAs. Here, we show that the editing activity of Escherichia coli leucyl-tRNA synthetase (EcLeuRS) is not required to prevent incorrect isoleucine incorporation. Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline. This conclusion follows from a reassessment of the discriminatory power of LeuRS against isoleucine and the demonstration that a LeuRS editing-deficient E. coli strain grows normally in high concentrations of isoleucine but not under oxygen deprivation conditions when norvaline accumulates to substantial levels. Thus, AARS-based translational quality control is a key feature for bacterial adaptive response to oxygen deprivation. The non-essential role for editing under normal bacterial growth has important implications for the development of resistance to antimicrobial agents targeting the LeuRS editing site.",
            "question": "Which is the physiological target for LeuRS translational quality control?",
            "answers": {
                "answer_start": 688,
                "text": "norvaline"
            }
        },
        {
            "context": "[Myotonia dystrophica]. Dystrophic myotonia is a sufficiently rare disease inherited mainly by the autosomal dominant type. Clinical picture is characterized by the myotonic, myopathic, and endocrine-autonomic syndrome. A clinical, genetic, and electromyographic study was carried out to elucidate the problem of this condition inheritance, its intra- and interfamilial clinical polymorphism, and effects of environmental factors on its course and outcomes.",
            "question": "How is myotonic dystrophy inherited?",
            "answers": {
                "answer_start": 99,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "Glial versus melanocyte cell fate choice: Schwann cell precursors as a cellular origin of melanocytes. Melanocytes and Schwann cells are derived from the multipotent population of neural crest cells. Although both cell types were thought to be generated through completely distinct pathways and molecular processes, a recent study has revealed that these different cell types are intimately interconnected far beyond previously postulated limits in that they share a common post-neural crest progenitor, i.e. the Schwann cell precursor. This finding raises interesting questions about the lineage relationships of hitherto unrelated cell types such as melanocytes and Schwann cells, and may provide clinical insights into mechanisms of pigmentation disorders and for cancer involving Schwann cells and melanocytes.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 180,
                "text": "neural crest cells"
            }
        },
        {
            "context": "Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma. p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic DeltaNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. DeltaNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate DeltaNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73beta and its target genes. COX inhibitors also downregulate the alternative-spliced DeltaNp73(AS) isoforms, Deltaexon2 and Deltaexon2/3. Furthermore, forced expression of DeltaNp73(AS) results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of DeltaNp73(AS) is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 340,
                "text": "7"
            }
        },
        {
            "context": "Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Persistent pain represents a major health problem, and most current therapeutic approaches are associated with unwanted effects and unsatisfactory pain relief. Therefore, an urgent need exists to develop more effective drugs that are directed toward new molecular targets. Nerve growth factor (NGF) is involved in pain transduction mechanisms, playing a key role as a master switch in many chronic and inflammatory pain states; the NGF ligand and its receptor TrkA constitute well-validated targets for pain therapy. Tanezumab (RN-624), a first-in-class recombinant humanized mAb targeting NGF, is being developed by Pfizer Inc for the potential treatment of pain associated with several conditions. In preclinical studies, tanezumab, and its murine precursor muMab-911, effectively targeted the NGF pathway in various chronic and inflammatory pain models. Phase I and II clinical trials in osteoarthritic pain and chronic lower back pain demonstrated good efficacy for the compound, as well as a good safety and tolerability profile. Given that tanezumab is an antibody, the drug demonstrates the general advantages of this class of products (including good specificity and favorable pharmacokinetics), and also appears to be particularly well suited for targeting the chronic and inflammatory-mediating pain actions of NGF and its receptor system.",
            "question": "What is the target of tanezumab?",
            "answers": {
                "answer_start": 1433,
                "text": "NGF"
            }
        },
        {
            "context": "Paediatric investigation plans for pain: painfully slow! PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.",
            "question": "How many clinical trials for off-label drugs in neonates are cited in the literature.",
            "answers": {
                "answer_start": 470,
                "text": "0"
            }
        },
        {
            "context": "Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. X chromosome inactivation represents one of the most dramatic examples of mono-allelic gene expression and long-term gene-silencing in mammals. The key regulatory molecule that triggers silencing is the Xist transcript, but little is known about its repressive action. Some progress has been made in deciphering the epigenetics of the inactive state that it triggers, however. During pre-implantation development, the inactive state is relatively labile. Later on, in the soma, the inactive state is highly stable and clonally heritable. This is ensured by the panoply of epigenetic modifications that characterize the inactive X and, presumably, is also a result of its spatio-temporal segregation. The inactive X chromosome has been associated with an increasing number of histone modifications, and several recent studies have implicated Polycomb group proteins in laying down some of these marks. Thanks to genetic and biochemical approaches to analyse these proteins, the epigenetic tapestry of the inactive X is just beginning to be unravelled. Lineage-specific differences provide a glimpse into the developmental complexity of the epigenetic marks that ensure the inactive state.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 308,
                "text": "Xist"
            }
        },
        {
            "context": "Solitary fibrous tumor of the pleura with associated Doege-Potter syndrome. Doege-Potter syndrome is a paraneoplastic syndrome characterized by tumor-associated hypoglycemia secondary to a solitary fibrous tumor of the pleura. We present a case of an 84-year-old man, who presented with acute mental confusion and therapy-resistant hypoglycemia. Diagnostic imaging revealed a large sharply defined pleural tumor based on the left diaphragm, after surgical resection the diagnosis was made of a malignant solitary fibrous tumor of the pleura and restoration of the glucose homeostasis was observed.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 161,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1248,
                "text": "Nox1"
            }
        },
        {
            "context": "Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria. Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.",
            "question": "Centor criteria are used for which disease?",
            "answers": {
                "answer_start": 32,
                "text": "streptococcal pharyngitis"
            }
        },
        {
            "context": "Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 899,
                "text": "xa"
            }
        },
        {
            "context": "Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 287,
                "text": "HEXA"
            }
        },
        {
            "context": "MITF: a stream flowing for pigment cells. Microphthalmia-associated transcription factor (MITF) is a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLHZip) structure. Mutations of the MITF gene cause a variety of phenotypes, most notably in pigmented cells, in several species. In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome. Four isoforms have been cloned so far: MITF-M is the most abundant and is expressed in neural-crest-derived melanocytes; MITF-A is expressed in various cultured cells including retinal pigment epithelium (RPE) and enriched in RPE of embryonal and developing eyes; MITF-H are expressed in many types of cultured cells and in the heart tissue; MITF-C is expressed in many types of cultured cells, but not in melanocytes. Many growth factor signaling pathways have been implicated for regulation of MITF at both protein and promoter levels. Most notably, Steel factor/c-Kit signaling pathway was linked to phosphorylation of MITF at Ser73 and Ser409 through activation of MAP kinase and RSK-1, respectively. Phosphorylation of MITF is also conducted at Ser298 through GSK3beta, although the signaling pathway for this event still remains to be elucidated. IGF-1 and HGF/SF pathways may merge with the c-Kit signaling pathway. WNT and MSH signaling pathways regulate MITF positively at the promoter level. Endothelins may regulate MITF at the protein and promoter levels. MITF is involved in the differentiation, growth and survival of pigment cells, employing a number of signaling pathways.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 332,
                "text": "MITF"
            }
        },
        {
            "context": "In vivo regulation of precursor cells in the subventricular zone of adult rat brain by thyroid hormone and retinoids. The mature central nervous system contains precursor cells in the subventricular zone of the lateral ventricle. In this study we examined the possibility to affect fate of precursor cells through exogenous manipulations. The results indicate that administration of thyroid hormone and retinoic acid increases the expression of Ki67, a nuclear antigen associated with cell proliferation, and of nestin, a marker protein for precursor cells in the subventricular zone of adult male rats. Moreover, retinoic acid increases polysialated-neural cell adhesion molecules (PSA-NCAM)-immunoreactivity. These data suggest that nuclear receptor ligands are potential candidates for fate determination of precursor cells in the subventricular zone also in the adult brain.",
            "question": "Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?",
            "answers": {
                "answer_start": 512,
                "text": "nestin"
            }
        },
        {
            "context": "A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. X chromosome inactivation (XCI) depends on a noncoding sense-antisense transcript pair, Xist and Tsix. At the onset of XCI, Xist RNA accumulates on one of two Xs, coating and silencing the chromosome in cis. The molecular basis for monoallelic Xist upregulation is not known, though evidence predominantly supports a posttranscriptional mechanism through RNA stabilization. Here, we test whether Tsix RNA destabilizes Xist RNA. Unexpectedly, we find that Xist upregulation is not based on transcript stabilization at all but is instead controlled by transcription in a sex-specific manner. Tsix directly regulates its transcription. On the future inactive X, Tsix downregulation induces a transient heterochromatic state in Xist, followed paradoxically by high-level Xist expression. A Tsix-deficient X chromosome adopts the heterochromatic state in pre-XCI cells. This state persists through XCI establishment and \"reverts\" to a euchromatic state during XCI maintenance. We have therefore identified chromatin marks that preempt and predict asymmetric Xist expression.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 188,
                "text": "Xist"
            }
        },
        {
            "context": "Association of Mycoplasma hominis and Ureaplasma urealyticum with some indicators of nonspecific vaginitis. The purpose of this study was to determine the isolation rates of Mycoplasma hominis and Ureaplasma urealyticum from three populations of women and also to relate the presence of these microorganisms with some indicators of nonspecific vaginitis. Three hundred vaginal swabs were taken from delivery, pregnant and control (not pregnant) women. Cultures were done in E broth supplemented with arginine or urea. M. hominis was isolated in 5% at delivery, 12% from pregnant and 5% from control women and U. urealyticum was isolated in 21%, 31% and 28% respectively. There was statistical difference in the isolation rate of M. hominis in pregnant women respect to the other groups. Both microorganisms were more frequently isolated in women with acid vaginal pH, amine-like odor in KOH test, clue cells and leucorrhea. M. hominis was isolated in 17% and U. urealyticum in 52% from women with nonspecific vaginitis. M. hominis was isolated in 2% and U. urealyticum in 13% from women without nonspecific vaginitis. Although the presence of clue cells and amine-like odor in KOH test have relationship with Gardnerella vaginalis, these tests could also suggest the presence of these mycoplasmas.",
            "question": "Clue cells are characteristics to which causative bacteria of vaginitis?",
            "answers": {
                "answer_start": 1209,
                "text": "Gardnerella vaginalis"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 37,
                "text": "Xa"
            }
        },
        {
            "context": "Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. BACKGROUND: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. DESIGN AND METHODS: To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. CONCLUSIONS: Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 395,
                "text": "CD38"
            }
        },
        {
            "context": "Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 1115,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Remission in post-traumatic stress disorder (PTSD): effects of sertraline as assessed by the Davidson Trauma Scale, Clinical Global Impressions and the Clinician-Administered PTSD scale. Rates of remission were examined in two controlled 12-week studies of sertraline and placebo for post-traumatic stress disorder (PTSD). The performance of three scales was evaluated: the self-rated Davidson Trauma Scale (DTS), and two interviewer scales: the Clinician Administered PTSD Scale (CAPS) and Clinical Global Impressions (CGI). Sertraline proved significantly superior to placebo with respect to remission on all three ratings. Rates of remission were very similar for all scales, ranging from 23.1-26.3% for sertraline and 13.9-14.9% for placebo. Traditional thresholds for the CAPS and DTS were tested relative to the CGI and to each other. The CAPS and DTS thresholds of < 20 and < 18 were found to be valid.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 175,
                "text": "PTSD"
            }
        },
        {
            "context": "Onyx 18 embolisation of dural arteriovenous fistula via arterial and venous pathways: preliminary experience and evaluation of the short-term outcomes. OBJECTIVE: This paper mainly focuses on our preliminary experience and short-term outcome evaluation of embolisation of non-cavernous dural arteriovenous fistulas (ncsDAVFs) and cavernous sinus dural arteriovenous fistulas (csDAVFs) using Onyx 18 (ev3, Plymouth, MN), and in combination with coils, via arterial and venous approaches, respectively. METHODS: Between August 2008 and March 2010, 21 DAVFs (11 ncsDAVFs and 10 csDAVFs; age range: 28-68 years; 12 females and 9 males) were undertaken. Borden classification showed Type III in 1 and Type II in 10 ncsDAVFs, and Type II in 4 and Type I in 6 csDAVFs. Onyx 18 was used in 11 ncsDAVFs (10 via single feeder and 1 via 2 feeders). Onyx 18 or in combination with coils was used in 10 csDAVFs (9 via the inferior petrosal sinus and 1 via the superior ophthalmic vein). RESULTS: Total occlusion in immediate angiography was achieved in 18 cases (85.7%; 10 ncsDAVFs and 8 csDAVFs), and near-total occlusion in 1 ncsDAVF and 2 csDAVFs. Onyx 18 was migrated into normal vasculature in two ncsDAVFs without any sequelae. One csDAVF had VI cranial nerve palsy post-operatively, which completely recovered 2 weeks post-embolisation. Follow-up angiography at 3-12 months showed complete occlusion in 20 cases (95.2%; 10 ncsDAVFs and 10 csDAVFs). One ncsDAVF (4.8%) recurred after 3 months and was successfully re-embolised. CONCLUSION: Preliminary results achieved after embolising 11 ncsDAVFs and 10 csDAVFs using Onyx 18 and in combination with coils via arterial and venous pathways, respectively, appeared to be safe, feasible and effective, as 95.2% of cases were totally occluded without any clinical sequelae.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 713,
                "text": "DAVF"
            }
        },
        {
            "context": "Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 147,
                "text": "connective tissue"
            }
        },
        {
            "context": "Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms \"anticoagulants\", \"blood coagulation inhibitors\", \"anticoagulants and venous thromboembolism\", \"anticoagulants and atrial fibrillation\", and \"'antithrombins.\" Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 511,
                "text": "xa"
            }
        },
        {
            "context": "Lucinactant for the prevention of respiratory distress syndrome in premature infants. Respiratory distress syndrome (RDS) is the leading cause of neonatal morbidity and mortality in premature infants. It is caused by surfactant deficiency and lung immaturity. Lucinactant is a synthetic surfactant containing sinapultide, a bioengineered peptide mimic of surfactant-associated protein B. A meta-analysis of clinical trials demonstrates that lucinactant is as effective as animal-derived surfactants in preventing RDS in premature neonates, and in vitro studies suggest it is more resistant to oxidative and protein-induced inactivation. Its synthetic origin confers lower infection and inflammation risks as well other potential benefits, which may make lucinactant an advantageous alternative to its animal-derived counterparts, which are presently the standard treatment for RDS.",
            "question": "Which disease is treated with lucinactant?",
            "answers": {
                "answer_start": 34,
                "text": "respiratory distress syndrome"
            }
        },
        {
            "context": "Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension. BACKGROUND: Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown. METHODS AND RESULTS: Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly upregulated in small remodeled pulmonary arteries and isolated distal PAVSMCs from subjects with idiopathic PAH that have increased ATP levels, proliferation, and survival that depend on glycolytic metabolism. Small interfering RNA- and pharmacology-based analysis showed that although both mTORC1 and mTORC2 contribute to proliferation, only mTORC2 is required for ATP generation and survival of idiopathic PAH PAVSMCs. mTORC2 downregulated the energy sensor AMP-activated protein kinase, which led to activation of mTORC1-S6 and increased proliferation, as well as a deficiency of the proapoptotic protein Bim and idiopathic PAH PAVSMC survival. NADPH oxidase 4 (Nox4) protein levels were increased in idiopathic PAH PAVSMCs, which was necessary for mTORC2 activation, proliferation, and survival. Nox4 levels and mTORC2 signaling were significantly upregulated in small pulmonary arteries from hypoxia-exposed rats at days 2 to 28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15 to 28 suppressed mTORC2 but not Nox4, induced smooth muscle-specific apoptosis in small pulmonary arteries, and reversed hypoxia-induced pulmonary vascular remodeling in rats. CONCLUSIONS: These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via the energy sensor AMP-activated protein kinase to increased proliferation and survival of PAVSMCs in PAH, which suggests a new potential pathway for therapeutic interventions.",
            "question": "What does mTOR stands for?",
            "answers": {
                "answer_start": 478,
                "text": "mammalian target of rapamycin"
            }
        },
        {
            "context": "Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, is under-expressed in Down syndrome fetal brains. Suppression subtractive hybridization performed on Down syndrome (DS) versus control fetal brains revealed differential expression of peroxiredoxin 2 (PRDX2), mapped at 13q12. Peroxiredoxins are antioxidant enzymes involved in protein and lipid protection against oxidative injury and in cellular signalling pathways regulating apoptosis. The under-expression of PRDX2 observed in DS samples was confirmed by real-time PCR (0.73-fold). To test whether decreased expression is associated with enhanced sensitivity of DS neurons to reactive oxygen species, we down-regulated PRDX2 through stable transfections of SH-SY5Y neuroblastoma cells with antisense contructs of the complete PRDX2 coding sequence. In addition, we over-expressed SOD1 and compared the effects of the two genes on cell viability. Cells transfected with either construct showed similar sensitivity to oxidative stress in addition to increased apoptosis under basal conditions and after treatment with oxidative cytotoxic agents. This suggests that the decreased expression of PRDX2 may contribute to the altered redox state in DS at levels comparable to that of the increased expression of SOD1.",
            "question": "What type of enzyme is peroxiredoxin 2 (PRDX2)?",
            "answers": {
                "answer_start": 293,
                "text": "antioxidant"
            }
        },
        {
            "context": "Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 1878,
                "text": "positive"
            }
        },
        {
            "context": "Natural RNA circles function as efficient microRNA sponges. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.",
            "question": "Which miRNA is targeted by SRY/Sox9?",
            "answers": {
                "answer_start": 1259,
                "text": "miR-138"
            }
        },
        {
            "context": "Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease. Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 114,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.",
            "question": "Which peptide plays a pivotal role in human cystatin C fibrillization?",
            "answers": {
                "answer_start": 767,
                "text": "LQVVR"
            }
        },
        {
            "context": "Patients harboring EGFR mutation after primary resistance to crizotinib and response to EGFR-tyrosine kinase inhibitor. Anaplastic lymphoma kinase (ALK) rearrangement lung cancer responds to ALK tyrosine kinase inhibitors. It is known that many cases ultimately acquired resistance to crizotinib. However, a case of primary resistance is rare. We present a case of harboring exon 19 deletion in epidermal growth factor receptor in ALK rearranged lung adenocarcinoma, who experienced a partial tumor response to icotinib after failure with crizotinib therapy and chemotherapy. Considering the partial response, we conclude that it is important to find the cause of resistance to crizotinib. We detected gene mutations with plasma by the next-generation sequencing; the next-generation sequencing demonstrates an attractive system to identify mutations improving the outcome of patients with a deadly disease.",
            "question": "What disease is the ALK tyrosine kinase associated with?",
            "answers": {
                "answer_start": 172,
                "text": "cancer"
            }
        },
        {
            "context": "Assembly characteristics of plant keratin intermediate filamentsin vitro. After selective extraction and purification, plant keratin intermediate filaments were reassembledin vitro. Scanning tunneling microscope (STM) and transmission electron microscope (TEM) micrographs showed that acidic keratins and basic keratins can assemble into dimers and further into 10 nm filamentsin vitro. In higher mcation images, it can be seen that fully assembled plant keratin intermediate filaments consist of several thinner filaments of 3 nm in diameter, which indicates the formation of protofilaments in the assembly processes. One of the explicit features of plant keratin intermediate filaments is a 24-25 nm periodic structural repeat alone the axis of both the 10 nm filaments and protofilarnents. The periodic repeat is one of the fundamental characteristic of all intermediate filaments, and demonstrates the half staggered arrangement of keratin molecules within the filaments.",
            "question": "What is the average diameter of intermediate filaments?",
            "answers": {
                "answer_start": 362,
                "text": "10 nm"
            }
        },
        {
            "context": "PU.1 positively regulates GATA-1 expression in mast cells. Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1(-/-) fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages.",
            "question": "Which gene controls the expression of GATA-1 isoforms?",
            "answers": {
                "answer_start": 309,
                "text": "PU.1"
            }
        },
        {
            "context": "Inhibition of acid secretion in gastric parietal cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-93. A novel Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) inhibitor, KN-93 potently inhibits gastric acid secretion from parietal cells. As previously reported (1), treatment of parietal cells with a selective inhibitor of CaM kinase II, KN-62 resulted in the inhibition of cholinergic-stimulated rabbit parietal cell secretion, whereas it failed to inhibit the histamine and forskolin response. In contrast effects of carbachol, histamine and forskolin were significantly inhibited by KN-93 with an IC50 of 0.15, 0.3 and 1 microM, respectively; these effects occurred without any changes in intracellular cyclic AMP and Ca2+ levels. In the present study we investigated the mechanism by which KN-93 acts upon the acid-secreting machinery of gastric parietal cells. Neither redistribution of the proton pump activity nor the morphological transformation were affected by KN-93. The drug only weakly inhibited the H+, K(+)-ATPase activity but strongly dissipated the proton gradient formed in the gastric membrane vesicles and reduced the volume of luminal space. Thus KN-93 acts at pH gradient formation whereas KN-62 acts only at CaM Kinase II.",
            "question": "Which kinase is inhibited by the small molecule KN-93?",
            "answers": {
                "answer_start": 176,
                "text": "CaM Kinase II"
            }
        },
        {
            "context": "Light-harvesting complex II (LHCII) and its supramolecular organization in Chlamydomonas reinhardtii. LHCII is the most abundant membrane protein on earth. It participates in the first steps of photosynthesis by harvesting sunlight and transferring excitation energy to the core complex. Here we have analyzed the LHCII complex of the green alga Chlamydomonas reinhardtii and its association with the core of Photosystem II (PSII) to form multiprotein complexes. Several PSII supercomplexes with different antenna sizes have been purified, the largest of which contains three LHCII trimers (named S, M and N) per monomeric core. A projection map at a 13Å resolution was obtained allowing the reconstruction of the 3D structure of the supercomplex. The position and orientation of the S trimer are the same as in plants; trimer M is rotated by 45° and the additional trimer (named here as LHCII-N), which is taking the position occupied in plants by CP24, is directly associated with the core. The analysis of supercomplexes with different antenna sizes suggests that LhcbM1, LhcbM2/7 and LhcbM3 are the major components of the trimers in the PSII supercomplex, while LhcbM5 is part of the \"extra\" LHCII pool not directly associated with the supercomplex. It is also shown that Chlamydomonas LHCII has a slightly lower Chlorophyll a/b ratio than the complex from plants and a blue shifted absorption spectrum. Finally the data indicate that there are at least six LHCII trimers per dimeric core in the thylakoid membranes, meaning that the antenna size of PSII of C. reinhardtii is larger than that of plants.",
            "question": "Which is the most abundant membrane protein on Earth?",
            "answers": {
                "answer_start": 102,
                "text": "LHCII"
            }
        },
        {
            "context": "Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 960,
                "text": "xa"
            }
        },
        {
            "context": "Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. PURPOSE: To develop polymeric films containing dual combinations of anti-HIV drug candidate tenofovir, maraviroc and dapivirine for vaginal application as topical microbicides. METHODS: A solvent casting method was used to manufacture the films. Solid phase solubility was used to identify potential polymers for use in the film formulation. Physical and chemical properties (such as water content, puncture strength and in vitro release) and product stability were determined. The bioactivity of the film products against HIV was assessed using the TZM-bl assay and a cervical explant model. RESULTS: Polymers identified from the solid phase solubility study maintained tenofovir and maraviroc in an amorphous state and prevented drug crystallization. Three combination film products were developed using cellulose polymers and polyvinyl alcohol. The residual water content in all films was <10% (w/w). All films delivered the active agents with release of >50% of film drug content within 30 min. Stability testing confirmed that the combination film products were stable for 12 months at ambient temperature and 6 months under stressed conditions. Antiviral activity was confirmed in TZM-bl and cervical explant models. CONCLUSIONS: Polymeric films can be used as a stable dosage form for the delivery of antiretroviral combinations as microbicides.",
            "question": "Which infection can be prevented with Dapivirine?",
            "answers": {
                "answer_start": 195,
                "text": "HIV"
            }
        },
        {
            "context": "X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 52,
                "text": "Slc9a6"
            }
        },
        {
            "context": "High frequency oscillations mirror disease activity in patients with focal cortical dysplasia. PURPOSE: The study analyzes the occurrence of high frequency oscillations in different types of focal cortical dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. METHODS: High frequency oscillations (80-450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal cortical dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b. KEY FINDINGS: Patients with focal cortical dysplasia type 2 had significantly more seizures than those with type 1 (p < 0.001). Rates of high frequency oscillations were significantly higher in patients with focal cortical dysplasia type 2 versus type 1 (p < 0.001). In addition, it could be confirmed that rates of high frequency oscillations were significantly higher in presumed epileptogenic areas than outside (p < 0.001). SIGNIFICANCE: Activity of high frequency oscillations mirrors the higher epileptogenicity of focal cortical dysplasia type 2 lesions compared to type 1 lesions. Therefore, rates of high frequency oscillations can reflect disease activity of a lesion. This has implications for the use of high frequency oscillations as biomarkers for epileptogenic areas, because a detailed analysis of their rates may be necessary to use high frequency oscillations as a predictive tool in epilepsy surgery.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 765,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Mutational analysis of the U12-dependent branch site consensus sequence. Highly conserved sequences at the 5' splice site and branch site of U12-dependent introns are important determinants for splicing by U12-dependent spliceosomes. This study investigates the in vivo splicing phenotypes of mutations in the branch site consensus sequence of the U12-dependent intron F from a human NOL1 (P120) minigene. Intron F contains a fully consensus branch site sequence (UUCCUUAAC). Mutations at each position were analyzed for their effects on U12-dependent splicing in vivo. Mutations at most positions resulted in a significant reduction of correct U12-dependent splicing. Defects observed included increased unspliced RNA levels, the activation of cryptic U2-dependent 5' and 3' splice sites, and the activation of cryptic U12-dependent branch/3' splice sites. A strong correlation was observed between the predicted thermodynamic stability of the branch site: U12 snRNA interaction and correct U12-dependent splicing. The lack of a polypyrimidine tract between the branch site and 3' splice site of U12-dependent introns and the observed reliance on base-pairing interactions for correct U12-dependent splicing emphasize the importance of RNA/RNA interactions during U12-dependent intron recognition and proper splice site selection.",
            "question": "Which is the branch site consensus sequence in U12-dependent introns?",
            "answers": {
                "answer_start": 464,
                "text": "UUCCUUAAC"
            }
        },
        {
            "context": "[Imatinib therapy for patients with chronic myelogenous leukemia]. Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 261,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "The S-methylmethionine cycle in angiosperms: ubiquity, antiquity and activity. Angiosperms synthesize S-methylmethionine (SMM) from methionine (Met) and S-adenosylmethionine (AdoMet) in a unique reaction catalyzed by Met S-methyltransferase (MMT). SMM serves as methyl donor for Met synthesis from homocysteine, catalyzed by homocysteine S-methyltransferase (HMT). MMT and HMT together have been proposed to constitute a futile SMM cycle that stops the free Met pool from being depleted by an overshoot in AdoMet synthesis. Arabidopsis and maize have one MMT gene, and at least three HMT genes that belong to two anciently diverged classes and encode enzymes with distinct properties and expression patterns. SMM, and presumably its cycle, must therefore have originated before dicot and monocot lineages separated. Arabidopsis leaves, roots and developing seeds all express MMT and HMTs, and can metabolize [35S]Met to [35S]SMM and vice versa. The SMM cycle therefore operates throughout the plant. This appears to be a general feature of angiosperms, as digital gene expression profiles show that MMT and HMT are co-expressed in leaves, roots and reproductive tissues of maize and other species. An in silico model of the SMM cycle in mature Arabidopsis leaves was developed from radiotracer kinetic measurements and pool size data. This model indicates that the SMM cycle consumes half the AdoMet produced, and suggests that the cycle serves to stop accumulation of AdoMet, rather than to prevent depletion of free Met. Because plants lack the negative feedback loops that regulate AdoMet pool size in other eukaryotes, the SMM cycle may be the main mechanism whereby plants achieve short-term control of AdoMet level.",
            "question": "Which is the methyl donor of histone methyltransferases?",
            "answers": {
                "answer_start": 153,
                "text": "S-adenosylmethionine"
            }
        },
        {
            "context": "Dimerization of DNA methyltransferase 1 is mediated by its regulatory domain. DNA methylation is a major epigenetic modification and plays a crucial role in the regulation of gene expression. Within the family of DNA methyltransferases (Dnmts), Dnmt3a and 3b establish methylation marks during early development, while Dnmt1 maintains methylation patterns after DNA replication. The maintenance function of Dnmt1 is regulated by its large regulatory N-terminal domain that interacts with other chromatin factors and is essential for the recognition of hemi-methylated DNA. Gelfiltration analysis showed that purified Dnmt1 elutes at an apparent molecular weight corresponding to the size of a dimer. With protein interaction assays we could show that Dnmt1 interacts with itself through its N-terminal regulatory domain. By deletion analysis and co-immunoprecipitations we mapped the dimerization domain to the targeting sequence TS that is located in the center of the N-terminal domain (amino acids 310-629) and was previously shown to mediate replication independent association with heterochromatin at chromocenters. Further mutational analyses suggested that the dimeric complex has a bipartite interaction interface and is formed in a head-to-head orientation. Dnmt1 dimer formation could facilitate the discrimination of hemi-methylated target sites as has been found for other palindromic DNA sequence recognizing enzymes. These results assign an additional function to the TS domain and raise the interesting question how these functions are spatially and temporarily co-ordinated.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 407,
                "text": "Dnmt1"
            }
        },
        {
            "context": "A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. The structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity at concentrations several hundredfold lower than cyclosporin A (CsA). Cyclosporin A, a cyclic peptide, has found widespread clinical use in the prevention of graft rejection following bone marrow and organ transplantation. The mechanisms of immunosuppression mediated by FK506 and CsA appear to be remarkably similar, suggesting that these unrelated structures act on a common receptor or on similar molecular targets, perhaps the CsA receptor, cyclophilin, which has recently been shown by Fischer et al. and Takahashi et al. to have cis-trans peptidyl-prolyl isomerase activity. We have prepared an FK506 affinity matrix and purified a binding protein for FK506 from bovine thymus and from human spleen. This FK506-binding protein (FKBP) has a relative molecular mass (Mr) of approximately 14,000(14K), a pI of 8.8-8.9, and does not cross-react with antisera against cyclophilin. The first 40 N-terminal residues of the bovine and 16 residues of the human FKBP were determined; the 16-residue fragments are identical to each other and unrelated to any known sequences. This protein catalyses the cis-trans isomerization of the proline amide in a tetrapeptide substrate and FK506 inhibits the action of this new isomerase. The FKBP and cyclophilin appear to be members of an emerging class of novel proteins that regulate T cell activation and other metabolic processes, perhaps by the recognition (and possibly the isomerization) of proline-containing epitopes in target proteins.",
            "question": "Which is the receptor for the immunosuppressive drug cyclosporin A (CsA)?",
            "answers": {
                "answer_start": 653,
                "text": "cyclophilin"
            }
        },
        {
            "context": "Signals from the lysosome: a control centre for cellular clearance and energy metabolism. For a long time, lysosomes were considered merely to be cellular 'incinerators' involved in the degradation and recycling of cellular waste. However, now there is compelling evidence indicating that lysosomes have a much broader function and that they are involved in fundamental processes such as secretion, plasma membrane repair, signalling and energy metabolism. Furthermore, the essential role of lysosomes in autophagic pathways puts these organelles at the crossroads of several cellular processes, with significant implications for health and disease. The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 692,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "The role of ultrasound-guided triamcinolone injection in the treatment of de Quervain's disease: treatment and a diagnostic tool? The purpose of this study was to describe the technique and usefulness of ultrasound-guided intrasheath injection of triamcinolone in the treatment of de Quervain's disease (dQD). Our study was retrospective in design. Seventy-one wrists of 62 patients who were treated with an ultrasound-guided triamcinolone injection for dQD were included. A literature search was performed to compare our results. In the literature we found supportive evidence that accurate injection of triamcinolone in the first dorsal compartment of the wrist is important for a good outcome. In this retrospective study we found that treatment with ultrasound-guided injections of triamcinolone is both safe and effective. After two injections, 91% of the patients had good long-term results, which is a higher cure rate than found in most other studies. Furthermore, we found that Finkelstein's test can give a false positive result. Therefore, ultrasound should not only be considered to improve the treatment outcome, but can also be useful as a diagnostic tool in the management of de Quervain's disease.",
            "question": "Which disease is diagnosed using the Finkelstein's test?",
            "answers": {
                "answer_start": 1191,
                "text": "de Quervain's disease"
            }
        },
        {
            "context": "CLAST: CUDA implemented large-scale alignment search tool. BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies.",
            "question": "How many times is CLAST faster than BLAST?",
            "answers": {
                "answer_start": 1036,
                "text": "80.8"
            }
        },
        {
            "context": "alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse \"cloud-like\" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 0,
                "text": "alpha-Synuclein"
            }
        },
        {
            "context": "Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence. Patient adherence to many osteoporosis treatments, primarily bisphosphonates, is generally poor, thus leading to a significant reduction in antifracture efficacy. Patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence, in addition to other factors, such as difficult dosing regimens and high dosing frequency. Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. It is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis. Preference and adherence to Dmab treatment were assessed in various clinical trials. Although with some limitations, available data suggest that Dmab is preferred to bisphosphonates, produces greater satisfaction than bisphosphonates, and would be preferentially chosen for long-term treatment. Moreover, patient perceptions about the necessity of Dmab treatment clearly outweigh the concerns about the injections, and positive beliefs about treatment positively influence medication-taking behavior. According to these data, Dmab may represent a reasonable alternative to bisphosphonates, particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected.",
            "question": "Which is the target of the drug Denosumab?",
            "answers": {
                "answer_start": 729,
                "text": "RANKL"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica (Bazex syndrome) with oropharyngeal squamous cell carcinoma. A 65-year-old white man presented with all the clinical features of acrokeratosis paraneoplastica of Bazex, characterized by violaceous erythema and scaling of the nose, aural helices, fingers, and toes, with keratoderma and severe nail dystrophy. Examination of the patient for possible associated malignancy disclosed an asymptomatic squamous cell carcinoma at the oropharyngeal region. The skin lesions resolved almost completely following radiation therapy of the neoplasm, but the onychodystrophy persisted. This case report illustrates the importance of early recognition of Bazex syndrome.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 31,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 757,
                "text": "CD38"
            }
        },
        {
            "context": "Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 854,
                "text": "L-dopa"
            }
        },
        {
            "context": "A mitotic topoisomerase II checkpoint in budding yeast is required for genome stability but acts independently of Pds1/securin. Topoisomerase II (Topo II) performs topological modifications on double-stranded DNA molecules that are essential for chromosome condensation, resolution, and segregation. In mammals, G2 and metaphase cell cycle delays induced by Topo II poisons have been proposed to be the result of checkpoint activation in response to the catenation state of DNA. However, the apparent lack of such controls in model organisms has excluded genetic proof that Topo II checkpoints exist and are separable from the conventional DNA damage checkpoint controls. But here, we define a Topo II-dependent G2/M checkpoint in a genetically amenable eukaryote, budding yeast, and demonstrate that this checkpoint enhances cell survival. Conversely, a lack of the checkpoint results in aneuploidy. Neither DNA damage-responsive pathways nor Pds1/securin are needed for this checkpoint. Unusually, spindle assembly checkpoint components are required for the Topo II checkpoint, but checkpoint activation is not the result of failed chromosome biorientation or a lack of spindle tension. Thus, compromised Topo II function activates a yeast checkpoint system that operates by a novel mechanism.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 146,
                "text": "Topo II"
            }
        },
        {
            "context": "Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Recent reports have described a distinct and recurrent pattern of systemic malformation that associates craniosynostosis and neurodevelopmental abnormalities with many clinical features of the Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular microfibril caused by defects in the gene encoding fibrillin-1, FBN1 (ref. 8). Additional common findings include other craniofacial anomalies, hypotonia, obstructive apnea, foot deformity, and congenital weakness of the abdominal wall. So far, only 11 cases have been reported precluding the assignment of definitive diagnostic criteria. While it remains unclear whether these cases represent a discrete clinical entity with a single aetiology, they have been pragmatically grouped under the rubric Marfanoid-craniosynostosis or Shprintzen-Goldberg syndrome (SGS). Because of the significant clinical overlap between MFS and SGS, we proposed that they may be caused by allelic mutations. We now report two SGS patients who harbour mutations in FBN1. While it remains unclear whether these mutations are sufficient for the clinical expression of the entire SGS phenotype, these data suggest a role for fibrillin-1 in early craniofacial and central nervous system development. Our recent observation that FBN1 transcript is expressed as early as the 8-cell stage of human embryogenesis is consistent with this hypothesis.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 42,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA). Daratumumab is a fully human anti-CD38 IgG1-κ monoclonal antibody (mAb) currently being evaluated in several Phase 2 and 3 clinical studies for the treatment of multiple myeloma (MM). In this clinical case study we demonstrate that daratumumab can be detected as an individual monoclonal band in serum immunofixation electrophoresis (IFE). M-protein follow-up by IFE is part of the International Myeloma Working Group (IMWG) criteria to assess treatment response. Therefore, it is crucial that the daratumumab band is not confused with the endogenous M-protein of the patient during IFE interpretation. Moreover, a significant number of IgG-κ M-proteins co-migrate with daratumumab. Co-migration introduces a bias in the M-protein quantification since pharmacokinetic studies show that daratumumab peak plasma concentrations reach up to 1 g/L. More importantly, co-migration can mask clearance of the M-protein by IFE which is necessary for classification of complete response by IMWG criteria (negative serum IFE). For optimal M-protein monitoring the laboratory specialist needs to be informed when patients receive daratumumab, and it is essential that the laboratory specialist is aware that a slow migrating band in the γ-region in those patients may be derived from the daratumumab. A daratumumab specific IFE reflex assay (DIRA) has been developed and can be utilized to abrogate interference. The here described mAb interference is not limited to daratumumab, and as therapeutic antibodies gain approval and enter into common clinical practice, laboratory specialists will need additional processes to characterize IFE interference and distinguish endogenous M-protein from therapeutic antibodies.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 209,
                "text": "CD38"
            }
        },
        {
            "context": "New anticoagulants for atrial fibrillation. Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 618,
                "text": "xa"
            }
        },
        {
            "context": "Psychiatric disorders in Ehlers-Danlos syndrome are frequent, diverse and strongly associated with pain. Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 175,
                "text": "connective tissue"
            }
        },
        {
            "context": "Molecular Detection of Persistent Francisella tularensis Subspecies holarctica in Natural Waters. Tularemia, caused by the bacterium Francisella tularensis, where F. tularensis subspecies holarctica has long been the cause of endemic disease in parts of northern Sweden. Despite this, our understanding of the natural life-cycle of the organism is still limited. During three years, we collected surface water samples (n = 341) and sediment samples (n = 245) in two areas in Sweden with endemic tularemia. Real-time PCR screening demonstrated the presence of F. tularenis lpnA sequences in 108 (32%) and 48 (20%) of the samples, respectively. The 16S rRNA sequences from those samples all grouped to the species F. tularensis. Analysis of the FtM19InDel region of lpnA-positive samples from selected sampling points confirmed the presence of F. tularensis subspecies holarctica-specific sequences. These sequences were detected in water sampled during both outbreak and nonoutbreak years. Our results indicate that diverse F. tularensis-like organisms, including F. tularensis subsp. holarctica, persist in natural waters and sediments in the investigated areas with endemic tularemia.",
            "question": "What organism causes tularemia?",
            "answers": {
                "answer_start": 133,
                "text": "Francisella tularensis"
            }
        },
        {
            "context": "Treating patients with ALK-rearranged non-small-cell lung cancer: mechanisms of resistance and strategies to overcome it. Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3-7% of patients with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was approved in 2011 for the treatment of ALK-positive lung cancer. Despite the initial enthusiasm, most of the patients develop resistance within the first year of treatment. The main mechanisms are secondary mutations and bypass track activation. Moreover, crizotinib has low penetration into the central nervous system. The need to overcome these limitations has led to the development of second-generation inhibitors that have better effectiveness against crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are the only approved drugs of this group. Many ongoing trials try to define the most appropriate agent for the treatment of ALK-positive lung cancer depending on the responsible mechanism. This review focuses on the current data regarding the potential mechanisms of resistance to ALK inhibitors and the strategies to overcome it.",
            "question": "Which disorder has been approved for treatment with Alk inhibitors?",
            "answers": {
                "answer_start": 314,
                "text": "ALK-positive lung cancer"
            }
        },
        {
            "context": "Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensory-motor neurological disorder with a circadian component. RLS is characterized by uncomfortable sensations in the extremities, generally at night or during sleep, which often leads to an uncontrollable urge to move them for relief. Recently, genomic studies identified single-nucleotide polymorphisms in BTBD9, along with three other genes, as being associated with a higher risk of RLS. Little is known about the function of BTBD9 or its potential role in the pathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we recently generated for phenotypes similar to symptoms found in RLS patients. We observed that the Btbd9 mutant mice had motor restlessness, sensory alterations likely limited to the rest phase, and decreased sleep and increased wake times during the rest phase. Additionally, the Btbd9 mutant mice had altered serum iron levels and monoamine neurotransmitter systems. Furthermore, the sensory alterations in the Btbd9 mutant mice were relieved using ropinirole, a dopaminergic agonist widely used for RLS treatment. These results, taken together, suggest that the Btbd9 mutant mice model several characteristics similar to RLS and would therefore be the first genotypic mouse model of RLS. Furthermore, our data provide further evidence that BTBD9 is involved in RLS, and future studies of the Btbd9 mutant mice will help shine light on its role in the pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 mutant mice to discover and screen novel therapeutics for RLS.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 121,
                "text": "Restless legs syndrome"
            }
        },
        {
            "context": "Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. BACKGROUND AND OBJECTIVES: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone. METHODS: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose. RESULTS: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments. CONCLUSION: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.",
            "question": "What enzyme is inhibied by Opicapone?",
            "answers": {
                "answer_start": 176,
                "text": "catechol-O-methyltransferase"
            }
        },
        {
            "context": "Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.",
            "question": "Which enzyme is inhibited by ribociclib?",
            "answers": {
                "answer_start": 1002,
                "text": "CDK4/6"
            }
        },
        {
            "context": "Treatment-refractory schizoaffective disorder in a patient with dyke-davidoff-masson syndrome. Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. Psychiatric symptoms are rarely reported. We report the first case of left cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective disorder after a stressful life event. The patient finally responded well to clozapine. The clinical history and results from structural neuroimaging are highlighted to discuss the possible developmental bias for psychotic disorders.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 129,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons. The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. We have compared the chromosomal mobilization efficiency and insertion site preference of the two transposons mobilized from the same donor site in mouse embryonic stem (ES) cells under conditions in which there were no selective constraints on the transposons' insertion sites. Compared with Sleeping Beauty, PiggyBac exhibits higher transposition efficiencies, no evidence for local hopping and a significant bias toward reintegration in intragenic regions, which demonstrate its utility for insertional mutagenesis. Although Sleeping Beauty had no detectable genomic bias with respect to insertions in genes or intergenic regions, both Sleeping Beauty and PiggyBac transposons displayed preferential integration into actively transcribed loci.",
            "question": "Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency?",
            "answers": {
                "answer_start": 521,
                "text": "PiggyBac"
            }
        },
        {
            "context": "The epigenetic basis for the aberrant expression of kallikreins in human cancers. The tissue kallikrein gene family consists of 15 genes tandemly arranged on human chromosome 19q13.4. Most kallikrein genes are characterized by aberrant expression patterns in various human cancers, a feature that makes them ideal cancer biomarkers. In the present study, we investigated the effect of the epigenetic drug compound 5-aza-2'-deoxycytidine on the expression of downregulated kallikrein genes in prostate, breast, and ovarian cancer cell lines. Reactivation of multiple kallikrein genes was observed, although some of these genes do not contain CpG islands in their genomic sequence. Epigenetic regulation provides a new mechanism for the pharmacological modulation of kallikreins in human cancers with putative therapeutic implications.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 128,
                "text": "15"
            }
        },
        {
            "context": "New and established tyrosine kinase inhibitors for chronic myeloid leukemia. Chronic myeloid leukemia (CML) is an uncommon malignancy, the treatment and prognosis of which have dramatically shifted over the last decade. Characterized by a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, small-molecule tyrosine kinase inhibitors (TKIs) targeted against the oncogenic BCR-ABL fusion protein have changed this once fatal disease into the model of targeted therapy. This article will review the pharmacological and clinical data supporting the use of imatinib and the second-generation TKIs dasatinib and nilotinib, and the novel TKIs bosutinib and ponatinib.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 401,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Daratumumab granted breakthrough drug status. Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 586,
                "text": "CD38"
            }
        },
        {
            "context": "A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 68,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Seipin promotes adipose tissue fat storage through the ER Ca²⁺-ATPase SERCA. Adipose tissue is central to the regulation of lipid metabolism. Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), one of the most severe lipodystrophy diseases, is caused by mutation of the Seipin gene. Seipin plays an important role in adipocyte differentiation and lipid homeostasis, but its exact molecular functions are still unknown. Here, we show that Seipin physically interacts with the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in both Drosophila and man. SERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen. Like dSeipin, dSERCA cell-autonomously promotes lipid storage in Drosophila fat cells. dSeipin affects dSERCA activity and modulates intracellular calcium homeostasis. Adipose tissue-specific knockdown of the ER-to-cytosol calcium release channel ryanodine receptor (RyR) partially restores fat storage in dSeipin mutants. Our results reveal that Seipin promotes adipose tissue fat storage by regulating intracellular calcium homeostasis.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 560,
                "text": "SERCA"
            }
        },
        {
            "context": "The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function.",
            "question": "How is OCT3 associated with serotonin?",
            "answers": {
                "answer_start": 367,
                "text": "serotonin clearance"
            }
        },
        {
            "context": "Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents. The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 605,
                "text": "NCX"
            }
        },
        {
            "context": "A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 295,
                "text": "SLC9A6"
            }
        },
        {
            "context": "Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. In metazoans, lysosomes are the center for the degradation of macromolecules and play a key role in a variety of cellular processes, such as autophagy, exocytosis and membrane repair. Defects of lysosomal pathways are associated with lysosomal storage disorders and with several late onset neurodegenerative diseases. We recently discovered the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network and its master gene transcription factor EB (TFEB), which regulates lysosomal biogenesis and function. Here, we used a combination of genomic approaches, including ChIP-seq (sequencing of chromatin immunoprecipitate) analysis, profiling of TFEB-mediated transcriptional induction, genome-wide mapping of TFEB target sites and recursive expression meta-analysis of TFEB targets, to identify 471 TFEB direct targets that represent essential components of the CLEAR network. This analysis revealed a comprehensive system regulating the expression, import and activity of lysosomal enzymes that control the degradation of proteins, glycosaminoglycans, sphingolipids and glycogen. Interestingly, the CLEAR network appears to be involved in the regulation of additional lysosome-associated processes, including autophagy, exo- and endocytosis, phagocytosis and immune response. Furthermore, non-lysosomal enzymes involved in the degradation of essential proteins such as hemoglobin and chitin are also part of the CLEAR network. Finally, we identified nine novel lysosomal proteins by using the CLEAR network as a tool for prioritizing candidates. This study provides potential therapeutic targets to modulate cellular clearance in a variety of disease conditions.",
            "question": "Which transcription factor is considered as a master regulator of lysosomal genes?",
            "answers": {
                "answer_start": 534,
                "text": "transcription factor EB (TFEB)"
            }
        },
        {
            "context": "Tall stature and gonadal dysgenesis in a non-mosaic girl 45,X. Turner's syndrome, also known as 'monosomy X', is a genetic disorder that occurs in 1/2,500 female births and is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. While the classic karyotype related to Turner's syndrome is 45,X, the majority of those affected actually have a mosaic chromosomal complement, most often with a second normal cell line (46,XX). The resulting phenotype is variable and related to the underlying chromosomal pattern, but it is characterized by three cardinal features: short stature (around 100%), ovarian failure (>90%) and congenital lymphedema (>80%). In this paper we report a molecular and cytogenetic investigation of a 26-year-old female with non-mosaic 45,X karyotype, who has a stature of 170 cm without GH treatment, and whose only apparent Turner feature is gonadal dysgenesis. The only possible explanation for the absence of Turner phenotype is the hidden mosaicism combined with an untreated gonadal dysgenesis. Our results support the theory that significant ascertainment bias exists in our understanding of Turner's syndrome.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 494,
                "text": "X"
            }
        },
        {
            "context": "The golden jubilee of vaccination against poliomyelitis. Inactivated poliovirus vaccine (IPV), developed in the USA by Jonas Salk in the early 1950s, was field tested in 1954, and found to be safe and effective. The year 2004 marks the golden jubilee of this breakthrough. From 1955 IPV was used extensively in the US and polio incidence declined by more than 95 per cent. However, in 1962, when oral poliovirus vaccine (OPV) became available, the national policy was shifted to its exclusive use, for reasons other than science and economics. The World Health Organisation (WHO) also adopted the policy of the exclusive use of OPV in developing countries. Thus IPV fell into disrepute in much of the world, while Northern European countries continued to use it. New research led to improving its potency, reducing its manufacturing costs and combining it with the diphtheria-tetanus-pertussis (DTP) vaccine to simplify its administration and reduce programmatic costs. All countries that chose to persist with IPV eliminated poliovirus circulation without OPV-induced polio or the risk of live vaccine viruses reverting to wild-like nature. IPV is highly immunogenic, confers mucosal immunity and exerts herd protective effect, all qualities of a good vaccine. It can be used in harmony with the extendend programme on immunization (EPI) schedule of infant immunisation with DTP, thus reducing programmatic costs. During the last ten years IPV has once again regained its popularity and some 25 industrialised countries use it exclusively. The demand is increasing from other countries and the supply has not caught up, leaving market forces to dictate the sale price of IPV. Anticipating such a turn of events India had launched its own IPV manufacturing programme in 1987, but the project was closed in 1992. Today it is not clear if we can complete the job of global polio eradication without IPV, on account of the genetic instability of OPV and the consequent tendency of vaccine viruses to revert to wild-like properties. The option to use IPV is complicated since it is not yet licensed in India, we do not manufacture it and imported vaccine would be prohibitively costly. However, in this golden jubilee year we have much to celebrate as the global eradication of wild polioviruses is within sight. Had we strictly followed the principles of science and health economics, perhaps we could have achieved success earlier and cheaper, with the absence of vaccine-induced polio as the bonus.",
            "question": "When did the polio vaccine becomes available?",
            "answers": {
                "answer_start": 170,
                "text": "1954"
            }
        },
        {
            "context": "Application of hydrophilic interaction chromatography for the analysis of polar contaminants in food and environmental samples. For the analysis of highly hydrophilic and polar compounds, Hydrophilic Interaction Chromatography (HILIC) has been established as a valuable complementary approach to reversed-phase liquid chromatography (RPLC). Moreover, the use of mobile phases with a high percentage of organic solvent in HILIC separation is beneficial for mass spectrometric (MS) detection, because of enhanced ionization which results in an increased sensitivity. In this review, various applications of HILIC are described for a number of environmental and food contaminants together with detailed methodological descriptions and the advantages or drawbacks of HILIC compared to other LC methods are critically discussed. In the first part of the review, an overview is given of the work that has been carried out with HILIC for the analysis of pharmaceuticals and pesticides in environmental samples. HILIC has shown its applicability for polar pharmaceuticals, such as antibiotics, estrogens and their metabolites, drugs of abuse, cytostatics, metformin and contrast agents. In the pesticide group, HILIC chromatography was helpful for polar phenylurea and organophosphorus pesticides. The second part of the review focuses on the analysis of antibiotic residues in food and feed with HILIC, while in the pesticide group, HILIC experiments have been reported for dithiocarbamates and quaternary ammonium compounds. The last chapter gives an overview of the analysis by HILIC of miscellaneous analytes in aquatic and food/feed samples.",
            "question": "What kind of chromatography is HILIC?",
            "answers": {
                "answer_start": 188,
                "text": "Hydrophilic Interaction Chromatography"
            }
        },
        {
            "context": "Asymmetric bidirectional transcription from the FSHD-causing D4Z4 array modulates DUX4 production. Facioscapulohumeral Disease (FSHD) is a dominantly inherited progressive myopathy associated with aberrant production of the transcription factor, Double Homeobox Protein 4 (DUX4). The expression of DUX4 depends on an open chromatin conformation of the D4Z4 macrosatellite array and a specific haplotype on chromosome 4. Even when these requirements are met, DUX4 transcripts and protein are only detectable in a subset of cells indicating that additional constraints govern DUX4 production. Since the direction of transcription, along with the production of non-coding antisense transcripts is an important regulatory feature of other macrosatellite repeats, we developed constructs that contain the non-coding region of a single D4Z4 unit flanked by genes that report transcriptional activity in the sense and antisense directions. We found that D4Z4 contains two promoters that initiate sense and antisense transcription within the array, and that antisense transcription predominates. Transcriptional start sites for the antisense transcripts, as well as D4Z4 regions that regulate the balance of sense and antisense transcripts were identified. We show that the choice of transcriptional direction is reversible but not mutually exclusive, since sense and antisense reporter activity was often present in the same cell and simultaneously upregulated during myotube formation. Similarly, levels of endogenous sense and antisense D4Z4 transcripts were upregulated in FSHD myotubes. These studies offer insight into the autonomous distribution of muscle weakness that is characteristic of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 128,
                "text": "FSHD"
            }
        },
        {
            "context": "Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1571,
                "text": "Xa"
            }
        },
        {
            "context": "Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. GATA-1 and the ets factor PU.1 have been reported to functionally antagonize one another in the regulation of erythroid versus myeloid gene transcription and development. The CCAAT enhancer binding protein epsilon (C/EBPepsilon) is expressed as multiple isoforms and has been shown to be essential to myeloid (granulocyte) terminal differentiation. We have defined a novel synergistic, as opposed to antagonistic, combinatorial interaction between GATA-1 and PU.1, and a unique repressor role for certain C/EBPepsilon isoforms in the transcriptional regulation of a model eosinophil granulocyte gene, the major basic protein (MBP). The eosinophil-specific P2 promoter of the MBP gene contains GATA-1, C/EBP, and PU.1 consensus sites that bind these factors in nuclear extracts of the eosinophil myelocyte cell line, AML14.3D10. The promoter is transactivated by GATA-1 alone but is synergistically transactivated by low levels of PU.1 in the context of optimal levels of GATA-1. The C/EBPepsilon(27) isoform strongly represses GATA-1 activity and completely blocks GATA-1/PU.1 synergy. In vitro mutational analyses of the MBP-P2 promoter showed that both the GATA-1/PU.1 synergy, and repressor activity of C/EBPepsilon(27) are mediated via protein-protein interactions through the C/EBP and/or GATA-binding sites but not the PU.1 sites. Co-immunoprecipitations using lysates of AML14.3D10 eosinophils show that both C/EBPepsilon(32/30) and epsilon(27) physically interact in vivo with PU.1 and GATA-1, demonstrating functional interactions among these factors in eosinophil progenitors. Our findings identify novel combinatorial protein-protein interactions for GATA-1, PU.1, and C/EBPepsilon isoforms in eosinophil gene transcription that include GATA-1/PU.1 synergy and repressor activity for C/EBPepsilon(27).",
            "question": "Which gene controls the expression of GATA-1 isoforms?",
            "answers": {
                "answer_start": 44,
                "text": "PU.1"
            }
        },
        {
            "context": "Chlamydial SET domain protein functions as a histone methyltransferase. SET domain genes have been identified in numbers of bacterial genomes based on similarity to SET domains of eukaryotic histone methyltransferases. Herein, a Chlamydophila pneumoniae SET domain gene was clarified to be coincidently expressed with hctA and hctB genes encoding chlamydial histone H1-like proteins, Hc1 and Hc2, respectively. The SET domain protein (cpnSET) is localized in chlamydial cells and interacts with Hc1 and Hc2 through the C-terminal SET domain. As expected from conservation of catalytic sites in cpnSET, it functions as a protein methyltransferase to murine histone H3 and Hc1. However, little is known about protein methylation in the molecular pathogenesis of chlamydial infection. cpnSET may play an important role in chlamydial cell maturation due to modification of chlamydial histone H1-like proteins.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 11,
                "text": "SET domain"
            }
        },
        {
            "context": "SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.",
            "question": "Which is the main calcium pump of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 601,
                "text": "SERCA"
            }
        },
        {
            "context": "Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer.",
            "question": "Are most driver gene mutations synonymous or non-synonymous?",
            "answers": {
                "answer_start": 395,
                "text": "non-synonymous"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 0,
                "text": "OikoBase"
            }
        },
        {
            "context": "Spontaneous low pressure headache - a review and illustrative patient. Low pressure headache typically occurs as a complication of dural puncture. \"Spontaneous\" low pressure headache is a relatively rare but under-recognised cause of intractable headache. Clinical suspicion of this condition warrants imaging of the brain to confirm the diagnosis; spinal imaging may be needed to identify the site of the leak. Epidural blood patching may be necessary to seal the leak - CT fluoroscopy may be helpful in delivering the patch directly to the site of the leak. Surgical intervention may be required in intractable cases. We describe a patient with spontaneous intracranial hypotension and review the clinical and radiological features of this syndrome.",
            "question": "What is the definitive treatment for low pressure headache?",
            "answers": {
                "answer_start": 412,
                "text": "Epidural blood patch"
            }
        },
        {
            "context": "Growth hormone deficiency in Costello syndrome. We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.",
            "question": "Which hormone deficiency is implicated in the Costello syndrome ?",
            "answers": {
                "answer_start": 0,
                "text": "Growth hormone deficiency"
            }
        },
        {
            "context": "Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.",
            "question": "Which metabolite activates AtxA?",
            "answers": {
                "answer_start": 1708,
                "text": "bicarbonate"
            }
        },
        {
            "context": "Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43-mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS.",
            "question": "Patients of which disease could be treated by utilizing knowledge obtained from experiments suppressing TDP-43 toxicity in yeast?",
            "answers": {
                "answer_start": 94,
                "text": "Amyotrophic lateral sclerosis (ALS)"
            }
        },
        {
            "context": "Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations. The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 316,
                "text": "5p15.3"
            }
        },
        {
            "context": "Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 202,
                "text": "Flumazenil"
            }
        },
        {
            "context": "Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing. Membrane antigens are critical to the pathogenesis of chronic lymphocytic leukemia (CLL) as they facilitate microenvironment homing, proliferation, and survival. Targeting the CLL membrane and associated signaling patterns is a current focus of therapeutic development. Many tumor membrane targets are simultaneously targeted by humoral immunity, thus forming recognizable immunoglobulin responses. We sought to use this immune response to identify novel membrane-associated targets for CLL. Using a novel strategy, we interrogated CLL membrane-specific autologous immunoglobulin G reactivity. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. Furthermore, we demonstrate that the Bruton's tyrosine kinase inhibitor ibrutinib or the PI3K inhibitor idelalisib block B-cell receptor induced activation of LCP1. Our data demonstrate a novel strategy to identify cancer membrane target antigens using humoral anti-tumor immunity. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance. This clinical trial was registered at clinicaltrials.gov; study ID number: OSU-0025 OSU-0156.",
            "question": "What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?",
            "answers": {
                "answer_start": 1287,
                "text": "ibrutinib"
            }
        },
        {
            "context": "The new oral anticoagulants: a challenge for hospital formularies. Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 805,
                "text": "xa"
            }
        },
        {
            "context": "Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase. Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm and +138,250/mm) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 65,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "The activation of the decapping enzyme DCP2 by DCP1 occurs on the EDC4 scaffold and involves a conserved loop in DCP1. The removal of the 5'-cap structure by the decapping enzyme DCP2 and its coactivator DCP1 shuts down translation and exposes the mRNA to 5'-to-3' exonucleolytic degradation by XRN1. Although yeast DCP1 and DCP2 directly interact, an additional factor, EDC4, promotes DCP1-DCP2 association in metazoan. Here, we elucidate how the human proteins interact to assemble an active decapping complex and how decapped mRNAs are handed over to XRN1. We show that EDC4 serves as a scaffold for complex assembly, providing binding sites for DCP1, DCP2 and XRN1. DCP2 and XRN1 bind simultaneously to the EDC4 C-terminal domain through short linear motifs (SLiMs). Additionally, DCP1 and DCP2 form direct but weak interactions that are facilitated by EDC4. Mutational and functional studies indicate that the docking of DCP1 and DCP2 on the EDC4 scaffold is a critical step for mRNA decapping in vivo. They also revealed a crucial role for a conserved asparagine-arginine containing loop (the NR-loop) in the DCP1 EVH1 domain in DCP2 activation. Our data indicate that DCP2 activation by DCP1 occurs preferentially on the EDC4 scaffold, which may serve to couple DCP2 activation by DCP1 with 5'-to-3' mRNA degradation by XRN1 in human cells.",
            "question": "Which is the enzyme that degrades decapped mRNAs?",
            "answers": {
                "answer_start": 295,
                "text": "XRN1"
            }
        },
        {
            "context": "Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation. Chromatin can be modified by posttranslational modifications of histones, ATP-dependent remodeling, and incorporation of histone variants. The Saccharomyces cerevisiae protein Yaf9 is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodeling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin. Yaf9 contains a YEATS domain, found in proteins associated with multiple chromatin-modifying enzymes and transcription complexes across eukaryotes. Here, we established the conservation of YEATS domain function from yeast to human, and determined the structure of this region from Yaf9 by x-ray crystallography to 2.3 A resolution. The Yaf9 YEATS domain consisted of a beta-sandwich characteristic of the Ig fold and contained three distinct conserved structural features. The structure of the Yaf9 YEATS domain was highly similar to that of the histone chaperone Asf1, a similarity that extended to an ability of Yaf9 to bind histones H3 and H4 in vitro. Using structure-function analysis, we found that the YEATS domain was required for Yaf9 function, histone variant H2A.Z chromatin deposition at specific promoters, and H2A.Z acetylation.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 407,
                "text": "SWR1"
            }
        },
        {
            "context": "Acrokeratosis paraneoplastica (Bazex syndrome): report of a case associated with small cell lung carcinoma and review of the literature. Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations.",
            "question": "Name synonym of Acrokeratosis paraneoplastica.",
            "answers": {
                "answer_start": 167,
                "text": "Bazex syndrome"
            }
        },
        {
            "context": "Phenotypic variability of a distinct deletion in McLeod syndrome. The X-linked McLeod neuroacanthocytosis syndrome strongly resembles Huntington's disease and has been reported in various countries world-wide. Herein, we report two Chilean brothers with predominant psychiatric features at disease onset including schizophrenia-like psychosis and obsessive compulsive disorder. Molecular genetic analysis revealed a small deletion in the XK gene (938-942delCTCTA), which has been already described in a North American patient of Anglo-Saxon descent and a Japanese family, presenting with seizures, muscle atrophy or chorea yet absence of psychiatric features. These findings argue against a founder effect and indicate a profound phenotypic variability associated with the 938-942delCTCTA deletion. Our report supports the inclusion of McLeod syndrome in the differential diagnosis of Huntington's disease as well as acute psychosis in male subjects.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 438,
                "text": "XK"
            }
        },
        {
            "context": "Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are dominant regulators of bone resorption. Many hormones, cytokines and growth factors mediate bone resorption by altering the ratio of RANKL to OPG. RANKL and OPG expression is also altered in numerous bone diseases, and these changes can reflect disease etiology or compensatory responses to disease. RANKL stimulates osteoclast formation, function and survival, and each of these effects is inhibited by OPG. OPG suppresses bone resorption and increases the density, area and strength of both cancellous and cortical bone. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, shares the pharmacologic attributes of OPG but has a significantly longer half-life that allows less frequent administration.",
            "question": "To the ligand of which receptors does Denosumab (Prolia) bind?",
            "answers": {
                "answer_start": 754,
                "text": "RANKL"
            }
        },
        {
            "context": "Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 615,
                "text": "L-dopa"
            }
        },
        {
            "context": "Anesthesia for deep brain stimulation in a patient with X-linked dystonia-parkinsonism/Lubag disease. Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men. This disease is characterized by dystonia dominating the first 10-15 years of the disorder, which is associated with or replaced by parkinsonian features in later years of life. A 49-year-old man with Lubag disease underwent general anesthesia for deep brain stimulation (DBS) surgery. Anesthesia was maintained mainly with propofol, remifentanil, rocuronium bromide, and sevoflurane. During magnetic resonance imaging, the patient was anesthetized with midazolam, fentanyl, and rocuronium bromide. The surgery was completed safely using these anesthetic agents. After DBS, some symptoms including involuntary movement improved within 10 days.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 56,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 27,
                "text": "melanocortin 1 receptor"
            }
        },
        {
            "context": "Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. BACKGROUND: The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort). INTERPRETATION: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.",
            "question": "RTS S AS01 vaccine was developed to prevent which disease?",
            "answers": {
                "answer_start": 224,
                "text": "malaria"
            }
        },
        {
            "context": "High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis. Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess.",
            "question": "Which gene is responsible for the development of the Mowat-Wilson syndrome?",
            "answers": {
                "answer_start": 1138,
                "text": "ZEB2"
            }
        },
        {
            "context": "Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 230,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Genetically determined neuromuscular disorders of some Roma families living in Hungary. The authors discuss the clinical and molecular genetic aspects of genetically determined neuromuscular disorders of some Roma families living in Hungary. Among the autosomal recessively inherited spinal muscular atrophic (SMA) group, 8 Caucasian children had the typical 7-8 exonal deletions of the SMA gene, but only 2 patients belonged to the Roma population. There was no difference in the molecular genetic findings among the Caucasian and the Roma SMA patients. All of them had 7-8 exonal deletions of the SMA gene. We wanted to call attention to the founder mutation of the Roma population in 7 patients suffering from congenital myasthenia (CMS) from 3 Roma families. The 1267G deletion for CMS was detected by molecular genetic method. Clinical onset was pubertal and relatively slow progression of specific and phenotypic features for this founder mutation of acetyl-cholin receptor epsylon gene. In 2 patients (sister and brother) the sarcoglycanopathy 2C type C283Q mutation was proven in one Roma family suffering from limb-girdle muscular dystrophy (LGMD). Two out of the three facioscapular-humeral dystrophy (FSHD) Roma families carried 21.8 kb and 18.5 kb alleles in FSHD A1 gene (D4S139). In one family together with prenatal diagnosis founder mutation in FSHD A1 gene was detected, according to the autosomal dominant (AD) inheritance. In (F2) prenatal diagnosis was carried out, 18.5 kb/18.5 kb homozygosity was proven in the fetus, so the pregnancy was interrupted. In the CMS, LGMD and FSHD Roma patients ancient typical Roma founder mutations were found.",
            "question": "What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?",
            "answers": {
                "answer_start": 1405,
                "text": "autosomal dominant"
            }
        },
        {
            "context": "CSEQ-SIMULATOR: A DATA SIMULATOR FOR CLIP-SEQ EXPERIMENTS. CLIP-Seq protocols such as PAR-CLIP, HITS-CLIP or iCLIP allow a genome-wide analysis of protein-RNA interactions. For the processing of the resulting short read data, various tools are utilized. Some of these tools were specifically developed for CLIP-Seq data, whereas others were designed for the analysis of RNA-Seq data. To this date, however, it has not been assessed which of the available tools are most appropriate for the analysis of CLIP-Seq data. This is because an experimental gold standard dataset on which methods can be accessed and compared, is still not available. To address this lack of a gold-standard dataset, we here present Cseq-Simulator, a simulator for PAR-CLIP, HITS-CLIP and iCLIP-data. This simulator can be applied to generate realistic datasets that can serve as surrogates for experimental gold standard dataset. In this work, we also show how Cseq-Simulator can be used to perform a comparison of steps of typical CLIP-Seq analysis pipelines, such as the read alignment or the peak calling. These comparisons show which tools are useful in different settings and also allow identifying pitfalls in the data analysis.",
            "question": "Which data simulator is available for CLIP-SEQ experiments?",
            "answers": {
                "answer_start": 0,
                "text": "CSEQ-SIMULATOR"
            }
        },
        {
            "context": "The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets. Phylogenetic and comparative genomic analyses suggest that the structures have arisen largely independently in the two lineages with the exception of a few seed sequences present in the common ancestor of humans and African apes. We propose a model where an ancestral human-chimpanzee pericentric inversion and the ancestral chromosome 2 fusion both predisposed and protected the chimpanzee and human genomes, respectively, to the formation of subtelomeric heterochromatin. Our findings highlight the complex interplay between duplicated sequences and chromosomal rearrangements that rapidly alter the cytogenetic landscape in a short period of evolutionary time.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 1085,
                "text": "2"
            }
        },
        {
            "context": "Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: Assessing absolute differences using a number needed to treat analysis. Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 951,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. BACKGROUND: Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged > 18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours ( > 25% of tumour cells with membrane staining of > 1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m intravenously; cisplatin 60 mg/m intravenously; capecitabine 625 mg/m orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. FINDINGS: Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. INTERPRETATION: Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. FUNDING: Amgen.",
            "question": "What is inhibited by a drug rilotumumab?",
            "answers": {
                "answer_start": 344,
                "text": "hepatocyte growth factor"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 218,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed.",
            "question": "What is the most common histological diagnosis of \"butterfly glioma\"?",
            "answers": {
                "answer_start": 53,
                "text": "glioblastoma multiforme"
            }
        },
        {
            "context": "The SF-36 Offers a Strong Measure of Mental Health Symptoms in Survivors of Acute Respiratory Failure. A Tri-National Analysis. RATIONALE: Survivors of acute respiratory failure commonly experience long-term psychological sequelae and impaired quality of life. For researchers interested in general mental health, using multiple condition-specific instruments may be unnecessary and inefficient when using the Medical Outcomes Study Short Form (SF)-36, a recommended outcome measure, may suffice. However, relationships between the SF-36 scores and commonly used measures of psychological symptoms in acute survivors of respiratory failure are unknown. OBJECTIVES: Our objective is to examine the relationship of the SF-36 mental health domain (MH) and mental health component summary (MCS) scores with symptoms of depression, anxiety, and post-traumatic stress disorder (PTSD) evaluated using validated psychological instruments. METHODS: We conducted a cross-sectional analysis of 1,229 participants at 6- and 12-month follow-up assessment using data from five studies from the United States, the United Kingdom, and Australia. MEASUREMENTS AND MAIN RESULTS: Symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), Depression Anxiety Stress Scales, the Davidson Trauma Scale, Impact of Event Scale (IES), and IES-Revised (IES-R). At 6-month assessment there were moderate to strong correlations of the SF-36 MH scores with HADS depression and anxiety symptoms (r = -0.74 and -0.79) and with IES-R PTSD symptoms (r = -0.60) in the pooled analyses. Using the normalized population mean of 50 on the SF-36 MH domain score as a cut-off, positive predictive values were 16 and 55% for substantial depression; 20 and 68% for substantial anxiety (Depression Anxiety Stress Scales and HADS, respectively); and 40, 44, and 67% for substantial PTSD symptoms (IES-R, IES, and Davidson Trauma Scale, respectively). Negative predictive values were high. The area under the receiver operating characteristics curve of the SF-36 MH score was high for depression, anxiety, and PTSD symptoms (0.88, 0.91, and 0.84, respectively). All results were consistent for the MCS, across the individual studies, and for the 12-month assessment. CONCLUSIONS: For researchers interested in general mental health status, the SF-36 MH or MCS offers a strong measure of psychological symptoms prevalent among survivors of acute respiratory failure. For researchers interested in specific conditions, validated psychological instruments should be considered.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 1859,
                "text": "PTSD"
            }
        },
        {
            "context": "Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. Different missense, nonsense and frameshift mutations in the GAN gene encoding gigaxonin have been described to cause giant axonal neuropathy, a severe early-onset progressive neurological disease with autosomal recessive inheritance. By oligonucleotide array CGH analysis, we identified a 57-131 kb microdeletion affecting this gene in a patient with developmental delay, ataxia, areflexia, macrocephaly, and strikingly frizzy hair. The microdeletion was inherited from the mother and mutation analysis revealed a paternally inherited missense mutation c.1456G>A in exon 9 on the other allele. Our findings illustrate the power of higher resolution array CGH studies and highlight the importance of considering copy number variations in autosomal recessive diseases.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 205,
                "text": "GAN gene"
            }
        },
        {
            "context": "One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 459,
                "text": "IL-1β"
            }
        },
        {
            "context": "Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations. The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations.",
            "question": "Which is the chromosome area that the human gene coding for the dopamine transporter (DAT1) is located to?",
            "answers": {
                "answer_start": 316,
                "text": "5p15.3"
            }
        },
        {
            "context": "Multiple roles of ubiquitination in the control of nucleotide excision repair. Nucleotide excision repair (NER) is a remarkably versatile DNA repair system, essential for maintenance of genomic stability. Hereditary alterations in NER enzymes can result in increased cancer propensity, but also in developmental, neurodegenerative, and progeroid syndromes. NER can be operationally divided in three subtypes, which share many common steps: global genomic repair (GGR) operates on the whole genome level, transcription domain-associated repair (DAR) is a concentration of NER activity within transcription factories, and transcription-coupled repair (TCR) provides faster repair of the transcribed strand of active genes. Interestingly, ubiquitination plays an important role in all three classes of NER, as well as in associated phenomena, such as damage signalling by histone ubiquitination, and degradation of stalled RNA polymerase II when repair does not occur in a timely manner.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 681,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 2482,
                "text": "flumazenil"
            }
        },
        {
            "context": "Early rheumatoid arthritis: does gender influence disease expression? OBJECTIVE: To investigate whether gender is an independent factor associated with disease expression in early rheumatoid arthritis (RA) patients. METHODS: 438 patients with early RA (disease duration less than one year) were studied. They all were patients with early RA who presented at the Rheumatology Clinic of the University Hospital of Ioannina during the period 1991-2000. All patients fulfilled the American College of Rheumatology criteria for RA. The demographic, clinical, laboratory, radiological and therapeutic characteristics of the disease at diagnosis, and at the last follow-up were analyzed according to gender. RESULTS: We studied 312 women and 126 men with early RA. The female to male ratio was 2.5:1 and the mean age at diagnosis was 49.4 +/- 14.9 years for women and 55.3 +/-15.6 years for men (P < 0.0003). Women had a longer duration of follow-up (P < 0.0003). There were no differences between genders in the general symptoms or the simmetricity of joint involvement at at disease onset. However at disease onset women had a higher erythrocyte sedimentation rate (ESR) (> 30 mm/1st hour), although there were no significant differences between the two groups concerninig the rest of the clinical, laboratory and radiological findings. At the last follow-up women still had a higher ESR (>30 min/1st hour), but no significant differences were found between the two groups concerning the rest of the parameters investigated independently of the follow-up duration. Finally, women and men showed the same degree of radiological changes and functional ability and were treated similarly except for the more frequent use of hydroxychloroquine in women. CONCLUSION: It seems that gender does not signficantly influence the expression of RA.",
            "question": "Is Rheumatoid Arthritis more common in men or women?",
            "answers": {
                "answer_start": 851,
                "text": "women"
            }
        },
        {
            "context": "Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist. PURPOSE: The incidence of sudden death appears to be 20 times higher in patients with epilepsy compared with the general population. Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is still underestimated by healthcare professionals and this may reflect the mistaken belief that epilepsy is a benign condition. The risk of death associated with epilepsy appeared rarely to have been discussed with patients or their families. It appears the decision to discuss SUDEP and also to peg SUDEP risk is arbitrary and clinical. Unfortunately there is no structured evidenced mechanism at present to represent person centered risk of SUDEP and there is currently no easy manner or template to have this discussion with the family and the patient. METHODS: We conducted a detailed literature review in Medline, Embase and Psychinfo databases to extract the common risk factors as evidenced from literature till date. Research into risk factors has identified a number of risk factors for SUDEP, some of which are potentially modifiable. RESULTS: Based on the literature review, we believe that the ascertained risk factors could be employed in clinical practice as a checklist to reduce an individual patient's risk of SUDEP. The SUDEP safety checklist may be of practical use in reducing risks in some individuals and is definitely of use in helping communication. CONCLUSIONS: An evidence based checklist identifying the major risk factors can help both clinicians and patients to focus on minimizing certain risk factors and promote safety by focusing on the modifiable factors and guide treatment. It can be a tool to open a person centered discussion with patients and to outline how individual behaviors could impact on risk.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 250,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The incidence of plantar fasciitis in the United States military. BACKGROUND: Although plantar fasciitis is the most common cause of heel pain, little has been reported on the incidence rates of this disorder. We sought to determine the incidence rate and demographic risk factors of plantar fasciitis in an ethnically diverse and physically active population of United States military service members. METHODS: A query was performed with use of the Defense Medical Epidemiology Database for the International Classification of Diseases, Ninth Revision, Clinical Modification, code for plantar fasciitis (728.71). Multivariate Poisson regression analysis was used to estimate the rate of plantar fasciitis per 1000 person-years, while controlling for sex, race, rank, service, and age. RESULTS: The overall unadjusted incidence rate of plantar fasciitis was 10.5 per 1000 person-years. Compared with men, women had a significantly increased adjusted incidence rate ratio for plantar fasciitis of 1.96 (95% confidence interval, 1.94 to 1.99). The adjusted incidence rate ratio for black service members compared with white service members was 1.12 (95% confidence interval, 1.09 to 1.12). With junior officers as the referent category, junior enlisted, senior enlisted, and senior officer rank groups had a significantly increased adjusted incidence rate ratio for plantar fasciitis: 1.20 (95% confidence interval, 1.18 to 1.23), 1.19 (95% confidence interval, 1.17 to 1.22), and 1.56 (95% confidence interval, 1.52 to 1.61), respectively. Compared with service members in the Air Force, those in the Army and Marines had a significantly increased adjusted incidence rate ratio for plantar fasciitis of 1.85 (95% confidence interval, 1.82 to 1.87) and 1.28 (95% confidence interval, 1.25 to 1.30), respectively. The adjusted incidence rate ratio for the age group of forty years old or more compared with the twenty to twenty-four-year-old group was 3.42 (95% confidence interval, 3.34 to 3.51). CONCLUSIONS: Female sex; black race; junior enlisted, senior enlisted, and senior officer rank groups; service in the Army or Marines; and increasing age are all risk factors for plantar fasciitis.",
            "question": "What is plantar fasciitis",
            "answers": {
                "answer_start": 133,
                "text": "heel pain"
            }
        },
        {
            "context": "Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.",
            "question": "Which gene is responsible for red hair?",
            "answers": {
                "answer_start": 1440,
                "text": "MC1R"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 54,
                "text": "Xa"
            }
        },
        {
            "context": "Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad).",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 805,
                "text": "tyr"
            }
        },
        {
            "context": "Altitudinal patterns of tick and host abundance: a potential role for climate change in regulating tick-borne diseases? The impact of climate change on vector-borne infectious diseases is currently controversial. In Europe the primary arthropod vectors of zoonotic diseases are ticks, which transmit Borrelia burgdorferi sensu lato (the agent of Lyme disease), tick-borne encephalitis virus and louping ill virus between humans, livestock and wildlife. Ixodes ricinus ticks and reported tick-borne disease cases are currently increasing in the UK. Theories for this include climate change and increasing host abundance. This study aimed to test how I. ricinus tick abundance might be influenced by climate change in Scotland by using altitudinal gradients as a proxy, while also taking into account the effects of hosts, vegetation and weather effects. It was predicted that tick abundance would be higher at lower altitudes (i.e. warmer climates) and increase with host abundance. Surveys were conducted on nine hills in Scotland, all of open moorland habitat. Tick abundance was positively associated with deer abundance, but even after taking this into account, there was a strong negative association of ticks with altitude. This was probably a real climate effect, with temperature (and humidity, i.e. saturation deficit) most likely playing an important role. It could be inferred that ticks may become more abundant at higher altitudes in response to climate warming. This has potential implications for pathogen prevalence such as louping ill virus if tick numbers increase at elevations where competent transmission hosts (red grouse Lagopus lagopus scoticus and mountain hares Lepus timidus) occur in higher numbers.",
            "question": "Which is the vector of Louping ill virus?",
            "answers": {
                "answer_start": 453,
                "text": "Ixodes ricinus"
            }
        },
        {
            "context": "The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 107,
                "text": "tyr"
            }
        },
        {
            "context": "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells. Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population.",
            "question": "Which enzyme is inhibited by Imetelstat?",
            "answers": {
                "answer_start": 4,
                "text": "telomerase"
            }
        },
        {
            "context": "The integrator complex is required for integrity of Cajal bodies. The nucleus in eukaryotic cells is a highly organized and dynamic structure containing numerous subnuclear bodies. The morphological appearance of nuclear bodies seems to be a reflection of ongoing functions, such as DNA replication, transcription, repair, RNA processing and RNA transport. The integrator complex mediates processing of small nuclear RNA (snRNA), so it might play a role in nuclear body formation. Here, we show that the integrator complex is essential for integrity of the Cajal body. Depletion of INTS4, an integrator complex subunit, abrogated 3'-end processing of snRNA. A defect in this activity caused a significant accumulation of the Cajal body marker protein coilin in nucleoli. Some fractions of coilin still formed nucleoplasmic foci; however, they were free of other Cajal body components, such as survival of motor neuron protein (SMN), Sm proteins and snRNAs. SMN and Sm proteins formed striking cytoplasmic granules. These findings demonstrate that the integrator complex is essential for snRNA maturation and Cajal body homeostasis.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 751,
                "text": "coilin"
            }
        },
        {
            "context": "Genetic analysis of oculocutaneous albinism type 1 (OCA1) in Indian families: two novel frameshift mutations in the TYR Gene. PURPOSE: Oculocutaneous albinism type 1 (OCA1) patients demonstrate a partial or total lack of melanin in the skin, hair and eye. OCA1 is an autosomal recessive genetic disorder caused by mutations in the TYR gene located at chromosome band 11q14-q25. The purpose of this study was to carry out genetic analysis of OCA1 in Indian families. METHODS: Genomic DNA was isolated from blood leukocytes of all the individuals in this study. Haplotype analysis was performed at the TYR locus using informative microsatellite markers. Eight sets of primers were used to amplify the entire coding region of the TYR gene for bidirectional direct sequencing mutation analysis. RESULTS: Two novel deletions (c.937del8, c.1379del2) and a previously known nonsense mutation (R278X) in the TYR gene were identified from a total of 8 oculocutaneous albinism patients in India. CONCLUSIONS: Our study reports the distribution of two novel frameshift and a previously reported nonsense mutations in four OCA1 families from the Indian population. These findings will contribute to the development of a diagnostic method for OCA1 carrier status and genetic counseling for OCA1 affected families.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 116,
                "text": "TYR"
            }
        },
        {
            "context": "Spontaneously arising red cells with a McLeod-like phenotype in normal donors. Very few human genes can be used to identify spontaneous inactivating somatic mutations. We hypothesized that because the XK gene is X-linked, it would be easy to identify spontaneously arising red cells with a phenotype resembling the McLeod syndrome, which results from inherited XK mutations. Here, by flow cytometry, we detect such phenotypic variants at a median frequency of 9 x 10(-6) in neonatal cord blood samples and 39 x 10(-6) in healthy adults (p=0.004). It may be possible to further investigate the relationship between aging, mutations, and cancer using this approach.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 201,
                "text": "XK"
            }
        },
        {
            "context": "Transcript versus transcription? Numerous sense-antisense gene pairs have been discovered in various organisms. Antisense genes play important roles in establishing parentally imprinted gene expression patterns in mammals. Typically, protein-coding sense genes are reciprocally regulated by their non-coding antisense partners. One example for antisense regulation is the Xist (X-inactive specific transcript) and Tsix gene pair, which is pivotal in X-inactivation. Xist works as a functional RNA molecule that recruits repressive chromatin factors towards one of the female Xs for inactivation. Antisense Tsix transcription negatively regulates Xist and protects one X-chromosome in cis from inactivation by Xist. Albeit, the precise molecular mechanism is still obscure it has been shown that Tsix transcription regulates the chromatin structure by altering histone tail modifications and DNA methylation at the Xist promoter. In addition, Xist and Tsix RNA form an RNA duplexes in vivo and are processed to small RNAs, which have a potential regulatory function. Here we review the latest findings and based on ample experimental data consider models for antisense-mediated gene regulation in X-inactivation.",
            "question": "Which is the transcript responsible for X-chromosome inactivation?",
            "answers": {
                "answer_start": 372,
                "text": "Xist"
            }
        },
        {
            "context": "A revised six-kingdom system of life. A revised six-kingdom system of life is presented, down to the level of infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi, Plantae and Chromista. Intermediate high level categories (superkingdom, subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are extensively used to avoid splitting organisms into an excessive number of kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms, Protozoa and Animalia, are subject to the International Code of Zoological Nomenclature, the kingdom Bacteria to the International Code of Bacteriological Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to the International Code of Botanical Nomenclature. Circumscriptions of the kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20 classes; fungal classification at the rank of subclass and above is comprehensively revised. The kingdoms Protozoa and Animalia are modified in the light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not Protozoa, and that mesozoans are related to bilaterian animals. Animalia are divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa, Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other phyla). Several new higher level groupings are made in the animal kingdom including three new phyla: Acanthognatha (rotifers, acanthocephalans, gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not as a separate kingdom. The recently revised phylum Rhizopoda is modified further by adding more flagellates and removing some 'rhizopods' and is therefore renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa and Archamoebae (both now infraphyla) as a new subphylum Conosa within the phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the (formerly microsporidian) metchnikovellids are now both placed within the phylum Sporozoa. These changes make a total of only 13 currently recognized protozoan phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is modified in circumscription by adding the Discicristata, a new infrakingdom comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in relation to the principles of megasystematics, here defined as systematics that concentrates on the higher levels of classes, phyla, and kingdoms. These principles also make it desirable to rank Archaebacteria as an infrakingdom of the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising all bacteria bounded by a single membrane. The bacterial subkingdom Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides in the outer leaflet of the outer membrane and phospholipids in its inner leaflet. (ABSTRACT TRUNCATED)",
            "question": "In which kingdom do microsporidia belong, according to their current classification scheme?",
            "answers": {
                "answer_start": 1123,
                "text": "Fungi"
            }
        },
        {
            "context": "GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.",
            "question": "Which genome browser database for DNA shape annotations is available?",
            "answers": {
                "answer_start": 695,
                "text": "GBshape"
            }
        },
        {
            "context": "r3Cseq: an R/Bioconductor package for the discovery of long-range genomic interactions from chromosome conformation capture and next-generation sequencing data. The coupling of chromosome conformation capture (3C) with next-generation sequencing technologies enables the high-throughput detection of long-range genomic interactions, via the generation of ligation products between DNA sequences, which are closely juxtaposed in vivo. These interactions involve promoter regions, enhancers and other regulatory and structural elements of chromosomes and can reveal key details of the regulation of gene expression. 3C-seq is a variant of the method for the detection of interactions between one chosen genomic element (viewpoint) and the rest of the genome. We present r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a number of different experimental designs. The package reads a common aligned read input format, provides data normalization, allows the visualization of candidate interaction regions and detects statistically significant chromatin interactions, thus greatly facilitating hypothesis generation and the interpretation of experimental results. We further demonstrate its use on a series of real-world applications.",
            "question": "Which package is available for analysing genomic interactions in R/Bioconductor?",
            "answers": {
                "answer_start": 768,
                "text": "r3Cseq"
            }
        },
        {
            "context": "Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites. N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them (WTAP, METTL14, and KIAA1429) are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing \"basal\" degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data shed light on the proteomic and transcriptional underpinnings of this RNA modification.",
            "question": "Which properties of the mRNA does N6-methyladenosine (m6A) affect?",
            "answers": {
                "answer_start": 786,
                "text": "mRNA stability"
            }
        },
        {
            "context": "Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and > 10 years) and baseline mobility testing passing level (pass at > 125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 10 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.",
            "question": "Which retinal dystrophy related gene is targeted by the AAV2-hRPE65v2 drug?",
            "answers": {
                "answer_start": 2755,
                "text": "RPE65"
            }
        },
        {
            "context": "Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure. The mammalian transcription factor Bach1 functions as a repressor of the enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1) by forming heterodimers with the small Maf proteins such as MafK. The transcription of Hmox-1 is regulated by the substrate of HO-1, heme. Heme induces expression of Hmox-1 in part by inhibiting the binding of Bach1 to the enhancers and inducing the nuclear export of Bach1. A dipeptide motif of cysteine and proline (CP motif) in Bach1 is essential for the heme-mediated regulation. In this study, we show that five molecules of heme bind to Bach1 by the heme-titration assay. The Bach1-heme complex exhibits an absorption spectrum with a major Soret peak at 371 nm and Raman band at 343 cm(-1) in high amounts of heme and a spectrum containing the major Soret peak at 423 nm at low heme concentrations. The spectroscopic characterization indicates that Bach1 has two kinds of heme-binding sites with different coordination structures. Mutagenesis studies have established that four molecules of heme bind to the cysteine residues of four CP motifs in the C terminus of Bach1. These results raise the possibility that two separated activities of Bach1, DNA-binding and nuclear export, are regulated by heme binding at the different CP motifs of Bach1 respectively, but not by cooperative heme-binding.",
            "question": "Is the transcriptional regulator BACH1 an activator or a repressor?",
            "answers": {
                "answer_start": 188,
                "text": "repressor"
            }
        },
        {
            "context": "Detection and characterization of ciRS-7: a potential promoter of the development of cancer. Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.",
            "question": "Which miRNA is associated with the circular RNA ciRS-7?",
            "answers": {
                "answer_start": 935,
                "text": "miR-7"
            }
        },
        {
            "context": "Stimulation of RNA polymerase II transcript cleavage activity contributes to maintain transcriptional fidelity in yeast. The transcription elongation factor S-II, also designated TFIIS, stimulates the nascent transcript cleavage activity intrinsic to RNA polymerase II. Rpb9, a small subunit of RNA polymerase II, enhances the cleavage stimulation activity of S-II. Here, we investigated the role of nascent transcript cleavage stimulation activity on the maintenance of transcriptional fidelity in yeast. In yeast, S-II is encoded by the DST1 gene. Disruption of the DST1 gene decreased transcriptional fidelity in cells. Mutations in the DST1 gene that reduce the S-II cleavage stimulation activity led to decreased transcriptional fidelity in cells. A disruption mutant of the RPB9 gene also had decreased transcriptional fidelity. Expression of mutant Rpb9 proteins that are unable to enhance the S-II cleavage stimulation activity failed to restore the phenotype. These results suggest that both S-II and Rpb9 maintain transcriptional fidelity by stimulating the cleavage activity intrinsic to RNA polymerase II. Also, a DST1 and RPB9 double mutant had more severe transcriptional fidelity defect compared with the DST1 gene deletion mutant, suggesting that Rpb9 maintains transcriptional fidelity via two mechanisms, enhancement of S-II dependent cleavage stimulation and S-II independent function(s).",
            "question": "Which RNA polymerase II subunit carries RNA cleavage activity?",
            "answers": {
                "answer_start": 179,
                "text": "TFIIS"
            }
        },
        {
            "context": "Hormonal and systemic regulation of sclerostin. The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation.",
            "question": "Sclerostin regulates what process?",
            "answers": {
                "answer_start": 321,
                "text": "bone metabolism"
            }
        },
        {
            "context": "Chromosome-Specific Centromere Sequences Provide an Estimate of the Ancestral Chromosome 2 Fusion Event in Hominin Genomes. Human chromosome 2 is a product of a telomere fusion of two ancestral chromosomes and loss/degeneration of one of the two original centromeres. Genomic signatures of this event are limited to inverted telomeric repeats at the precise site of chromosomal fusion and to the small amount of relic centromeric sequences that remain on 2q21.2. Unlike the site of fusion, which is enriched for sequences that are shared elsewhere in the human genome, the region of the nonfunctioning and degenerate ancestral centromere appears to share limited similarity with other sites in the human genome, thereby providing an opportunity to study this genomic arrangement in short, fragmented ancient DNA genomic datasets. Here, chromosome-assigned satellite DNAs are used to study shared centromere sequence organization in Denisovan and Neandertal genomes. By doing so, one is able to provide evidence for the presence of both active and degenerate centromeric satellite profiles on chromosome 2 in these archaic genomes, supporting the hypothesis that the chromosomal fusion event took place prior to our last common ancestor with Denisovan and Neandertal hominins and presenting a genomic reference for predicting karyotype in ancient genomic datasets.",
            "question": "Which human chromosome is the product of fusion?",
            "answers": {
                "answer_start": 130,
                "text": "chromosome 2"
            }
        },
        {
            "context": "Flumazenil: an antidote for benzodiazepine toxicity. Flumazenil, a specific benzodiazepine antagonist, is useful in reversing the sedation and respiratory depression that often occur when benzodiazepines are administered to patients undergoing anesthesia or when patients have taken an intentional benzodiazepine overdose. Judicious use of flumazenil may provide useful diagnostic information and may obviate the need for mechanical ventilation and other invasive supportive measures. Although some controversy exists regarding the possible precipitation of seizure activity in the setting of mixed tricyclic antidepressant-benzodiazepine overdose, worldwide experience with flumazenil has validated its safety and efficacy.",
            "question": "Which drug should be used as an antidote in benzodiazepine overdose?",
            "answers": {
                "answer_start": 53,
                "text": "Flumazenil"
            }
        },
        {
            "context": "The Fusarium oxysporum effector Six6 contributes to virulence and suppresses I-2-mediated cell death. Plant pathogens secrete effectors to manipulate their host and facilitate colonization. Fusarium oxysporum f. sp. lycopersici is the causal agent of Fusarium wilt disease in tomato. Upon infection, F. oxysporum f. sp. lycopersici secretes numerous small proteins into the xylem sap (Six proteins). Most Six proteins are unique to F. oxysporum, but Six6 is an exception; a homolog is also present in two Colletotrichum spp. SIX6 expression was found to require living host cells and a knockout of SIX6 in F. oxysporum f. sp. lycopersici compromised virulence, classifying it as a genuine effector. Heterologous expression of SIX6 did not affect growth of Agrobacterium tumefaciens in Nicotiana benthamiana leaves or susceptibility of Arabidopsis thaliana toward Verticillium dahliae, Pseudomonas syringae, or F. oxysporum, suggesting a specific function for F. oxysporum f. sp. lycopersici Six6 in the F. oxysporum f. sp. lycopersici- tomato pathosystem. Remarkably, Six6 was found to specifically suppress I-2-mediated cell death (I2CD) upon transient expression in N. benthamiana, whereas it did not compromise the activity of other cell-death-inducing genes. Still, this I2CD suppressing activity of Six6 does not allow the fungus to overcome I-2 resistance in tomato, suggesting that I-2-mediated resistance is independent from cell death.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 276,
                "text": "tomato"
            }
        },
        {
            "context": "Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.",
            "question": "How is oprozomib administered?",
            "answers": {
                "answer_start": 814,
                "text": "orally"
            }
        },
        {
            "context": "Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab). OBJECTIVE: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. METHODS: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. RESULTS: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. CONCLUSION: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.",
            "question": "What molecule is targeted by Avelumab?",
            "answers": {
                "answer_start": 954,
                "text": "PD-L1"
            }
        },
        {
            "context": "Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.",
            "question": "When was empagliflozin FDA approved?",
            "answers": {
                "answer_start": 228,
                "text": "2014"
            }
        },
        {
            "context": "The physiological target for LeuRS translational quality control is norvaline. The fidelity of protein synthesis depends on the capacity of aminoacyl-tRNA synthetases (AARSs) to couple only cognate amino acid-tRNA pairs. If amino acid selectivity is compromised, fidelity can be ensured by an inherent AARS editing activity that hydrolyses mischarged tRNAs. Here, we show that the editing activity of Escherichia coli leucyl-tRNA synthetase (EcLeuRS) is not required to prevent incorrect isoleucine incorporation. Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline. This conclusion follows from a reassessment of the discriminatory power of LeuRS against isoleucine and the demonstration that a LeuRS editing-deficient E. coli strain grows normally in high concentrations of isoleucine but not under oxygen deprivation conditions when norvaline accumulates to substantial levels. Thus, AARS-based translational quality control is a key feature for bacterial adaptive response to oxygen deprivation. The non-essential role for editing under normal bacterial growth has important implications for the development of resistance to antimicrobial agents targeting the LeuRS editing site.",
            "question": "Which is the physiological target for LeuRS translational quality control?",
            "answers": {
                "answer_start": 68,
                "text": "norvaline"
            }
        },
        {
            "context": "RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.",
            "question": "Which annotated database of A-to-I RNA editing is available?",
            "answers": {
                "answer_start": 315,
                "text": "RADAR"
            }
        },
        {
            "context": "Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk. Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine's effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.",
            "question": "What alternate indication has Vanoxerine been repositioned for?",
            "answers": {
                "answer_start": 486,
                "text": "atrial fibrillation and flutter"
            }
        },
        {
            "context": "Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 524,
                "text": "xa"
            }
        },
        {
            "context": "Growing skull fracture in a patient with cerebral hemiatrophy. A growing skull fracture or leptomeningeal cyst most commonly occurs in children under the age of 3 years, and is extremely rare in adults. The reason for a growing skull fracture is usually a dural tear in association with the fracture. This paper presents an 18-year-old mentally retarded patient with cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome) associated with a growing skull fracture in the ipsilateral hemicranium, in whom not only a dural tear but also the ipsilaterally displaced and dilated lateral ventricle due to the original disease apparently contributed to the development of growing skull fracture.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 367,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Giant axonal neuropathy diagnosed on skin biopsy. Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 506,
                "text": "GAN gene"
            }
        },
        {
            "context": "A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome. OBJECTIVE: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome. PATIENT & METHODS: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed. RESULTS: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation. CONCLUSIONS: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 397,
                "text": "Xq28"
            }
        },
        {
            "context": "Evidence supporting idarucizumab for the reversal of dabigatran. Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or in those requiring an urgent procedure. In an interim analysis of the first 90 participants, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88%-98% of participants, and there were no safety concerns, with no deaths or serious adverse events being attributable to idarucizumab. Supported by these interim results, idarucizumab has been approved in the United States and the European Union for use when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in patients with life-threatening or uncontrolled bleeding. Clinical use of idarucizumab should follow the same processes as patient enrollment in this study, which is projected to be completed in 2016. The outcomes achieved with this specific reversal agent are likely to be of continued interest to treating physicians.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 137,
                "text": "dabigatran"
            }
        },
        {
            "context": "Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3'-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 1967,
                "text": "mTOR"
            }
        },
        {
            "context": "Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DeltaNp73 expression show enhanced resistance to chemotherapy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 142,
                "text": "7"
            }
        },
        {
            "context": "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 728,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-hospital management. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected ingestion of dextromethorphan by 1) describing the process by which an ingestion of dextromethorphan might be managed, 2) identifying the key decision elements in managing cases of dextromethorphan ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to the ingestion of dextromethorphan alone. Co-ingestion of additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions might be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) Patients who exhibit more than mild effects (e.g., infrequent vomiting or somnolence [lightly sedated and arousable with speaking voice or light touch]) after an acute dextromethorphan ingestion should be referred to an emergency department (Grade C). 3) Patients who have ingested 5-7.5 mg/kg should receive poison center-initiated follow-up approximately every 2 hours for up to 4 hours after ingestion. Refer to an emergency department if more than mild symptoms develop (Grade D). 4) Patients who have ingested more than 7.5 mg/kg should be referred to an emergency department for evaluation (Grade C). 5) If the patient is taking other medications likely to interact with dextromethorphan and cause serotonin syndrome, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, poison center-initiated follow-up every 2 hours for 8 hours is recommended (Grade D). 6) Patients who are asymptomatic and more than 4 hours have elapsed since the time of ingestion can be observed at home (Grade C). 7) Do not induce emesis (Grade D). 8) Do not use activated charcoal at home. Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of dextromethorphan within the preceding hour. Its administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grade D). 9) For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression (Grade C). 10) Use intravenous benzodiazepines for seizures and benzodiazepines and external cooling measures for hyperthermia (>104 degrees F, >40 degrees C) for serotonin syndrome. This should be done in consultation with and authorized by EMS medical direction, by a written treatment protocol or policy, or with direct medical oversight (Grade C). 11) Carefully ascertain by history whether other drugs, such as acetaminophen, were involved in the incident and assess the risk for toxicity or for a drug interaction.",
            "question": "Which medication should be administered when managing patients with suspected acute opioid overdose?",
            "answers": {
                "answer_start": 3016,
                "text": "naloxone"
            }
        },
        {
            "context": "Dinutuximab: first global approval. United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 209,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 812,
                "text": "(HAX-1)"
            }
        },
        {
            "context": "Incidence of red-green color blindness in the Basque population. The incidence of red-green colour vision defects was studied in a sample of 392 Basque students (174 males and 218 females), using the Ishihara test cards (1987). The frequency of red-green colour blindness was 4.02 percent in the males and 0.46 percent in the females. The colour blindness frequencies found among males are within the range of other Spanish samples. Nevertheless they are lower than the values reported in other European populations.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 200,
                "text": "Ishihara test"
            }
        },
        {
            "context": "Chaperone-mediated autophagy components are upregulated in sporadic inclusion-body myositis muscle fibres. AIMS: Sporadic inclusion-body myositis (s-IBM) is an age-associated degenerative muscle disease. Characteristic features are muscle-fibre vacuolization and intramuscle-fibre accumulations of multiprotein aggregates, which may result from the demonstrated impairments of the 26S proteasome and autophagy. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif. Lysosome-associated membrane protein type 2A (LAMP2A) and the heat-shock cognate protein 70 (Hsc70) constitute specific CMA components. Neither CMA components nor CMA activity has been studied in normal or disease human muscle, to our knowledge. METHODS: We studied CMA components by immunocytochemistry, immunoblots, real-time PCR and immunoprecipitation in: (a) 16 s-IBM, nine aged-matched normal and nine disease control muscle biopsies; and (b) cultured human muscle fibres (CHMFs) with experimentally inhibited activities of either the 26S proteasome or autophagy. RESULTS: Compared with age-matched controls, in s-IBM muscle, LAMP2A and Hsc70 were on a given transverse section accumulated as aggregates in approximately 5% of muscle fibres, where they (a) colocalized with each other and α-synuclein (α-syn), a CMA-targeted protein; and (b) were bound to each other and to α-syn by immunoprecipitation. By immunoblots, LAMP2A was increased sevenfold P < 0.001 and Hsc70 2.6-fold P < 0.05. LAMP2A mRNA was increased 4.4-fold P < 0.001 and Hsc70 mRNA 1.9-fold P < 0.05. In CHMFs inhibition of either the 26S proteasome or autophagy induced CMA, evidenced by a significant increase of both LAMP2A and Hsc70. CONCLUSIONS: Our study demonstrates, for the first time, up-regulation of CMA components in s-IBM muscle, and it provides further evidence that altered protein degradation is likely an important pathogenic aspect in s-IBM.",
            "question": "Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?",
            "answers": {
                "answer_start": 411,
                "text": "Chaperone-mediated autophagy (CMA)"
            }
        },
        {
            "context": "Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 353,
                "text": "7"
            }
        },
        {
            "context": "The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 812,
                "text": "(HAX-1)"
            }
        },
        {
            "context": "Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. CONTEXT: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T(3) levels. Lack of MCT8 transport of T(3) in neurons could explain the neurological phenotype. OBJECTIVE: Our objective was to determine whether the high T(3) levels could also contribute to some critical features observed in these patients. RESULTS: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T(3) (FT(3)) level (11.3 pmol/liter), without FT(4) and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT(4)) was tested. After PTU (200 mg/d), serum FT(4) was undetectable, FT(3) was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU prescription was continued, high LT(4) doses (100 microg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At that time, serum FT(4) was normal (16.4 pmol/liter), and FT(3) was slightly high (6.6 pmol/liter). Tachycardia was abated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 nmol/liter. CONCLUSIONS: 1) When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT(4) could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.",
            "question": "Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome?",
            "answers": {
                "answer_start": 1695,
                "text": "MCT8"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 286,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Radiographic findings in Shprintzen-Goldberg syndrome. We report the case of a Japanese boy whose dysmorphic features were consistent with those of Shprintzen-Goldberg syndrome. The radiological features were characterized by late-onset craniosynostosis, arachnodactyly, undermodeling of short tubular bones, mildly undermodeled and slightly bowed long bones, twisted ribs and tall vertebral bodies with elongated neural arches. Apart from the craniosynostosis, these skeletal changes resembled those of frontometaphyseal dysplasia, a well-known craniotubular dysplasia. Shprintzen-Goldberg syndrome also shares many clinical features with frontometaphyseal dysplasia.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 237,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. DNA methylation is an epigenetic mark critical for regulating transcription, chromatin structure and genome stability. Although many studies have shed light on how methylation impacts transcription and interfaces with the histone code, far less is known about how it regulates genome stability. We and others have shown that DNA methyltransferase 1 (DNMT1), the maintenance methyltransferase, contributes to the cellular response to DNA damage, yet DNMT1's exact role in this process remains unclear. DNA damage, particularly in the form of double-strand breaks (DSBs), poses a major threat to genome integrity. Cells therefore possess a potent system to respond to and repair DSBs, or to initiate cell death. In the current study, we used a near-infrared laser microirradiation system to directly study the link between DNMT1 and DSBs. Our results demonstrate that DNMT1 is rapidly but transiently recruited to DSBs. DNMT1 recruitment is dependent on its ability to interact with both PCNA and the ATR effector kinase CHK1, but is independent of its catalytic activity. In addition, we show for the first time that DNMT1 interacts with the 9-1-1 PCNA-like sliding clamp and that this interaction also contributes to DNMT1 localization to DNA DSBs. Finally, we demonstrate that DNMT1 modulates the rate of DSB repair and is essential for suppressing abnormal activation of the DNA damage response in the absence of exogenous damage. Taken together, our studies provide compelling additional evidence for DNMT1 acting as a regulator of genome integrity and as an early responder to DNA DSBs.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 513,
                "text": "DNMT1"
            }
        },
        {
            "context": "Temporo-spatial analyses define epileptogenic and functional zones in a case of Dyke-Davidoff-Masson syndrome. Dyke-Davidoff-Masson syndrome (DDMS) is a rare epilepsy syndrome that is characterized by cerebral hemiatrophy, homolateral skull hyperplasia, hyperpneumatization of the paranasal sinuses, seizures with or without mental retardation, and contralateral hemiparesis. We describe a case of DDMS in a 40-year-old female who had complex partial seizures with occasional secondary generalization since the age of 4 years. Her seizure frequency was 10-20 seizures/month even though she took four antiepileptic drugs. We applied magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI, and invasive electroencephalography (EEG) to define her epileptogenic and functional zones. Brain MRI showed prominent atrophy in the left frontal dorsal and lateral regions and mild atrophy of the left superior temporal gyrus and left parietal gyri. Interictal PET revealed decreased glucose metabolism in the atrophic regions. Functional MRI demonstrated that the inferior frontal and inferior parieto-occipital regions of the right hemisphere were activated by language testing. Invasive EEG revealed that the left lateral temporal lobe was the sole source of her seizures. Our results imply that the \"metabolic border zone\" rather than the atrophic region plays an important role in seizure activity, and that reorganization of functional zones occur after cerebral damage early in life.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 201,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 2705,
                "text": "dabigatran"
            }
        },
        {
            "context": "McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1013,
                "text": "XK"
            }
        },
        {
            "context": "A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China. BACKGROUND: The mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. METHODS: Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. RESULTS: A novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. CONCLUSION: This study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 148,
                "text": "TYR"
            }
        },
        {
            "context": "Classification schemes of cranial dural arteriovenous fistulas. The clinical presentation of dural arteriovenous fistulas (DAVFs), in particular the associated risk of intracranial hemorrhage, shows a strong correlation with their pattern of venous drainage. The two most commonly used and clinically accepted DAVF classifications are the Merland-Cognard classification and the Borden classification, both based on the morphology of the venous drainage. A revised classification that grades DAVFs through a combination of angiographic and clinical features has also been proposed. This article offers a review of these various classification schemes, and discusses their application to treatment decision making.",
            "question": "Borden classification is used for which disease?",
            "answers": {
                "answer_start": 310,
                "text": "DAVF"
            }
        },
        {
            "context": "Successful resolution of bowel obstruction in a patient with hereditary angioedema. Hereditary angioedema (HAE), a rare genetic disorder caused by a deficiency of the C1 esterase inhibitor, leads to an episodic, self-limiting increase in vascular permeability. Related symptoms commonly include recurrent, intractable abdominal pain, vomiting, and/or diarrhea. DX-88 (ecallantide), a 60-amino acid recombinant protein discovered through phage display technology, is a highly specific, potent inhibitor of human plasma kallikrein that has been used successfully in the treatment of patients experiencing acute HAE attacks. This case study involves a 65-year-old woman who presented with severe abdominal pain, cramping, and nausea. The study describes the use of a video obtained by capsule endoscopy for the direct imaging of bowel occlusion in a patient with HAE that resolved upon treatment with DX-88. After administration of DX-88, 80 mg intravenously, abdominal pain and nausea resolved within 30 min. Capsule endoscopy demonstrated a coincident resolution of the bowel wall edema, with a return to normal within approximately 1.5 h of DX-88 administration. This case study demonstrates that DX-88 can produce dramatic clinical benefits in a patient with an acute abdominal HAE attack, resolving both symptoms and pathologic signs. Furthermore, it illustrates the usefulness of videos obtained from capsule endoscopy in identifying the presence of bowel occlusion and demonstrating its subsequent rapid resolution upon administration of DX-88.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 368,
                "text": "ecallantide"
            }
        },
        {
            "context": "Future agents and treatment directions in multiple myeloma. The development of bortezomib and immunomodulatory agents resulted in a revolution in the treatment of multiple myeloma (MM). Moreover, second-generation proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide) have recently been approved. Nevertheless, the incurability of this disease requires other drugs with different mechanisms of action to either prolong the survival of patients refractory to current therapies, or achieve cure. Active research has been done exploring the pathogenesis of MM and searching for novel, druggable targets. In this regard, some of these novel agents seem promising, such as monoclonal antibodies (anti-CD38 - daratumumab or anti-CS1 - elotuzumab) or the kinesin protein inhibitor Arry-520. Other agents under investigation are kinase inhibitors, signaling pathways inhibitors or deacetylase inhibitors. With so many novel agents under investigation, future therapy in MM will probably involve the combined use of the already approved drugs with some of those newly discovered.",
            "question": "What is the target of daratumumab?",
            "answers": {
                "answer_start": 721,
                "text": "CD38"
            }
        },
        {
            "context": "MR enterography of small-bowel lymphoma: potential for suggestion of histologic subtype and the presence of underlying celiac disease. OBJECTIVE: The objective of our study was to evaluate the morphologic appearances of small-bowel lymphoma using MR enterography to identify key morphologic traits capable of providing an association between imaging manifestations and likely histologic diagnosis. MATERIALS AND METHODS: Over a 54-month period, 10 patients with subsequently confirmed small-bowel lymphoma were imaged using a standardized MR enterography technique. Retrospective chart review was performed to detect associated disease processes, such as celiac disease. The morphologic characteristics of each segment with lymphomatous involvement were evaluated with respect to tumor location, tumor size, mural characteristics, fold features, loop dilatation, luminal stricturing, mesenteric or antimesenteric distribution, mesenteric involvement, and signal intensity. RESULTS: Nineteen distinct segments of lymphomatous involvement were identified in 10 patients, and underlying celiac disease was confirmed in six of the 10 patients. This patient group comprised 10 patients with non-Hodgkin's lymphoma (NHL) of various subtypes. No cases of Hodgkin's lymphoma were encountered. Analysis revealed celiac NHL enteropathy to have a tendency toward localization to a single, long (> 10 cm), smooth continuous bowel segment, often with aneurysmal loop dilatation, in the absence of a distinct mesenteric or antimesenteric distribution. Luminal stricturing was encountered in cases of low-grade lymphoma, whereas mesenteric fat infiltration represented a characteristic of high-grade disease. CONCLUSION: We describe the characteristics of small-bowel lymphoma on MR enterography, identifying a number of key features that may help the interpreting radiologist in suggesting the underlying histologic subtype and whether the presence of underlying celiac disease is likely.",
            "question": "What disease is small bowel lymphoma commonly associated with",
            "answers": {
                "answer_start": 119,
                "text": "celiac disease"
            }
        },
        {
            "context": "Carpal Tunnel Syndrome: Initial Management and the Treatment of Recalcitrant Patients. Carpal tunnel syndrome (CTS) is a focal compressive neuropathy of the median nerve at the level of the wrist. CTS is the most common type of compressive neuropathy that occurs in the upper extremity. Typically, patients with CTS have paresthesia, pain, and numbness in the radial three and one-half digits. Nighttime symptoms are more common earlier in the disease process, with daytime symptoms becoming more frequent as CTS progresses. Electrodiagnostic studies may be performed to confirm a diagnosis of CTS or to obtain a baseline before surgical treatment; however, electrodiagnostic studies may be normal in a subset of patients who have CTS. Patients who have mild CTS should undergo an initial trial of nonsurgical treatment that includes lifestyle modifications, nighttime splinting, and corticosteroid injections. Carpal tunnel release should be performed in patients in whom nonsurgical treatment fails and patients who have acute CTS secondary to infection or trauma or have advanced symptoms. Recalcitrant CTS, which may occur in as many as 25% of patients who undergo carpal tunnel release, most commonly results from an incomplete transverse carpal ligament release or an incorrect initial diagnosis. Patients with recurrent symptoms often have perineural fibrosis that tethers the median nerve.",
            "question": "What nerve is involved in carpal tunnel syndrome?",
            "answers": {
                "answer_start": 1384,
                "text": "median"
            }
        },
        {
            "context": "Identification of a heteromeric complex that promotes DNA replication origin firing in human cells. Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holohelicase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.",
            "question": "Which factor interacts with Treslin/TICRR throughout the cell cycle of human cells?",
            "answers": {
                "answer_start": 403,
                "text": "MDM two binding protein (MTBP)"
            }
        },
        {
            "context": "Idarucizumab for Dabigatran Reversal. BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 1951,
                "text": "dabigatran"
            }
        },
        {
            "context": "Type I interferon in organ-targeted autoimmune and inflammatory diseases. A significant role for IFNα in the pathogenesis of systemic lupus erythematosus is well supported, and clinical trials of anti-IFNα monoclonal antibodies are in progress in this disease. In other autoimmune diseases characterized by substantial inflammation and tissue destruction, the role of type I interferons is less clear. Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus. In both of those diseases, presence of the interferon signature has been associated with more significant clinical manifestations. At the same time, evidence supports an anti-inflammatory and beneficial role of IFNβ locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNβ. As can also be proposed for type I diabetes mellitus, type I interferon appears to contribute to the development of autoimmunity and disease progression in multiple autoimmune diseases, while maintaining some capacity to control established disease - particularly at local sites of inflammation. Recent studies in both rheumatoid arthritis and multiple sclerosis suggest that quantification of type I interferon activity or target gene expression might be informative in predicting responses to distinct classes of therapeutic agents.",
            "question": "Which is the most common gene signature in Rheumatoid Arthritis patients?",
            "answers": {
                "answer_start": 531,
                "text": "interferon signature"
            }
        },
        {
            "context": "European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 359,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 131,
                "text": "MRSA"
            }
        },
        {
            "context": "Explaining intermediate filament accumulation in giant axonal neuropathy. Giant axonal neuropathy (GAN)(1) is a rare autosomal recessive neurological disorder caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptor proteins.(1) This disease is characterized by the aggregation of Intermediate Filaments (IF)-cytoskeletal elements that play important roles in cell physiology including the regulation of cell shape, motility, mechanics and intra-cellular signaling. Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or \"giant axons.\" A mechanistic understanding of GAN IF pathology has eluded researchers for many years. In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome. Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 186,
                "text": "GAN gene"
            }
        },
        {
            "context": "Oculocutaneous albinism type 1: the last 100 years. Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 737,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Bacterial vaginosis. Bacterial vaginosis is the most common cause of vaginitis, affecting over 3 million women in the United States annually. Depopulation of lactobacilli from the normal vaginal flora and overgrowth of Gardnerella vaginalis and other anaerobic species are the presumed etiology. To date, no scientific evidence shows that bacterial vaginosis is a sexually transmitted disease. Malodorous vaginal discharge is the most common symptom. Differential diagnoses include trichomoniasis, moniliasis, and allergic or chemical dermatitis. The diagnosis is confirmed when at least three of the following four findings are present (Amsel's criteria): 1) thin, homogenous discharge, 2) pH greater than 4.5, 3) positive amine test, and 4) presence of clue cells. The sensitivity and positive predictive value are both 90%. Vaginal Gram stain is also reliable and allows for permanent record. Cultures are nonspecific because G. vaginalis resides in normal vaginal flora as well. Papanicolaou smears are not particularly sensitive, but their positive predictive value is very high. The Centers for Disease Control and Prevention recommend three treatment regimens in nonpregnant patients: oral metronidazole (500 mg twice daily for 7 days), intravaginal 2% clindamycin cream (one applicatorful at bedtime for 7 days), or intravaginal metronidazole gel (one to two applicatorfuls per day for 5 days). Alternative regimens include a single 2-g oral dose of metronidazole or a 7-day course of oral clindamycin, 300 mg twice daily. The association between bacterial vaginosis and adverse pregnancy outcomes has satisfied many criteria for a causal inference. Treatment of bacterial vaginosis in women with previous history of preterm labor results in fewer preterm deliveries than in untreated women from the same population.",
            "question": "Clue cells are characteristics to which causative bacteria of vaginitis?",
            "answers": {
                "answer_start": 219,
                "text": "Gardnerella vaginalis"
            }
        },
        {
            "context": "ACS chemical neuroscience molecule spotlight on semagacestat (LY450139). Semagacestat (LY450139) is a novel γ-secretase inhibitor currently in late-stage development by Eli Lilly and Company as a potential treatment for Alzheimer's disease (AD). Semagacestat is currently being studied in two phase III clinical trials.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 48,
                "text": "semagacestat"
            }
        },
        {
            "context": "The role of LOX and LOXL2 in scar formation after glaucoma surgery. PURPOSE: The aim of this study was to elucidate the role of lysyl oxidase (LOX) and lysyl oxidase like (LOXL) 2 in pathologic wound healing after glaucoma surgery. We therefore investigated the expression of LOX and LOXL2 and evaluated the therapeutic potential of anti-LOX (GS-639556, formerly M64) and anti-LOXL2 (GS-607601, formerly AB0023) antibodies in a rabbit model of glaucoma trabeculectomy. METHODS: Ocular expression of LOX and LOXL2 was investigated by immunohistologic staining at different time points after trabeculectomy. Treatment with GS-639556 or GS-607601 was initiated in rabbits immediately after trabeculectomy by giving both intracameral and subconjunctival injections. Thereafter, the antibodies were given twice a week subconjunctivally until day 30 after surgery (day of euthanization). Treatment outcome was studied by clinical investigation of the bleb and by immunohistochemical analysis of angiogenesis, inflammation, and collagen deposition. RESULTS: LOX and LOXL2 were both upregulated in Tenon's capsule and the conjunctiva after glaucoma surgery. Repeated administration of LOX- or LOXL2-targeting monoclonal antibodies increased bleb area and bleb survival. Analyses of immunohistologic stainings showed that both antibodies significantly decreased fibrosis, whereas the anti-LOXL2 antibody also significantly reduced blood vessel density and inflammation. CONCLUSIONS: Targeting LOXL2 with an inhibitory monoclonal antibody (GS-607601) reduced pathologic angiogenesis, inflammation, and fibrosis. These results suggest that LOXL2 could be an appealing target for treatment of scar formation after glaucoma surgery, and point to the potential therapeutic benefits of simtuzumab, a humanized monoclonal antibody derived from GS-607601.",
            "question": "What is the drug target for Simtuzumab?",
            "answers": {
                "answer_start": 1629,
                "text": "LOXL2"
            }
        },
        {
            "context": "Bertolotti's syndrome revisited. Transitional vertebrae of the lumbar spine. Bertolotti's syndrome refers to the association of back pain with lumbosacral transitional vertebrae. Such vertebrae were observed in 140 of 2,000 adults with back pain over a 4-year period of study. Each patient had radiographic evaluation of the lumbar spine by plain films as well as a sectional imaging modality (magnetic resonance [MR] or computed tomography [CT]). The overall incidence of structural pathology (eg, spinal stenosis and disc protrusion) detected by CT or MR was not apparently higher in patients with transitional vertebrae, but the distribution of these lesions was significantly different. Disc bulge or herniation, when it occurred, was nearly nine times more common at the interspace immediately above the transitional vertebra than at any other level. Spinal stenosis and nerve root canal stenosis were more common at or near the interspace above the transitional vertebra than at any other level. Degenerative change at the articulation between the transverse process of the transitional vertebra and the pelvis was an uncommon occurrence; when seen there was no significant correlation with the reported side of pain. It is postulated that hypermobility and altered stresses become concentrated in the spine at the level immediately above a lumbar transitional vertebra. Accelerated disc and facet joint degeneration at this level may then result.",
            "question": "Abnormality in which vertebral region is important in the Bertolotti's syndrome?",
            "answers": {
                "answer_start": 143,
                "text": "lumbosacral"
            }
        },
        {
            "context": "Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.",
            "question": "Which type of cells is affected in Amyotrophic Lateral Sclerosis?",
            "answers": {
                "answer_start": 238,
                "text": "motor neurons"
            }
        },
        {
            "context": "Chicken trunk neural crest migration visualized with HNK1. The development of the nervous system involves cells remaining within the neural tube (CNS) and a group of cells that delaminate from the dorsal neural tube and migrate extensively throughout the developing embryo called neural crest cells (NCC). These cells are a mesenchymal highly migratory group of cells that give rise to a wide variety of cell derivatives: melanocytes, sensory neurons, bone, Schwann cells, etc. But not all NCC can give rise to all derivatives, they have fate restrictions based on their axial level of origin: cranial, vagal, trunk and sacral. Our aim was to provide a thorough presentation on how does trunk neural crest cell migration looks in the chicken embryo, in wholemount and in sections using the unique chicken marker HNK1. The description presented here makes a good guideline for those interested in viewing trunk NCC migration patterns. We show how before HH14 there are few trunk NCC delaminating and migrating, but between HH15 through HH19 trunk NCC delaminate in large numbers. Melanocytes precursors begin to enter the dorsolateral pathway by HH17. We found that by HH20 HNK1 is not a valid good marker for NCC and that HNK1 is a better marker than Sox10 when looking at neural crest cells morphology and migration details.",
            "question": "Where do the Schwann cells and melanocytes originate from?",
            "answers": {
                "answer_start": 280,
                "text": "neural crest cells"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 1224,
                "text": "CisMapper"
            }
        },
        {
            "context": "INCA: synonymous codon usage analysis and clustering by means of self-organizing map. UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.",
            "question": "Which tool employs self organizing maps for analyzing synonymous codon usage?",
            "answers": {
                "answer_start": 132,
                "text": "INCA"
            }
        },
        {
            "context": "Use of SERMs for treatment in postmenopausal women. Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have varying estrogen agonist and antagonist activities in different tissues, most likely due to the receptor conformation changes associated with that SERM's binding and the subsequent effect on transcription. Clinical trials aim to differentiate amongst SERMs on selected target tissues for use in postmenopausal women including effects on breast, bone, cardiovascular venous thrombosis risk, endometrium, vagina, vasomotor symptoms, and brain. This paper describes differences in clinical effects on selected target tissues of SERMs that are approved, discontinued or in development. FDA approved SERMs include tamoxifen and toremifene used for prevention and treatment of breast cancer, raloxifene approved for prevention and treatment of osteoporosis and prevention of invasive breast cancer, and ospemifene approved for treatment of dyspareunia from menopausal vaginal atrophy. The FDA approved first tissue selective estrogen complex (TSEC) a pairing of conjugated equine estrogens with the SERM, bazedoxifene. This pairing reduces the risk of endometrial hyperplasia that can occur with the estrogenic component of the TSEC without the need for a progestogen in women with a uterus. It also allows for the estrogenic benefits on relief of hot flashes and prevention of bone loss without stimulating the breast or the endometrium. In clinical practice, the tissue-selective actions of SERMs, alone or paired with estrogens, allow for individualization in meeting the treatment needs of postmenopausal women by providing targeted tissue effects. This article is part of a Special Issue entitled 'Menopause'.",
            "question": "What is a SERM?",
            "answers": {
                "answer_start": 52,
                "text": "Selective estrogen receptor modulator"
            }
        },
        {
            "context": "Biochemical assay for histone H2A.Z replacement by the yeast SWR1 chromatin remodeling complex. The evolutionarily conserved histone variant H2A.Z has an important role in the regulation of gene expression and the establishment of a buffer to the spread of silent heterochromatin. Saccharomyces cerevisiae Swr1, a Swi2/Snf2-related ATPase, is the catalytic core of a multisubunit chromatin remodeling enzyme, called the SWR1 complex, that efficiently replaces conventional histone H2A in nucleosomes with histone H2A.Z. Swr1 is required for the deposition of histone H2A.Z at stereotypical promoter locations in vivo, and Swr1 and H2A.Z commonly regulate a subset of yeast genes. Here, we describe an integrated nucleosome assembly-histone replacement system whereby histone exchange by chromatin remodeling activities may be analyzed in vitro. The system demonstrates ATP- and SWR1-complex-dependent replacement of histone H2A for histone H2A.Z on a preassembled nucleosome array. This system may also be adapted to analyze dynamic interactions between chromatin remodeling and modifying enzymes, histone chaperones, and nucleosome substrates containing canonical, variant, or covalently modified histones.",
            "question": "Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?",
            "answers": {
                "answer_start": 420,
                "text": "SWR1"
            }
        },
        {
            "context": "A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 201,
                "text": "Xa"
            }
        },
        {
            "context": "RET mutation Tyr791Phe: the genetic cause of different diseases derived from neural crest. Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 479,
                "text": "RET"
            }
        },
        {
            "context": "Focal cortical dysplasia - review. Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults.Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed - from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes.New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life.Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias.THE MOST COMMON FINDINGS ON MRI IMAGING INCLUDE: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure-free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy.However, in type I cortical dysplasia, MR imaging is often normal, and also in both types the lesion seen on MRI may be smaller than the seizure-generating region seen in the EEG. The abnormalities may also involve vital for life brain parts, where curative surgery will not be an option. Therefore, other diagnostic imaging techniques such as FDG PET, MEG, DTI and intra-cranial EEG are widely used to establish the diagnosis and to decide on management.With advances in both genetics and neuroimaging, we may develop a better understanding of patients with drug-resistant epilepsy, which will help us to provide more successful pharmacological and/or surgical treatment in the future.",
            "question": "Which disorder is rated by Palmini classification?",
            "answers": {
                "answer_start": 439,
                "text": "focal cortical dysplasia"
            }
        },
        {
            "context": "Tall stature and gonadal dysgenesis in a non-mosaic girl 45,X. Turner's syndrome, also known as 'monosomy X', is a genetic disorder that occurs in 1/2,500 female births and is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. While the classic karyotype related to Turner's syndrome is 45,X, the majority of those affected actually have a mosaic chromosomal complement, most often with a second normal cell line (46,XX). The resulting phenotype is variable and related to the underlying chromosomal pattern, but it is characterized by three cardinal features: short stature (around 100%), ovarian failure (>90%) and congenital lymphedema (>80%). In this paper we report a molecular and cytogenetic investigation of a 26-year-old female with non-mosaic 45,X karyotype, who has a stature of 170 cm without GH treatment, and whose only apparent Turner feature is gonadal dysgenesis. The only possible explanation for the absence of Turner phenotype is the hidden mosaicism combined with an untreated gonadal dysgenesis. Our results support the theory that significant ascertainment bias exists in our understanding of Turner's syndrome.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 495,
                "text": "X"
            }
        },
        {
            "context": "CTCF Binding Polarity Determines Chromatin Looping. CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional (3D) organization of chromatin. In this study, we assayed the 3D genomic contact profiles of a large number of CTCF binding sites with high-resolution 4C-seq. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR/Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal, convergent CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher-order chromatin structure.",
            "question": "What is the preferred orientation of CTCF binding sites for chromatin looping?",
            "answers": {
                "answer_start": 696,
                "text": "convergent"
            }
        },
        {
            "context": "In UV-irradiated Saccharomyces cerevisiae, overexpression of Swi2/Snf2 family member Rad26 increases transcription-coupled repair and repair of the non-transcribed strand. Nucleotide excision repair (NER) in eukaryotes is a pathway conserved from yeast to humans that removes many bulky chemical adducts and UV-induced photoproducts from DNA in a relatively error-free manner. In addition to the recognition and excision of DNA damage throughout the genome (GGR), there exists a mechanism, transcription-coupled nucleotide excision repair (TCR), for recognizing some types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast and mammalian cells. An obstacle in the repair of the transcribed strand of active genes is the RNA polymerase complex stalled at sites of DNA damage. The stalled RNA polymerase complex may then mediate recruitment of repair proteins to damage in the transcribed strand. Proteins enabling TCR are the Cockayne syndrome B (CSB) protein in humans and its yeast homologue Rad26. Both CSB and Rad26 belong to the Swi2/Snf2 family of DNA-dependent ATPases, which change DNA accessibility to proteins by altering chromatin structure. To address how Rad26 functions in yeast repair, we used the genetic approach of overexpressing Rad26 and examined phenotypic changes, i.e. changes in NER. We found that repair of both the transcribed and the non-transcribed strands is increased. In addition, overexpression of Rad26 partially bypasses the requirement for Rad7 in GGR, specifically in the repair of non-transcribed sequences. As TCR takes place in very localized regions of DNA (i.e. within genes) in wild-type cells, we propose that overexpression of recombinant Rad26 increases accessibility of the damaged DNA in chromatin for interaction with repair proteins.",
            "question": "Which gene strand is targeted by transcription-coupled repair (TCR)?",
            "answers": {
                "answer_start": 590,
                "text": "the transcribed strand"
            }
        },
        {
            "context": "Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.",
            "question": "In which yeast chromosome does the rDNA cluster reside?",
            "answers": {
                "answer_start": 1366,
                "text": "chromosome XII"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 406,
                "text": "Stroke"
            }
        },
        {
            "context": "Tyrosine kinase inhibitor use in pediatric Philadelphia chromosome-positive acute lymphoblastic anemia. Until recently, pediatric Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when treated with chemotherapy alone, and only modest survival benefits were obtained with the widespread use of hematopoietic stem cell transplantation (HSCT). The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial showed that the addition of imatinib to intensive chemotherapy did not cause increased toxicity and resulted in 3-year event-free survival rates that were more than double those of historical control data from the pre-imatinib era. These findings create a new paradigm for integrating molecularly targeted agents with conventional chemotherapy and call for a reassessment of the routine use of HSCT for children and adolescents with Ph(+) ALL. Second-generation TKIs have theoretical advantages over imatinib, and are now being tested in Ph(+) ALL. The focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, and TKI in Ph(+) ALL. In the coming years, it is anticipated that additional agents will become available to potentiate TKI therapy and/or circumvent TKI resistance in Ph(+) ALL. Recent genomic studies have identified a subtype of high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar to that of Ph(+) ALL, suggestive of active kinase signaling. Many of these Ph-like ALL cases harbor chromosome rearrangements and mutations that dysregulate cytokine receptor and kinase signaling, and these leukemias may also be candidates for TKI therapy.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 558,
                "text": "BCR-ABL"
            }
        },
        {
            "context": "Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with α-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 519,
                "text": "FSHD"
            }
        },
        {
            "context": "Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis. Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the \"giant\" axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot-Marie-Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as \"giant axonal neurodegeneration.\"",
            "question": "Which gene is involved in Giant Axonal Neuropathy?",
            "answers": {
                "answer_start": 391,
                "text": "GAN gene"
            }
        },
        {
            "context": "Regulation of chromatin structure by site-specific histone H3 methyltransferases. The organization of chromatin into higher-order structures influences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modifier factors. Here we show that human SUV39H1 and murine Suv39h1--mammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4--encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also influenced by pre-existing modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-specific H3 tail modifications and suggest a dynamic mechanism for the regulation of higher-order chromatin.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 726,
                "text": "SET domain"
            }
        },
        {
            "context": "Effects of the tomato pathogen Fusarium oxysporum f. sp. radicis-lycopersici and of the biocontrol bacterium Pseudomonas fluorescens WCS365 on the composition of organic acids and sugars in tomato root exudate. The effects of the pathogenic fungus Fusarium oxysporum f. sp. radicis-lycopersici and of the bacterial biocontrol strain Pseudomonas fluorescens WCS365, and of both microbes, on the amounts and composition of root exudate components of tomato plants grown in a gnotobiotic stonewool substrate system were studied. Conditions were selected under which introduction of F. oxysporum f. sp. radicis-lycopersici caused severe foot and root rot, whereas inoculation of the seed with P. fluorescens WCS365 decreased the percentage of diseased plants from 96 to 7%. This is a much better disease control level than was observed in potting soil. Analysis of root exudate revealed that the presence of F. oxysporum f. sp. radicis-lycopersici did not alter the total amount of organic acids, but that the amount of citric acid decreased and that of succinic acid increased compared with the nontreated control. In contrast, in the presence of the P. fluorescens biocontrol strain WCS365, the total amount of organic acid increased, mainly due to a strong increase of the amount of citric acid, whereas the amount of succinic acid decreased dramatically. Under biocontrol conditions, when both microbes are present, the content of succinic acid decreased and the level of citric acid was similar to that in the nontreated control. The amount of sugar was approximately half that of the control sample when either one of the microbes was present alone or when both were present. Analysis of the interactions between the two microbes grown together in sterile tomato root exudate showed that WCS365 inhibited multiplication of F. oxysporum f. sp. radicis-lycopersici, whereas the fungus did not affect the number of CFU of the bacterium.",
            "question": "Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?",
            "answers": {
                "answer_start": 15,
                "text": "tomato"
            }
        },
        {
            "context": "Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.",
            "question": "Which gene has been implicated in Majeed Syndrome?",
            "answers": {
                "answer_start": 1598,
                "text": "LPIN2"
            }
        },
        {
            "context": "Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DeltaNp73 expression show enhanced resistance to chemotherapy.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 239,
                "text": "7"
            }
        },
        {
            "context": "Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. BACKGROUND: In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti-interleukin-17-receptor monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis. METHODS: We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physician's global assessment at week 12. RESULTS: A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physician's global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%). CONCLUSIONS: Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).",
            "question": "What molecule is targeted by brodalumab?",
            "answers": {
                "answer_start": 20,
                "text": "interleukin-17"
            }
        },
        {
            "context": "Mechanistic insight into the relationship between N-terminal acetylation of α-synuclein and fibril formation rates by NMR and fluorescence. Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body inclusions of patients with Parkinson's disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylation on fibrillation by first establishing a quantitative relationship between monomer secondary structural propensity and fibril assembly kinetics, and secondly by demonstrating in the N-terminal acetylated form of the early onset A53T mutation, that N-terminal transient helices formed and/or inhibited by N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical shifts and fluorescence experiments, we report that secondary structural propensity in residues 5-8, 14-31, and 50-57 are highly correlated to fibril growth rate. A four-way comparison of secondary structure propensity and fibril growth rates of N-terminally acetylated A53T and WT αSyn with non-acetylated A53T and WT αSyn present novel mechanistic insight into the role of N-terminal acetylation in amyloid fibril formation. We show that N-terminal acetylation inhibits the formation of the \"fibrillation promoting\" transient helix at residues 14-31 resulting from the A53T mutation in the non-acetylated variant and supports the formation of the \"fibrillation inhibiting\" transient helix in residues 1-12 thereby resulting in slower fibrillation rates relative to the previously studied non-acetylated A53T variant. Our results highlight the critical interplay of the region-specific transient secondary structure of the N-terminal region with fibrillation, and the inhibitory role of the N-terminal acetyl group in fibril formation.",
            "question": "Which is the primary protein component of Lewy bodies?",
            "answers": {
                "answer_start": 168,
                "text": "αSyn"
            }
        },
        {
            "context": "Food sharing is linked to urinary oxytocin levels and bonding in related and unrelated wild chimpanzees. Humans excel in cooperative exchanges between unrelated individuals. Although this trait is fundamental to the success of our species, its evolution and mechanisms are poorly understood. Other social mammals also build long-term cooperative relationships between non-kin, and recent evidence shows that oxytocin, a hormone involved in parent-offspring bonding, is likely to facilitate non-kin as well as kin bonds. In a population of wild chimpanzees, we measured urinary oxytocin levels following a rare cooperative event--food sharing. Subjects showed higher urinary oxytocin levels after single food-sharing events compared with other types of social feeding, irrespective of previous social bond levels. Also, urinary oxytocin levels following food sharing were higher than following grooming, another cooperative behaviour. Therefore, food sharing in chimpanzees may play a key role in social bonding under the influence of oxytocin. We propose that food-sharing events co-opt neurobiological mechanisms evolved to support mother-infant bonding during lactation bouts, and may act as facilitators of bonding and cooperation between unrelated individuals via the oxytocinergic system across social mammals.",
            "question": "Which is the \"bonding hormone\"?",
            "answers": {
                "answer_start": 408,
                "text": "oxytocin"
            }
        },
        {
            "context": "Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. BACKGROUND: Eosinophils may play an important role in the pathogenesis of atopic dermatitis (AD). Interleukin-5 is essential for eosinophil growth, differentiation and migration. A monoclonal antibody to human interleukin-5 (mepolizumab) was developed for atopic diseases. This study was designed to study the effect of mepolizumab in AD. METHODS: Two single doses of 750 mg mepolizumab, given 1 week apart, were studied in patients with moderate to severe AD using a randomized, placebo-controlled parallel group design. The primary endpoint of 'success' to treatment was defined as the percentage of patients with at least 'marked improvement' after 2 weeks as assessed by the Physician's Global Assessment of Improvement (PGA). Furthermore, SCORing AD (SCORAD), pruritus scoring, number of blood eosinophils and serum thymus and activation-regulated chemokine (TARC) values served as secondary endpoints. Fluticasone propionate cream 0.05%, once daily could be used as rescue medication from day 16 if no improvement was recorded. RESULTS: Eighteen patients received mepolizumab and 22 placebo treatment. Peripheral blood eosinophil numbers were significantly reduced in the treatment group compared with placebo (P < 0.05). No clinical success was reached by PGA assessment (P = 0.115), SCORAD (P = 0.293), pruritus scoring and TARC values in the mepolizumab-treated group compared with placebo. However, modest improvement (<50% improvement) assessed by PGA was scored significantly more in the mepolizumab-treated group compared with placebo (P < 0.05). CONCLUSION: Two single doses of 750 mg mepolizumab did not result in clinical success in patients with AD, despite a significant decrease in peripheral blood eosinophils.",
            "question": "Which molecule is targeted by a monoclonal antibody Mepolizumab?",
            "answers": {
                "answer_start": 316,
                "text": "interleukin-5"
            }
        },
        {
            "context": "Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is less effective in maintaining hematologic remissions in blast crisis patients. Our group has previously described several cell lines made resistant to imatinib. We now examine the question of cross-resistance to other chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML cell lines were assessed by caspase-3 and MTS assays for their proliferative response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine (HHT) and hydroxyurea (HU), either alone or in combination with imatinib. Primary blasts from advanced-stage CML patients refractory to imatinib therapy were studied by semi-solid media clonogenic assays. We found that these drugs are generally capable of major inhibition of proliferation of the CML cell lines, although differential responses to DNR and HHT were noted between some sensitive and resistant cell line pairs, implying that resistance to imatinib may confer a growth advantage under such conditions. The four drugs were also effective in preventing the formation of progenitor cell colonies from CML patients both before treatment with imatinib, and after relapse on the drug. Isobolographic analysis implied that these drugs will generally combine well with imatinib, and in some cases will be synergistic. We conclude that Ara-C, DNR or HHT, either alone or in combination with imatinib, are likely to be the best therapeutic alternatives in the management of patients who become resistant to imatinib monotherapy.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 213,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Slings in iatrogenic male incontinence: Current status. OBJECTIVES: The increasing number of prostatectomies entails an increasing number of patients suffering from iatrogenic incontinence despite improved surgical techniques. The severity of this problem often requires invasive treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options. Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems. The aim of this review is to critically report the current status of sling systems in the treatment of iatrogenic male incontinence. MATERIALS AND METHODS: MEDLINE and PubMed databases were searched and all articles between 1974 and 2009 were evaluated. RESULTS: With regard to bone-anchored, readjustable, and trans-obturator slings systems, cure rates ranged between 58.0% and 86.0%, 55.5% and 73.0%, and 40.0% and 63.0%, respectively, while major complication rates ranged between 0 and 14.5%, 10.0 and 22.2%, and 0 and 10.0%, respectively. CONCLUSIONS: Suburethral slings are the only alternative techniques which can be favorably compared with the AUS, showing more advantages with respect to AUS implantations which are mainly represented by a quick and less invasive approach, low morbidity, and low costs. In spite of the difficulty in identifying the most effective sling procedure, overall, sling systems can be recommended for patients with persistent mild or moderate incontinence. However, the indication can also be extended to patients with severe incontinence, after appropriate counseling, allowing AUS implantation in the event of sling failure.",
            "question": "What is the gold standard treatment for Iatrogenic male incontinence?",
            "answers": {
                "answer_start": 430,
                "text": "artificial urethral sphincter"
            }
        },
        {
            "context": "[Alpha-synucleinopathies]. The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known.",
            "question": "What is the main component of the Lewy bodies?",
            "answers": {
                "answer_start": 295,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "Drug development based on the metals hypothesis of Alzheimer's disease. The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-beta to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2 is a once per day, orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer's disease.",
            "question": "PBT2 has been tested for which disorder?",
            "answers": {
                "answer_start": 309,
                "text": "Alzheimer's disease"
            }
        },
        {
            "context": "[Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin binding site: structural characterisation of the related copper complex]. Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine.",
            "question": "How many disulfide bridges has the protein hepcidin got?",
            "answers": {
                "answer_start": 588,
                "text": "Hepcidin contains eight cysteine residues that form four disulfide bridges"
            }
        },
        {
            "context": "Phenomenology of \"Lubag\" or X-linked dystonia-parkinsonism. X-linked dystonia-parkinsonism (XDP), or Lubag syndrome, is known to cause progressive dystonia, with or without parkinsonism, among Filipino male adults with maternal roots from the Philippine island of Panay. We present cinematographic material of 11 cases of Lubag carrying the XDP haplotypes who manifest with a wide spectrum of movement disorders, including dystonia, tremor, parkinsonism, myoclonus, chorea, and myorhythmia. Because of overlapping features, Lubag patients are commonly misdiagnosed as idiopathic dystonia, essential tremor, Parkinson's disease, or Parkinson's-plus syndromes. Thus, it is imperative to elicit an exhaustive family history in any Filipino male adult who presents with a movement disorder.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 28,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurofibromatosis type 1 (NF1) is a common genetic disease caused by haploinsufficiency of the NF1 tumor-suppressor gene. Different pathogenetic mechanisms have been identified, with the majority (95%) causing intragenic lesions. Single or multiexon NF1 copy number changes occur in about 2% of patients, but little is known about the molecular mechanisms behind these intragenic deletions. We report here on the molecular characterization of a novel NF1 multiexonic deletion. The application of a multidisciplinary approach including multiplex ligation-dependent probe amplification, allelic segregation analysis, and fluorescent in situ hybridization allowed us to map the breakpoints in IVS27b and IVS48. Furthermore, the breakpoint junction was characterized by sequencing. Using bioinformatic analysis, we identified some recombinogenic motifs in close proximity to the centromeric and telomeric breakpoints and predicted the presence of a mutated messenger ribonucleic acid, which was deleted between exons 28 and 48 and encodes a neurofibromin that lacks some domains essential for its function. Through reverse transcriptase-polymerase chain reaction, the expression of the mutated allele was verified, showing the junction between exons 27b and 49 and, as expected, was not subjected to nonsense-mediated decay. Multiexonic deletions represent 2% of NF1 mutations, and until now, the breakpoint has been identified in only a few cases. The fine characterization of multiexonic deletions broadens the mutational repertoire of the NF1 gene, allowing for the identification of different pathogenetic mechanisms causing NF1.",
            "question": "Which is the gene mutated in type 1 neurofibromatosis?",
            "answers": {
                "answer_start": 209,
                "text": "NF1"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 478,
                "text": "Xa"
            }
        },
        {
            "context": "Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon. The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons' electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 152,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.",
            "question": "ROSIER scale is used for which disorder?",
            "answers": {
                "answer_start": 2096,
                "text": "stroke"
            }
        },
        {
            "context": "[Doege-Potter syndrome. about one new case]. Syndrome Doege-Potter is a paraneoplastic syndrome in which hypoglycemia is the result of tumors producing insulin growth factor-like (IGF-II) it is most often solitary fibrous tumor of the pleura (TFSP). These are rare and may be discovered incidentally, during non-specific respiratory symptoms or during hypoglycemia. Hypoglycemia occurs in tumors of large volume and it disappears after surgery, which is the treatment of choice for a permanent cure in most cases. We present a case of Doege-Potter syndrome whose interest is to consider the TFSP as a cause of hypoglycemia in patients with pleural tumors.",
            "question": "What is the most common feature of the Doege–Potter syndrome?",
            "answers": {
                "answer_start": 105,
                "text": "hypoglycemia"
            }
        },
        {
            "context": "Randomized trial of graft materials in transobturator tape operation: biological versus synthetic. OBJECTIVE: To compare the outcome of outside-in biological and synthetic transobturator tape (TOT) operation, including subjective and objective success rates, urodynamics, and quality of life. MATERIALS AND METHODS: One hundred patients suffering from clinical and/or urodynamic stress urinary incontinence (SUI) were randomized into biological material TOT (PELVILACE® TO) or synthetic material TOT (ALIGN®TO Urethral Support System) groups. Preoperative and at 1 year postoperative urogynecological symptom assessment, 1-h pad test, 4-day bladder diary, stress test, Q-tip test, and urodynamics were performed. For the evaluation of quality of life, the King's Health Questionnaire, Urogenital Distress Inventory-6, Incontinence Impact Questionnaire-7, and Prolapse Quality of Life were used. RESULTS: There was no significant difference between the two groups regarding objective and subjective cure rates and quality of life. At 1-year follow-up, the subjective cure rate was 68 % in the biological material TOT and 70 % in the synthetic material TOT group. No perioperative complications developed. Groin pain developed in 2 patients in the biological TOT group and 1 patient had dehiscence in the periurethral incision, which healed with local estrogen. Two patients had transient urinary retention in the synthetic TOT group, 1 patient developed groin pain, and 1 patient had mesh erosion observed at the 1-year follow-up. CONCLUSION: Transobturator tape with biological material in the management of SUI has a rate of success and patient satisfaction similar to those of synthetic material at 1-year follow-up. Studies with longer follow-up and larger cohorts are necessary to evaluate possible autolysis and degradation of biological slings and a possible reduction in efficacy over time.",
            "question": "Which type of urinary incontinence is diagnosed with the Q tip test?",
            "answers": {
                "answer_start": 379,
                "text": "stress urinary incontinence"
            }
        },
        {
            "context": "[Turner's syndrome--correlation between karyotype and phenotype]. Turner's syndrome is defined as a congenital disease determining by quantitative and/or structural aberrations of one from two X chromosomes with frequent presence of mosaicism. Clinically it is characterized by growth and body proportion abnormalities, gonadal dysgenesis resulting in sexual infantilism, primary amenorrhoea, infertility, characteristic stigmata, anomalies of heart, renal and bones and the presence of some diseases like Hashimoto thyroiditis with hypothyroidism, diabetes mellitus type 2, osteoporosis, hypertension. Turner's syndrome occurs in 1:2000 to 1:2500 female livebirth. The most frequent X chromosome aberrations in patients with phenotype of Turner syndrome are as follows: X monosomy - 45,X; mosaicism (50-75%), including 45,X/46,XX (10-15%), 45,X/46,XY (2-6%), 45,X/46,X,i(Xq), 45,X/46,X,del(Xp), 45,X/46,XX/47,XXX; aberration of X structure: total or partial deletion of short arm of X chromosome (46,X,del(Xp)) isochromosom of long arm of X chromosome (46,X,(i(Xq)), ring chromosome (46, X,r(X)), marker chromosome (46,X+m). Searching of X chromosome and mapping and sequencing of genes located at this chromosome (such as SHOX, ODG2, VSPA, SOX 3) have made possible to look for linkage between phenotypes and adequate genes or regions of X chromosome. In this paper current data concerning correlation between phenotype and karyotype in patients with TS have been presented.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 193,
                "text": "X"
            }
        },
        {
            "context": "Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 252,
                "text": "7"
            }
        },
        {
            "context": "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.",
            "question": "Against which protein is the antibody used for immonostaining of Lewy bodies raised?",
            "answers": {
                "answer_start": 125,
                "text": "alpha-synuclein"
            }
        },
        {
            "context": "New anticoagulants for atrial fibrillation. Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 608,
                "text": "xa"
            }
        },
        {
            "context": "Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 879,
                "text": "xa"
            }
        },
        {
            "context": "Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 581,
                "text": "xa"
            }
        },
        {
            "context": "Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination. Humans have seven APOBEC3 DNA cytosine deaminases. The activity of these enzymes allows them to restrict a variety of retroviruses and retrotransposons, but may also cause pro-mutagenic genomic uracil lesions. During interphase the APOBEC3 proteins have different subcellular localizations: cell-wide, cytoplasmic or nuclear. This implies that only a subset of APOBEC3s have contact with nuclear DNA. However, during mitosis, the nuclear envelope breaks down and cytoplasmic proteins may enter what was formerly a privileged zone. To address the hypothesis that all APOBEC3 proteins have access to genomic DNA, we analyzed the localization of the APOBEC3 proteins during mitosis. We show that APOBEC3A, APOBEC3C and APOBEC3H are excluded from condensed chromosomes, but become cell-wide during telophase. However, APOBEC3B, APOBEC3D, APOBEC3F and APOBEC3G are excluded from chromatin throughout mitosis. After mitosis, APOBEC3B becomes nuclear, and APOBEC3D, APOBEC3F and APOBEC3G become cytoplasmic. Both structural motifs as well as size may be factors in regulating chromatin exclusion. Deaminase activity was not dependent on cell cycle phase. We also analyzed APOBEC3-induced cell cycle perturbations as a measure of each enzyme's capacity to inflict genomic DNA damage. AID, APOBEC3A and APOBEC3B altered the cell cycle profile, and, unexpectedly, APOBEC3D also caused changes. We conclude that several APOBEC3 family members have access to the nuclear compartment and can impede the cell cycle, most likely through DNA deamination and the ensuing DNA damage response. Such genomic damage may contribute to carcinogenesis, as demonstrated by AID in B cell cancers and, recently, APOBEC3B in breast cancers.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 1045,
                "text": " nuclear"
            }
        },
        {
            "context": "Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production. The neurotoxicity of aluminum (Al) - the most abundant metal element on earth - has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of β-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.",
            "question": "Which protein is found to be mutated in Friedreich's ataxia?",
            "answers": {
                "answer_start": 715,
                "text": "frataxin"
            }
        },
        {
            "context": "McLeod phenotype without the McLeod syndrome. BACKGROUND: McLeod neuroacanthocytosis syndrome is a late-onset X-linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype-genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published. STUDY DESIGN AND METHODS: Two asymptomatic or minimally symptomatic cases at ages expected to manifest the McLeod syndrome (MLS) were evaluated. The first case had been authenticated as a genuine McLeod both by serology and by genotyping (R222G missense mutation) and the second case had a mutation in XK (IVS2+5G>A) and by serology exhibited very weak Kx antigen and no detectable Kell antigens, except extremely low k antigen by adsorption-elution technique. The patients were examined for hematologic, neurologic, and other clinical abnormalities. RESULTS: Despite documented McLeod phenotype on RBCs, and identified mutations of XK, neurologic and other clinical findings were minimal at ages expected to manifest MLS. CONCLUSIONS: The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1400,
                "text": "XK"
            }
        },
        {
            "context": "Color blindness among multiple sclerosis patients in Isfahan. BACKGROUND: Multiple sclerosis (MS) is a disease of young and middle aged individuals with a demyelinative axonal damage nature in central nervous system that causes various signs and symptoms. As color vision needs normal function of optic nerve and macula, it is proposed that MS can alter it via influencing optic nerve. In this survey, we evaluated color vision abnormalities and its relationship with history of optic neuritis and abnormal visual evoked potentials (VEPs) among MS patients. MATERIALS AND METHODS: The case group was included of clinically definitive MS patients and the same number of normal population was enrolled as the control group. Color vision of all the participants was evaluated by Ishihara test and then visual evoked potential (VEPs) and history of optic neuritis (ON) was assessed among them. Then, frequency of color blindness was compared between the case and the control group. Finally, color blinded patients were compared to those with the history of ON and abnormal VEPs. RESULTS: 63 MS patients and the same number of normal populations were enrolled in this study. 12 patients had color blindness based on the Ishihara test; only 3 of them were among the control group, which showed a significant different between the two groups (P = 0.013). There was a significant relationship between the color blindness and abnormal VEP (R = 0.53, P = 0.023) but not for the color blindness and ON (P = 0.67). CONCLUSIONS: This study demonstrates a significant correlation between color blindness and multiple sclerosis including ones with abnormal prolonged VEP latencies. Therefore, in individuals with acquired color vision impairment, an evaluation for potentially serious underlying diseases like MS is essential.",
            "question": "Which test is used for the definition of colour-blindness?",
            "answers": {
                "answer_start": 1215,
                "text": "Ishihara test"
            }
        },
        {
            "context": "A bug's life. This article explains what methicillin-resistant Staphylococcus aureus (MRSA) is, how it is spread and what the real challenges are in healthcare settings in the UK. It explores the different strains of MRSA and points out the main ways to control their spread. It is intended to be a reference source for all nurses.",
            "question": "What is MRSA?",
            "answers": {
                "answer_start": 86,
                "text": "MRSA"
            }
        },
        {
            "context": "CSEQ-SIMULATOR: A DATA SIMULATOR FOR CLIP-SEQ EXPERIMENTS. CLIP-Seq protocols such as PAR-CLIP, HITS-CLIP or iCLIP allow a genome-wide analysis of protein-RNA interactions. For the processing of the resulting short read data, various tools are utilized. Some of these tools were specifically developed for CLIP-Seq data, whereas others were designed for the analysis of RNA-Seq data. To this date, however, it has not been assessed which of the available tools are most appropriate for the analysis of CLIP-Seq data. This is because an experimental gold standard dataset on which methods can be accessed and compared, is still not available. To address this lack of a gold-standard dataset, we here present Cseq-Simulator, a simulator for PAR-CLIP, HITS-CLIP and iCLIP-data. This simulator can be applied to generate realistic datasets that can serve as surrogates for experimental gold standard dataset. In this work, we also show how Cseq-Simulator can be used to perform a comparison of steps of typical CLIP-Seq analysis pipelines, such as the read alignment or the peak calling. These comparisons show which tools are useful in different settings and also allow identifying pitfalls in the data analysis.",
            "question": "Which data simulator is available for CLIP-SEQ experiments?",
            "answers": {
                "answer_start": 936,
                "text": "Cseq-Simulator"
            }
        },
        {
            "context": "PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation.",
            "question": "The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?",
            "answers": {
                "answer_start": 30,
                "text": "PD-1"
            }
        },
        {
            "context": "Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.",
            "question": "Which drug was tested in the TEMSO Trial for multiple sclerosis?",
            "answers": {
                "answer_start": 286,
                "text": "teriflunomide"
            }
        },
        {
            "context": "Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided insight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 117,
                "text": "tyr"
            }
        },
        {
            "context": "Pestivirus virion morphogenesis in the absence of uncleaved nonstructural protein 2-3. The family Flaviviridae contains three genera of positive-strand RNA viruses, namely, Flavivirus, Hepacivirus (e.g., hepatitis C virus [HCV]), and Pestivirus. Pestiviruses, like bovine viral diarrhea virus (BVDV), bear a striking degree of similarity to HCV concerning polyprotein organization, processing, and function. Along this line, in both systems, release of nonstructural protein 3 (NS3) is essential for viral RNA replication. However, both viruses differ significantly with respect to processing efficiency at the NS2/3 cleavage site and abundance as well as functional relevance of uncleaved NS2-3. In BVDV-infected cells, significant amounts of NS2-3 accumulate at late time points postinfection and play an essential but ill-defined role in the production of infectious virions. In contrast, complete cleavage of the HCV NS2-3 counterpart has been reported, and unprocessed NS2-3 is not required throughout the life cycle of HCV, at least in cell culture. Here we describe the selection and characterization of the first pestiviral genome with the capability to complete productive infection in the absence of uncleaved NS2-3. Despite the insertion of a ubiquitin gene or an internal ribosomal entry site between the NS2 and NS3 coding sequences, the selected chimeric BVDV-1 genomes gave rise to infectious virus progeny. In this context, a mutation in the N-terminal third of NS2 was identified as a critical determinant for efficient production of infectious virions in the absence of uncleaved NS2-3. These findings challenge a previously accepted dogma for pestivirus replication and provide new implications for virion morphogenesis of pestiviruses and HCV.",
            "question": "How many genera comprise the Flaviviridae family?",
            "answers": {
                "answer_start": 120,
                "text": "three"
            }
        },
        {
            "context": "Patient with craniosynostosis and marfanoid phenotype (Shprintzen-Goldberg syndrome) and cloverleaf skull. Marfanoid phenotype with craniosynostosis (Shprintzen-Goldberg syndrome) is a rare disorder previously described in only 5 patients. We report on the sixth known patient with this condition. The findings which distinguish our patient from others reported previously are that she was ascertained prenatally as having a cloverleaf skull; this is the first female patient described with this condition. Postnatally, she presented with arachnodactyly, camptodactyly, and clover-leaf skull. Imaging studies of the brain documented microcephaly with malformed brain, hydrocephaly, and hypoplasia of the corpus callosum. She also had choanal atresia and stenosis, a clinical finding previously reported only once, in this disorder.",
            "question": "Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?",
            "answers": {
                "answer_start": 132,
                "text": "craniosynostosis"
            }
        },
        {
            "context": "Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle. BACKGROUND: The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. Mutations in TAZ are associated with Barth syndrome (BTHS), the X-linked recessive condition with dilated cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and organic aciduria. TAZ mutations also contribute to left ventricular noncompaction (LVNC), a cardiomyopathy characterized by loose, trabeculated myocardium. CASE REPORT: We report a family with a novel TAZ mutation and the clinical spectrum from severe BTHS in an infant to skeletal myopathy with LVNC in an adult, the oldest individual with BTHS reported. The proband is a 51-year-old male with muscle weakness since early childhood. He remained stable until the age of 43. His initial evaluations found LVNC and borderline neutropenia with no elevation of urine 3-methylglutaconic acid. The proband's great nephew is a 3-year-old who presented at birth with poor feeding, hypotonia, lactic acidosis and hypoglycemia. At three months he was admitted with failure to thrive, lethargy and respiratory distress due to heart failure. Cardiac studies revealed dilated cardiomyopathy with a spongiform trabeculated pattern of the left ventricle. Laboratory studies showed cyclic neutropenia and elevated urine 3-methylglutaconic and 3-methylglutaric acids. At age 11months the patient had a heart transplant. We conducted sequence analysis of the TAZ gene for two affected individuals, the proband first and then his great-nephew. A novel, hemizygous nonsense mutation in TAZ exon 7 (c.583G>T, p.Gly195X) was detected. CONCLUSION: At his current age of 51years-old, the proband is the oldest surviving individual reported with a confirmed molecular diagnosis and features of Barth syndrome. Further studies will be conducted to identify the genetic modifying factor(s) associated with the wide phenotypic range seen in this family.",
            "question": "Where is the TAZ (G4.5) is located in humans?",
            "answers": {
                "answer_start": 234,
                "text": "Xq28"
            }
        },
        {
            "context": "Structure-function relationship of the plant photosynthetic pigment-protein complex LHCII studied with molecular spectroscopy techniques. LHCII, the largest plant photosynthetic pigment-protein complex of photosystem II, is a most abundant membrane protein in living organisms and comprises approximately half of the pool of chlorophyll molecules in the biosphere. The principal role of this pigment-protein complex is to collect sunlight quanta and transfer electronic excitations toward the reaction centers, where the primary photosynthetic electric charge separation reactions take place. The LHCII protein, as a major protein component of the photosynthetic membranes, modulates also the structural and dynamic properties of the lipid phase of the membranes. According to the recent concepts, one of the physiological roles of LHCII is also a protection of the photosynthetic apparatus against oxidative damage caused by illumination with high intensity light. Detailed examination of all those physiological functions of LHCII, in relation to the complex structure, was possible owing to the application of several molecular spectroscopy techniques. Some examples of such studies are presented in this chapter. The examples of application of steady-state and time-resolved fluorescence spectroscopy, Fourier-transform infrared absorption spectroscopy, and resonance Raman scattering spectroscopy are presented and discussed.",
            "question": "Which is the most abundant membrane protein on Earth?",
            "answers": {
                "answer_start": 138,
                "text": "LHCII"
            }
        },
        {
            "context": "Heme and FLVCR-related transporter families SLC48 and SLC49. Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.",
            "question": "Which SLC family is FLVCR1 a member of?",
            "answers": {
                "answer_start": 265,
                "text": "SLC49"
            }
        },
        {
            "context": "Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab-A Case Report. INTRODUCTION: Idarucizumab is a reversal agent for dabigatran etexilate. By reversing the anticoagulating effect of dabigatran etexilate with idarucizumab (Praxbind), patients presenting with an acute ischemic stroke can now be eligible for thrombolysis. PATIENT: We describe our experience with idarucizumab in a 71-year-old male patient pretreated with dabigatran etexilate. The patient arrived with a hemiparesis, central facial palsy, and dysarthria. METHOD: Dabigatran etexilate was antagonized with idarucizumab, approximately 2.5 hours after the patient's last dose. Immediately after the infusion of idarucizumab, the patient received thrombolytic therapy. RESULTS: The hemiparesis and the central facial palsy were fully remitted 3 days after the onset of symptoms, and the dysarthria was remitted 2 days afterwards. DISCUSSION: Non-vitamin K oral anticoagulants (NOACs) are widely used for the prevention of embolic stroke in patients with atrial fibrillation. Dabigatran etexilate is an oral thrombin inhibitor that can be reversed by idarucizumab. Idarucizumab, a monoclonal antibody fragment, directly binds dabigatran etexilate and neutralizes its activity. CONCLUSION: Reversal of dabigatran etexilate using idarucizumab was safe and successful with no recombinant tissue plasminogen activator interactions.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 167,
                "text": "dabigatran"
            }
        },
        {
            "context": "Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs disease. Two affected HEXA alleles were found in an Israeli Druze Tay-Sachs child born to first-cousin parents. His paternal allele contained two adjacent changes in exon 5: delta496C, which resulted in a frameshift and premature termination codon 96 nucleotides downstream, and 498C-->G, a silent mutation. The maternal allele had a 835T-->C transition in exon 8 (S279P). Phosphoimaging quantitation of the parents' RNAs showed that the steady-state levels of mRNAs of the mutant exons 5 and 8 were 5% and 50%, respectively, of normal levels. The exon 5 mutated allele with the premature translation termination resulted in severe deficiency of Hex A. Transient expression of the exon 8 mutated alpha-chain cDNA in COS-1 cells resulted in deficiency of enzymatic activity. The child exhibited a late-infantile-type disease.",
            "question": "Which is the gene most commonly mutated in Tay-Sachs disease?",
            "answers": {
                "answer_start": 12,
                "text": "HEXA"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 623,
                "text": "xa"
            }
        },
        {
            "context": "A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.",
            "question": "What is the typical rash associated with gluten ?",
            "answers": {
                "answer_start": 80,
                "text": "Dermatitis herpetiformis"
            }
        },
        {
            "context": "Overcoming endocrine therapy resistance by signal transduction inhibition. Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR(+)) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small \"proof of concept\" phase II study of letrozole (Femara; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.",
            "question": "Which is the molecular target of the immunosuppressant drug Rapamycin?",
            "answers": {
                "answer_start": 2036,
                "text": "mTOR"
            }
        },
        {
            "context": "Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. Patients with Tietz syndrome have congenital profound deafness and generalised hypopigmentation, inherited in a fully penetrant autosomal dominant fashion. The pigmentary features and complete penetrance make this syndrome distinct among syndromes with pigmentary anomalies and deafness, which characteristically have patchy depigmentation and variable penetrance. Only one family has been reported with the exact features described in the original report of this syndrome. This family was reascertained and a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome. Mutations in other regions of this gene have been found to produce Waardenburg syndrome type 2 (WS2), which also includes pigmentary changes and hearing loss, but in contrast to Tietz syndrome, depigmentation is patchy and hearing loss is variable in WS2.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 636,
                "text": "MITF"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 0,
                "text": "methylKit"
            }
        },
        {
            "context": "LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org).",
            "question": "Which tool is used for the identification of recurrent variants in noncoding regions?",
            "answers": {
                "answer_start": 1293,
                "text": "LARVA"
            }
        },
        {
            "context": "[McLeod syndrome: Multisystem involvement associated with neuroacanthocytosis linked to X chromosome. report of two related cases]. Neurological abnormalities associated with spiculated, \"acanthocytic\" red cells in blood have been described as neuroacanthocytosis. This is a heterogeneous group of conditions that can be clearly subdivided on the basis of recent genetic findings. The McLeod Syndrome, one of the core neuroacanthocytosis syndromes, is a rare X-linked disorder caused by mutations of the XK gene, an X-chromosomal gene of unknown function characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. We report two Chilean brothers with the McLeod phenotype who showed important psychiatric features. The diagnosis may be elusive if the presence of acanthocytosis is not properly studied. We describe a method which allowed the diagnosis that unmasked acanthocytosis. Otherwise the condition could have remained undiagnosed as it had been for decades in this family. This syndrome must be considered when assessing a familial movement disorder, specially affecting males with relevant psychiatric features. A reliable test for acanthocytosis assessment is available.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 504,
                "text": "XK"
            }
        },
        {
            "context": "Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene. Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth impairment pre- and postnatally with abnormal glucose metabolism and a characteristic pattern of soft tissue overgrowth. We report a 5 day old neonate with refractory hyperglycemia and paradoxical hypoglycemia, severe intrauterine growth retardation, typical 'elfin' facies (hypertrichosis, large and low-set ears, broad nasal tip, flared nares, thick lips), reduced subcutaneous fat, distended abdomen, and enlarged external genitalia and nipples. Fasting serum insulin and C-peptide were severely elevated at >2,100 pmol/l and >2,331 pmol/l, respectively. In addition, hepatic, ovarian and renal enlargement was demonstrated by ultrasonography. The neonate died within two months secondary to hypoglycemia. Diplex PCR analysis of the insulin receptor gene revealed the neonate to be homozygous for deletion of exon 3. Both parents were heterozygous for this deletion but were metabolically healthy. As such a deletion has previously been reported in Israel, we suggest that it may show a founder effect in the Middle East.",
            "question": "Which hormone receptor function is altered in patients with Donohue syndrome?",
            "answers": {
                "answer_start": 183,
                "text": "insulin receptor"
            }
        },
        {
            "context": "APOBEC3B and AID have similar nuclear import mechanisms. Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage.",
            "question": "Is APOBEC3B protein predominantly cytoplasmic or nuclear?",
            "answers": {
                "answer_start": 454,
                "text": " nuclear"
            }
        },
        {
            "context": "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.",
            "question": "Which protein is regulated by Tudor interacting repair regulator (TIRR)?",
            "answers": {
                "answer_start": 15,
                "text": "53BP1"
            }
        },
        {
            "context": "Gangliosidoses. The gangliosidoses comprise a family of lysosomal storage diseases characterized by the accumulation of complex glycosphingolipids in the nervous system and other tissues, secondary to the deficient activity of lysosomal hydrolases or their associated activator proteins. GM1 and GM2 gangliosidosis are associated with deficiency of β-galactosidase and β-hexosaminidase respectively. All gangliosidoses are characterized by progressive neurodegeneration, the severity of which is proportional to the residual enzyme activity. The GM1 gangliosidoses are characterized by dysostosis, organomegaly and coarsening in their most severe forms, whereas children with classic infantile GM2 gangliosidosis (Tay-Sachs disease) are usually spared systemic involvement, except in the case of the Sandhoff variant, in which organomegaly may occur. Cherry-red macular spots occur in the early onset forms of the gangliosidoses, but are less frequently seen in the less severe, later onset phenotypes. Macrocephaly, an exaggerated startle response, cognitive decline, seizures, ataxia, and progressive muscular atrophy may occur in different forms of gangliosidosis. The diagnosis is made by assay of enzyme activity, and can be confirmed by mutation analysis. Carrier screening for Tay-Sachs disease has been remarkably successful in reducing the incidence of this disease in the at-risk Ashkenazi population. There are no proven disease-modifying therapies for the gangliosidoses.",
            "question": "Which enzyme deficiency can cause GM1 gangliosidoses?",
            "answers": {
                "answer_start": 349,
                "text": "β-galactosidase"
            }
        },
        {
            "context": "Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 1327,
                "text": "XK"
            }
        },
        {
            "context": "The role of SMARCAL1 in replication fork stability and telomere maintenance. SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.",
            "question": "Mutations in which gene cause Schimke immune-osseous dysplasia?",
            "answers": {
                "answer_start": 77,
                "text": "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1)"
            }
        },
        {
            "context": "Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies.",
            "question": "Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?",
            "answers": {
                "answer_start": 1140,
                "text": "FSHD"
            }
        },
        {
            "context": "PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma. PARP inhibitors are mostly effective as anticancer drugs in association with DNA damaging agents. We have previously shown that the oncolytic adenovirus dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic antitumoral effect of the PARP inhibitor olaparib in association with dl922-947. Anaplastic thyroid carcinoma was chosen as model since it is a particularly aggressive tumor and, because of its localized growth, it is suitable for intratumoral treatment with oncolytic viruses. Here, we show that dl922-947 infection induces PARP activation, and we confirm in vitro and in vivo that PARP inhibition increases dl922-947 replication and oncolytic activity. In vitro, the combination with olaparib exacerbates the appearance of cell death markers, such as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium iodide permeability. In vivo, we also observed a better viral distribution upon PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on tumor vascularization and on the viral distribution within the tumor mass. The observation that PARP inhibition enhances the effects of dl922-947 is highly promising not only for the treatment of anaplastic thyroid carcinoma but, in general, for the treatment of other tumors that could benefit from the use of oncolytic viruses.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 0,
                "text": "PARP"
            }
        },
        {
            "context": "A spontaneous novel XK gene mutation in a patient with McLeod syndrome. A 29-year-old man with a history of elevated creatine kinase and necrotizing myopathy was reviewed. Prominent red cell acanthocytosis in association with reduced Kell antigen expression was present, findings consistent with the McLeod syndrome. Investigation of the patient's XK gene revealed a novel TGG- to-TAG transition at position 1023 in exon 3. This point mutation creates an in-frame stop codon (W314X), and predicts a truncated XK protein of 313 amino acids, compared with 444 amino acids in the normal XK protein. The mutation was not identified in the patient's mother or sister indicating that this mutation was spontaneous.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 20,
                "text": "XK"
            }
        },
        {
            "context": "Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",
            "question": "Which type of myeloma is ixazomib being evaluated for?",
            "answers": {
                "answer_start": 444,
                "text": "multiple myeloma"
            }
        },
        {
            "context": "Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate. Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreER and GFP from ten different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium, including sources for specific subtypes of amygdala neurons. We then focused on deciphering transcriptional mechanisms that control enhancer activity. Using machine-learning computations, in vivo chromosomal occupancy of 13 transcription factors that regulate subpallial patterning and differentiation and analysis of enhancer activity in Dlx1/2 and Lhx6 mutants, we elucidated novel molecular mechanisms that regulate region-specific enhancer activity in the developing brain. Thus, these subpallial enhancer transgenic lines are data and tool resources to study transcriptional regulation of GABAergic cell fate.",
            "question": "Which resource has been developed in order to study the transcriptional regulation of GABAergic cell fate?",
            "answers": {
                "answer_start": 0,
                "text": "Subpallial Enhancer Transgenic Lines"
            }
        },
        {
            "context": "Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).",
            "question": "Which NADPH oxidase family member requires interaction with NOXO1 for function?",
            "answers": {
                "answer_start": 1703,
                "text": "Nox1"
            }
        },
        {
            "context": "MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.",
            "question": "Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?",
            "answers": {
                "answer_start": 1119,
                "text": "MARS"
            }
        },
        {
            "context": "The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 676,
                "text": "NCX"
            }
        },
        {
            "context": "Circular RNA: A new star of noncoding RNAs. Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. Recent studies have discovered thousands of endogenous circRNAs in mammalian cells. CircRNAs are largely generated from exonic or intronic sequences, and reverse complementary sequences or RNA-binding proteins (RBPs) are necessary for circRNA biogenesis. The majority of circRNAs are conserved across species, are stable and resistant to RNase R, and often exhibit tissue/developmental-stage-specific expression. Recent research has revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, and modifiers of parental gene expression. Emerging evidence indicates that circRNAs might play important roles in atherosclerotic vascular disease risk, neurological disorders, prion diseases and cancer; exhibit aberrant expression in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some diseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are becoming a new research hotspot in the field of RNA and could be widely involved in the processes of life. Herein, we review the formation and properties of circRNAs, their functions, and their potential significance in disease.",
            "question": "What is the function of circular RNA?",
            "answers": {
                "answer_start": 633,
                "text": "Recent research has revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, and modifiers of parental gene expression."
            }
        },
        {
            "context": "Sodium glucose co-transporter 2 (SGLT2) inhibition with canagliflozin in type 2 diabetes mellitus. The sodium glucose cotransporter 2 (SGLT2) is expressed primarily in the kidneys and is involved in the reabsorption of filtered glucose in the renal tubule. Clinical trials of SGLT2 inhibitors in patients with type 2 diabetes mellitus demonstrate a significant clinical effect in decreasing serum glucose, hemoglobin A1C, body weight, systolic blood pressure, improving β-cell function, and minimizing the risk of hypoglycemia. This report reviews the potentially beneficial effects of SGLT2 inhibitors in type 2 diabetes mellitus, specifically focusing on canagliflozin, the only SGLT2 inhibitor approved for use in the United States.",
            "question": "Inhibition of which transporter is the mechanism of action of drug Canagliflozin?",
            "answers": {
                "answer_start": 0,
                "text": "Sodium glucose co-transporter 2"
            }
        },
        {
            "context": "A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade > 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed > 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.",
            "question": "Which interleukin is blocked by Siltuximab?",
            "answers": {
                "answer_start": 58,
                "text": "interleukin-6"
            }
        },
        {
            "context": "NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 235,
                "text": "NEDD8-activating enzyme"
            }
        },
        {
            "context": "The spatiotemporal program of replication in the genome of Lachancea kluyveri. We generated a genome-wide replication profile in the genome of Lachancea kluyveri and assessed the relationship between replication and base composition. This species diverged from Saccharomyces cerevisiae before the ancestral whole genome duplication. The genome comprises eight chromosomes among which a chromosomal arm of 1 Mb has a G + C-content much higher than the rest of the genome. We identified 252 active replication origins in L. kluyveri and found considerable divergence in origin location with S. cerevisiae and with Lachancea waltii. Although some global features of S. cerevisiae replication are conserved: Centromeres replicate early, whereas telomeres replicate late, we found that replication origins both in L. kluyveri and L. waltii do not behave as evolutionary fragile sites. In L. kluyveri, replication timing along chromosomes alternates between regions of early and late activating origins, except for the 1 Mb GC-rich chromosomal arm. This chromosomal arm contains an origin consensus motif different from other chromosomes and is replicated early during S-phase. We showed that precocious replication results from the specific absence of late firing origins in this chromosomal arm. In addition, we found a correlation between GC-content and distance from replication origins as well as a lack of replication-associated compositional skew between leading and lagging strands specifically in this GC-rich chromosomal arm. These findings suggest that the unusual base composition in the genome of L. kluyveri could be linked to replication.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 726,
                "text": "early"
            }
        },
        {
            "context": "Phenotypic characterization of endometrial stromal sarcoma of the uterus. Endometrial stromal sarcoma (ESS) of the uterus is a rare uterine malignancy that has not been characterized in detail. To characterize the phenotype of ESS of the uterus, we extracted RNA from ESS and the stroma of normal endometrium using a tissue microdissection system and compared the expression profiles in the two tissues. After suppression subtractive hybridization and differential screening, we detected the metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene as one of the major genes upregulated in ESS, and a full-length placental cDNA clone (CS0DI066YJ10) as one of the major genes downregulated. The results were confirmed by in situ hybridization in four resected specimens of ESS and 36 biopsy specimens of normal endometrial tissue. All ESS (4/4) and all cases of endometrial stromal cells in the proliferative phase (13/13) were positive for MALAT-1, but samples of normal stroma in the secretory phase and menopausal state included some that were negative or weakly positive for MALAT-1 (5/13 and 3/10, respectively). In contrast, all ESS and 12 of 13 cases of stromal cells in the proliferative phase were negative for the full-length placental cDNA clone but 10 of 13 cases of endometrial stromal cells in the secretory phase were positive for transcripts of the gene (P < 0.05). These results indicated that endometrial stromal cells have different phenotypic characteristics between proliferative and secretory phases and the tumor cells of ESS have the phenotypic character of endometrial stromal cells in the proliferative phase.",
            "question": "Is the long non- coding RNA malat-1 up or downregulated in cancer?",
            "answers": {
                "answer_start": 588,
                "text": "upregulated"
            }
        },
        {
            "context": "Diagnosis and characterization of presymptomatic patients with Wilson's disease and the use of molecular genetics to aid in the diagnosis. Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. Although fatal if untreated, the condition can be treated effectively. Autosomal recessive inheritance indicates that siblings of affected patients are at 25% risk of having the disease. If they are diagnosed prior to becoming symptomatic, affected siblings can be kept free of symptoms by prophylactic therapy. In this paper we have examined the utility of copper-related variables, along with other clinical and molecular findings, in identifying those siblings of affected patients who should be further evaluated with a liver biopsy. Data are presented on a series of 13 presymptomatic patients in whom we have made the diagnosis of WD based on liver biopsy findings. Signs of liver disease were present in 12 out of 13 cases. The classic, noninvasive, screening approaches that we evaluated were not adequate to identify all cases of WD in this group of patients. These included positive Kayser-Fleischer (KF) rings, elevated liver serum alanine transferase, elevated urine copper, or elevated plasma nonceruloplasmin copper. We have introduced the use of molecular genetics for screening siblings of affected patients for WD. We show that a probe from the linked retinoblastoma (RB) gene can be very helpful in problem cases. However, at this time, the quantitative determination of liver copper concentration remains as the definitive diagnostic criterion.",
            "question": "What is the mode of inheritance of Wilson's disease?",
            "answers": {
                "answer_start": 328,
                "text": "Autosomal recessive"
            }
        },
        {
            "context": "Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.",
            "question": "When was empagliflozin FDA approved?",
            "answers": {
                "answer_start": 228,
                "text": "2014"
            }
        },
        {
            "context": "Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 340,
                "text": "Dabigatran"
            }
        },
        {
            "context": "Dinutuximab: An Anti-GD2 Monoclonal Antibody for High-Risk Neuroblastoma. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab. DATA SOURCES: MEDLINE was searched (1964 to January 2016) using the terms ch14.18, dinutuximab, immunotherapy, and neuroblastoma. Other information was identified from package insert, Biologics License Application, abstracts, news releases, and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: Identified English-language articles were reviewed. Selected studies included phase I through III. DATA SYNTHESIS: High-risk neuroblastoma is primarily a childhood cancer with 5-year survival rates of 40% to 50%. Treatment for high-risk neuroblastoma includes induction chemotherapy, surgery, myeloablative chemotherapy with autologous hematopoietic stem cell transplant, and radiation therapy. For patients achieving clinical remission, limited treatments exist for preventing relapse. Dinutuximab is a chimeric, human-murine, anti-GD2 monoclonal antibody approved in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. In phase III trials, dinutuximab increased 2-year event-free survival and overall survival when compared to standard treatment. Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension. CONCLUSIONS: Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. Ongoing research will determine if dinutuximab could be used earlier in treatment, in nonresponders to initial therapies, in combination with chemotherapy, or in other cancers.",
            "question": "Dinutuximab is used for treatment of which disease?",
            "answers": {
                "answer_start": 1313,
                "text": "neuroblastoma"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 766,
                "text": "L-dopa"
            }
        },
        {
            "context": "The clinical presentation of Ehlers-Danlos syndrome. Ehlers-Danlos syndrome (EDS), a heterogeneous group of inheritable connective tissue disorders, is attributed to mutations in connective tissue genes. These mutations cause defects in collagen. Collagen, a connective tissue protein that acts like glue, gives strength to the body and provides support and elasticity for movement. Thus, the altered gene affects the mechanical properties of skin, joints, ligaments, and blood vessels. Ehlers-Danlos syndrome is transmitted through autosomal dominant, autosomal recessive, or x-linked patterns of inheritance. The life expectancy of an affected infant varies with the type of EDS. This article provides an overview of the 6 major classifications of EDS, their unique clinical presentations, a focused physical assessment guide, considerations for nursing care, and resources for parents. Ehlers-Danlos syndrome can be a potentially debilitating syndrome. It requires preventative and protective measures starting at birth to preserve joint function to improve infant outcomes. Caring for patients with EDS requires an understanding of the potential associated complications to help minimize the physical and emotional impact of the syndrome and improve the quality of life for affected individuals.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 179,
                "text": "connective tissue"
            }
        },
        {
            "context": "SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor. Down-regulation of activated signaling receptors in response to their ligands plays a key role in restricting the extent and duration of the signaling. Mechanisms underlying down-regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown. Here we show that IFNAR1 interacts with the Homolog of Slimb (HOS) F-box protein in a phosphorylation-dependent manner, and that this interaction is promoted by interferon alpha (IFNalpha). IFNAR1 is ubiquitinated by the Skp1-Cullin1-HOS-Roc1 (SCF(HOS)) ubiquitin ligase in vitro. HOS expression and activities are required for IFNalpha-stimulated ubiquitination of IFNAR1, endocytosis of the type I interferon receptor, down-regulation of IFNAR1 levels, and IFNAR1 proteolysis via the lysosomal pathway. Furthermore, modulations of HOS activities affect the extent of Stat1 phosphorylation and Stat-mediated transcriptional activities as well as the extent of antiproliferative effects of type I interferons. These findings characterize SCF(HOS) as an E3 ubiquitin ligase that is essential for ubiquitination, proteolysis and down-regulation of IFNAR1, and implicate HOS in the regulation of cellular responses to IFNalpha.",
            "question": "Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)?",
            "answers": {
                "answer_start": 614,
                "text": "Skp1-Cullin1-HOS-Roc1 (SCF(HOS))"
            }
        },
        {
            "context": "Quantification of UCP1 function in human brown adipose tissue. Brown adipose tissue (BAT) mitochondria are distinct from their counterparts in other tissues in that ATP production is not their primary physiologic role. BAT mitochondria are equipped with a specialized protein known as uncoupling protein 1 (UCP1). UCP1 short-circuits the electron transport chain, allowing mitochondrial membrane potential to be transduced to heat, making BAT a tissue capable of altering energy expenditure and fuel metabolism in mammals without increasing physical activity. The recent discovery that adult humans have metabolically active BAT has rekindled an interest in this intriguing tissue, with the overarching aim of manipulating BAT function to augment energy expenditure as a countermeasure for obesity and the metabolic abnormalities it incurs. Subsequently, there has been heightened interest in quantifying BAT function and more specifically, determining UCP1-mediated thermogenesis in BAT specimens - including in those obtained from humans. In this article, BAT mitochondrial bioenergetics will be described and compared with more conventional mitochondria in other tissues. The biochemical methods typically used to quantify BAT mitochondrial function will also be discussed in terms of their specificity for assaying UCP1 mediated thermogenesis. Finally, recent data concerning BAT UCP1 function in humans will be described and discussed.",
            "question": "Which is the main protein in brown adipose tissue (BAT) active in thermogenesis?",
            "answers": {
                "answer_start": 307,
                "text": "UCP1"
            }
        },
        {
            "context": "Cancer vaccination with telomerase peptide GV1001. Telomerase is highly expressed in essentially all cancer forms, while the expression in normal tissues is restricted. Moreover, telomerase activity is considered indispensable for tumor immortalization and growth. Human telomerase reverse transcriptase (hTERT), the rate-limiting subunit of the telomerase complex, is therefore an attractive target for cancer vaccination. The present review provides an update on the development of GV1001, a peptide vaccine representing a 16-aa hTERT sequence. GV1001 binds multiple HLA class II molecules and harbors putative HLA class I epitopes. The peptide may therefore elicit combined CD4/CD8 T-cell responses, considered important to initiate tumor eradication and long-term memory. Phase I/II trials in advanced pancreatic and pulmonary cancer patients have demonstrated GV1001-specific T-cell responses in > 50% of subjects, without clinically important toxicity. The results indicate a correlation between development of GV1001-specific responses and prolonged survival. However, as in most cancer vaccine trials, a large proportion of immune responders experience no clinical benefit. Long-term survivors harbor durable GV1001-specific T-cell responses with high IFN-gamma/IL-10 ratios and polyfunctional cytokine patterns. Interestingly, the cytokine profiles do not follow a T(H)1/T(H)2 delineation. Here, the author discusses how immunomonitoring may be improved to discriminate between efficient and pointless immune responses, and which questions to address in the further development of GV1001.",
            "question": "GV1001 vaccine targets which enzyme?",
            "answers": {
                "answer_start": 265,
                "text": "Human telomerase reverse transcriptase"
            }
        },
        {
            "context": "Localization of the Lys, Asp, Glu, Leu tetrapeptide receptor to the Golgi complex and the intermediate compartment in mammalian cells. The carboxyl-terminal Lys-Asp-Glu-Leu (KDEL), or a closely-related sequence, is important for ER localization of both lumenal as well as type II membrane proteins. This sequence functions as a retrieval signal at post-ER compartment(s), but the exact compartment(s) where the retrieval occurs remains unresolved. With an affinity-purified antibody against the carboxyl-terminal sequence of the mammalian KDEL receptor, we have investigated its subcellular localization using immunogold labeling on thawed cryosections of different tissues, such as mouse spermatids and rat pancreas, as well as HeLa, Vero, NRK, and mouse L cells. We show that rab1 is an excellent marker of the intermediate compartment, and we use this marker, as well as budding profiles of the mouse hepatitis virus (MHV) in cells infected with this virus, to identify this compartment. Our results demonstrate that the KDEL receptor is concentrated in the intermediate compartment, as well as in the Golgi stack. Lower but significant labeling was detected in the rough ER. In general, only small amounts of the receptor were detected on the trans side of the Golgi stack, including the trans-Golgi network (TGN) of normal cells and tissues. However, some stress conditions, such as infection with vaccinia virus or vesicular stomatitis virus, as well as 20 degrees C or 43 degrees C treatment, resulted in a significant shift of the distribution towards the trans-TGN side of the Golgi stack. This shift could be quantified in HeLa cells stably expressing a TGN marker. No significant labeling was detected in structures distal to the TGN under all conditions tested. After GTP gamma S treatment of permeabilized cells, the receptor was detected in the beta-COP-containing buds/vesicles that accumulate after this treatment, suggesting that these vesicles may transport the receptor between compartments. We propose that retrieval of KDEL-containing proteins occurs at multiple post-ER compartments up to the TGN along the exocytotic pathway, and that within this pathway, the amounts of the receptor in different compartments varies according to physiological conditions.",
            "question": "Which is the most typical peptide sequence responsible for retrieval of endoplasmic reticulum (ER) lumenal proteins from the Golgi apparatus?",
            "answers": {
                "answer_start": 135,
                "text": "The carboxyl-terminal Lys-Asp-Glu-Leu (KDEL)"
            }
        },
        {
            "context": "Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. BACKGROUND: Screening medullary thyroid carcinomas (MTCs) for rearranged during transfection (RET) mutations becomes increasingly important for clinical assessment of the disease. The role of mutations in other genes including RAS (i.e. HRAS, KRAS, and NRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-akt murine thymoma viral oncogene homolog 1 (AKT1), and CTNNB1 (β-catenin) is unknown or not fully explored yet for this disease. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded (FFPE) material was the primary source for screening 13 sporadic and inherited MTCs and matched non-tumor specimens. Multiplex PCR was included in the PCR protocol. Sequence analysis encompassed mutational hotspot regions in RET exons 5, 8, 10, 11, and 13 to 16; HRAS exons 1 and 2; KRAS exons 1 and 2; NRAS exons 1 and 2; BRAF exon 15; AKT1 exon 2, and CTNNB1 exon 3. RESULTS: We identified RET mutations in seven of 13 MTCs: five RET-positive cases revealed a mutation in exon 16 (M918T) and two a mutation in exon 10 (C618S and C620S). In four of the RET-positive cases, the mutation was inherited, out of which three were reportedly associated with a multiple endocrine neoplasia type 2 (MEN2) syndrome, i.e. MEN2A (C618S), MEN2A/familial MTC (FMTC) (C620S), and MEN2B (M918T). These cases reflect the known MEN2 genotype-phenotype correlation. Three of the five stage IVc MTCs were inherited RET-positive cases. Mutational screening in HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 disclosed one sporadic RET-negative MTC (stage III) with mutation in HRAS codon 13 (G13R). CONCLUSION: Our study supports the clinical relevance of screening MTC patients for RET mutations. The role of RAS mutations, in particular HRAS mutations, in sporadic RET-negative MTC has not been fully explored yet. Mutations in BRAF, AKT1, and CTNNB1 are likely not to play a role in MTC.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 1001,
                "text": "RET"
            }
        },
        {
            "context": "traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.",
            "question": "Which R / bioconductor package is used for performing SNP enrichment analysis?",
            "answers": {
                "answer_start": 784,
                "text": "traseR"
            }
        },
        {
            "context": "CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html.",
            "question": "Which tool is used for promoterome mining using CAGE data?",
            "answers": {
                "answer_start": 551,
                "text": "CAGEr"
            }
        },
        {
            "context": "Demographics of the UK cystic fibrosis population: implications for neonatal screening. The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.",
            "question": "Which is the most common CFTR mutation in Caucasians?",
            "answers": {
                "answer_start": 1134,
                "text": "deltaF508"
            }
        },
        {
            "context": "Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease. The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing. Data from preclinical studies and clinical trials suggest that gevokizumab is a potentially effective and well-tolerated treatment for the indicated diseases. At the time of publication, phase II clinical trials were ongoing in patients with T1D, T2D and RA, with the T2D trials assessing key cardiovascular markers. Following promising data from a recent pilot trial, XOMA was also planning a phase I/II trial of gevokizumab for the potential treatment of uveitis in patients with the vasculitic inflammatory disorder Behçet's disease and the autoinflammatory conditions familial cold autoinflammatory syndrome and Muckle-Wells syndrome.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 478,
                "text": "IL-1β"
            }
        },
        {
            "context": "Imatinib mesylate for the treatment of chronic myeloid leukemia. Chronic myeloid leukemia (CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion--the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene is formed on the 22q- derivative (traditionally known as the Philadelphia chromosome) and the deregulated tyrosine kinase activity of the protein encoded by this gene has been shown to be both necessary and sufficient for initiation and maintenance of the disease. Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl, entered clinical evaluation in 1998. Its efficacy surpassed almost everyone's predictions, and the observation of high response rates and favorable toxicity profile associated with imatinib therapy led to its approval as first-line treatment for all newly diagnosed CML patients over an exceptionally short period of time. The 6-year results of the Phase III trial have recently been reported and confirm durability of responses and declining incidence of adverse events over time, although, at present, occurrence of unexpected side effects in the long term cannot be excluded. Although imatinib does not 'cure' CML and has to be administered chronically to patients, it has revolutionized both outcome and quality of life of CML patients.",
            "question": "What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?",
            "answers": {
                "answer_start": 688,
                "text": "Bcr-Abl"
            }
        },
        {
            "context": "Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Fused in sarcoma (FUS) is an RNA-binding protein involved in pathogenesis of several neurodegenerative diseases. Aggregation of mislocalized FUS into non-amyloid inclusions is believed to be pivotal in the development of cell dysfunction, but the mechanism of their formation is unclear. Using transient expression of a panel of deletion and chimeric FUS variants in various cultured cells, we demonstrated that FUS accumulating in the cytoplasm nucleates a novel type of RNA granules, FUS granules (FGs), that are structurally similar but not identical to physiological RNA transport granules. Formation of FGs requires FUS N-terminal prion-like domain and the ability to bind specific RNAs. Clustering of FGs coupled with further recruitment of RNA and proteins produce larger structures, FUS aggregates (FAs), that resemble but are clearly distinct from stress granules. In conditions of attenuated transcription, FAs lose RNA and dissociate into RNA-free FUS complexes that become precursors of large aggresome-like structures. We propose a model of multistep FUS aggregation involving RNA-dependent and RNA-independent stages. This model can be extrapolated to formation of pathological inclusions in human FUSopathies.",
            "question": "Which domain allowing self-association do exist in TDP-43 and FUS proteins?",
            "answers": {
                "answer_start": 750,
                "text": "prion-like domain"
            }
        },
        {
            "context": "Current diagnosis and management of infectious mononucleosis. PURPOSE OF REVIEW: Infectious mononucleosis is a common, usually self-limited disease. However, infectious mononucleosis may present with severe manifestations. Complications may also occur. Consequently, diagnostic and treatment issues regarding infectious mononucleosis are of major importance. RECENT FINDINGS: In this review, we focus on the evaluation of articles providing diagnosis and treatment data for infectious mononucleosis, published during the past 2 years. Twelve studies, deriving from extended search in PubMed, were included. Nine studies provided diagnosis data. The evaluated diagnostic methods were real-time PCR (RT-PCR), IgM/IgG antibodies measured with different assays [measurement of Epstein-Barr virus viral load (EBV-VL) in peripheral blood, neutrophil/lymphocyte/monocyte counts, C-reactive protein values, and monospot test]. The sensitivities reported for RT-PCR were high. The available treatment data were scarce (three studies). Two of them suggested that antivirals (mainly acyclovir and valacyclovir) may have a role in the treatment of infectious mononucleosis with complications, whereas the remaining study presented novel potential therapeutic patents including 5-substituted uracyle, azacytosine derivatives, and peptides inhibiting EBV-mediated membrane fusion. SUMMARY: RT-PCR and measurement of EBV-VL may provide useful tools for the early diagnosis of infectious mononucleosis in cases with inconclusive serological results. Antiviral agents may provide a useful treatment option in patients with severe infectious mononucleosis.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 773,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 1884,
                "text": "Xa"
            }
        },
        {
            "context": "libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.",
            "question": "Which library is used for fixed-length approximate string matching?",
            "answers": {
                "answer_start": 1242,
                "text": "libFLASM"
            }
        },
        {
            "context": "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen.",
            "question": "Which disease is treated with Nusinersen?",
            "answers": {
                "answer_start": 29,
                "text": "spinal muscular atrophy"
            }
        },
        {
            "context": "Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study. BACKGROUND AND OBJECTIVES: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS: Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses > 2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS: Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01955720.",
            "question": "Which drug can be reversed with idarucizumab?",
            "answers": {
                "answer_start": 104,
                "text": "Dabigatran"
            }
        },
        {
            "context": "2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine. Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is involved in the regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which include several subtypes (4). There are three receptor subtypes within the G-protein–coupled 5-HT2 receptor family: 5-HT2A, 5-HT2B, and 5-HT2C. 5-HT2A receptors are abundantly present in the cerebral cortex, basal forebrain, hippocampus, amygdala, dorsal thalamus, hypothalamus, superior colliculus, substantia nigra, pedunculopontine nucleus, legmental area, and myelencephalon (5). 5-HT2A receptors are involved in mediation of normal and psychotic states, working memory, regulation of GABAergic and cholinergic neuronal cells, sleep, peripheral pain, and cardiovascular functions. 5-HT2B receptors are found mainly in several peripheral tissues, such as the stomach, intestine, pulmonary smooth muscle, and myocardium. In the brain, 5-HT2B receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT2C receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT2A receptors are implicated in several psychiatric disorders, such as schizophrenia, depression, and obsessive-compulsive disorder. Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT2A receptors. There have been several studies to develop specific 5-HT2A radioligands, such as [11C]ketanserin (6), [18F]spiperone (7), [11C]methylspiperone ([11C]NMSP), and [18F]setoperone [PubMed], for positron emission tomography (8) imaging. However, none of these ligands has proven to be specific for 5-HT2A receptors because these compounds also bind to other receptors, such as dopamine receptors and the 5-HT1 receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent antagonist of 5-HT2A receptors with >100-fold selectivity over D2/3 receptors, 5-HT1A, 5-HT6, and 5-HT7 (9, 10). This led to the development of 3-{2-[4-(4-[18F]fluorobenzoyl)-1-piperidyl]ethyl}-2-sulfanyl-3H-quinazolin-4-one ([18F]altanserin) as a useful tool for 5-HT2A receptor PET imaging in vivo (11). 5-HT2A antagonists bind to the total pool of receptors, whereas 5-HT2A agonists bind only to the high-affinity functional state of the receptor but may be more important in disease states because the high affinity sites are the ones that transmit the intracellular signals. Furthermore, 2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine ([11C]CIMBI-5), a potent and selective 5-HT2A agonist, has been developed as a tool for studying 5-HT2A agonist binding in the brain (12).",
            "question": "Which receptors can be evaluated with the [18F]altanserin?",
            "answers": {
                "answer_start": 2423,
                "text": "5-HT2A"
            }
        },
        {
            "context": "Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 113,
                "text": "MITF"
            }
        },
        {
            "context": "A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. INTRODUCTION: The Li-Fraumeni Syndrome is caused by a germline TP53 mutation and is associated with a high risk of breast cancer at young ages. Basal (triple negative) breast cancers are now well recognised to be a typical sub-type of breast cancer developing in a large proportion of BRCA1 gene carriers. We considered whether a similar narrow sub-type of breast cancer was found in TP53 gene mutation carriers. OBJECTIVE: A hypothesis generating study to investigate whether there are specific breast tumour characteristics associated with germline TP53 mutations. METHODS: Pathological characteristics in 12 breast cancers arising in nine patients carrying pathogenic TP53 mutations were compared to a reference panel of 231 young onset breast tumours included in the POSH study. RESULTS: Patients carrying a TP53 mutation showed a significantly higher likelihood of developing a breast cancer with Human Epidermal growth factor Receptor (HER2) amplification (83%) when compared to the cohort of young onset breast cancer cases (16%); ER and PR status were equivalent between groups. CONCLUSION: These findings suggest that breast cancer developing on a background of an inherited TP53 mutation is highly likely to present with amplification of HER2.",
            "question": "What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?",
            "answers": {
                "answer_start": 13,
                "text": "positive"
            }
        },
        {
            "context": "Role of agents for reversing the effects of target-specific oral anticoagulants. PURPOSE: The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed. SUMMARY: The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials. CONCLUSION: Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 862,
                "text": "Xa"
            }
        },
        {
            "context": "Using Mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes. Plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. To understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. Since extensive data support the proposal that foreign DNA acquires the host's nucleotide composition during long-term residence, comparison of nucleotide composition of plasmids and chromosomes could shed light on a plasmid's evolutionary history. The average absolute dinucleotide relative abundance difference, termed delta-distance, has been commonly used to measure differences in dinucleotide composition, or 'genomic signature', between bacterial chromosomes and plasmids. Here, we introduce the Mahalanobis distance, which takes into account the variance-covariance structure of the chromosome signatures. We demonstrate that the Mahalanobis distance is better than the delta-distance at measuring genomic signature differences between plasmids and chromosomes of potential hosts. We illustrate the usefulness of this metric for proposing candidate long-term hosts for plasmids, focusing on the virulence plasmids pXO1 from Bacillus anthracis, and pO157 from Escherichia coli O157:H7, as well as the broad host range multi-drug resistance plasmid pB10 from an unknown host.",
            "question": "Which is the most common measure of differences between dinucleotide relative abundance \"genomic signatures\"",
            "answers": {
                "answer_start": 767,
                "text": "delta-distance"
            }
        },
        {
            "context": "Spinal hematoma: a literature survey with meta-analysis of 613 patients. Spinal hematoma has been described in autopsies since 1682 and as a clinical diagnosis since 1867. It is a rare and usually severe neurological disorder that, without adequate treatment, often leads to death or permanent neurological deficit. Epidural as well as subdural and subarachnoid hematomas have been investigated. Some cases of subarachnoid spinal hematoma may present with symptoms similar to those of cerebral hemorrhage. The literature offers no reliable estimates of the incidence of spinal hematoma, perhaps due to the rarity of this disorder. In the present work, 613 case studies published between 1826 and 1996 have been evaluated, which represents the largest review on this topic to date. Most cases of spinal hematoma have a multifactorial etiology whose individual components are not all understood in detail. In up to a third of cases (29.7%) of spinal hematoma, no etiological factor can be identified as the cause of the bleeding. Following idiopathic spinal hematoma, cases related to anticoagulant therapy and vascular malformations represent the second and third most common categories. Spinal and epidural anesthetic procedures in combination with anticoagulant therapy represent the fifth most common etiological group and spinal and epidural anesthetic procedures alone represent the tenth most common cause of spinal hematoma. Anticoagulant therapy alone probably does not trigger spinal hemorrhage. It is likely that there must additionally be a \"locus minoris resistentiae\" together with increased pressure in the interior vertebral venous plexus in order to cause spinal hemorrhage. The latter two factors are thought to be sufficient to cause spontaneous spinal hematoma. Physicians should require strict indications for the use of spinal anesthetic procedures in patients receiving anticoagulant therapy, even if the incidence of spinal hematoma following this combination is low. If spinal anesthetic procedures are performed before, during, or after anticoagulant treatment, close monitoring of the neurological status of the patient is warranted. Time limits regarding the use of anticoagulant therapy before or after spinal anesthetic procedures have been proposed and are thought to be safe for patients. Investigation of the coagulation status alone does not necessarily provide an accurate estimate of the risk of hemorrhage. The most important measure for recognizing patients at high risk is a thorough clinical history. Most spinal hematomas are localized dorsally to the spinal cord at the level of the cervicothoracic and thoracolumbar regions. Subarachnoid hematomas can extend along the entire length of the subarachnoid space. Epidural and subdural spinal hematoma present with intense, knife-like pain at the location of the hemorrhage (\"coup de poignard\") that may be followed in some cases by a pain-free interval of minutes to days, after which there is progressive paralysis below the affected spinal level. Subarachnoid hematoma can be associated with meningitis symptoms, disturbances of consciousness, and epileptic seizures and is often misdiagnosed as cerebral hemorrhage based on these symptoms. Most patients are between 55 and 70 years old. Of all patients with spinal hemorrhage, 63.9% are men. The examination of first choice is magnetic resonance imaging. The treatment of choice is surgical decompression. Of the patients investigated in the present work, 39.6% experienced complete recovery. The less severe the preoperative symptoms are and the more quickly surgical decompression can be performed, the better are the chances for complete recovery. It is therefore essential to recognize the relatively typical clinical presentation of spinal hematoma in a timely manner to allow correct diagnostic and therapeutic measures to be taken to maximize the patient's chance of complete recovery.",
            "question": "What drug treatment can cause a spinal epidural hematoma?",
            "answers": {
                "answer_start": 1431,
                "text": "Anticoagulant therapy"
            }
        },
        {
            "context": "Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data.",
            "question": "Which tool is available for predicting regulatory interactions from ChIP-seq data?",
            "answers": {
                "answer_start": 557,
                "text": "CisMapper"
            }
        },
        {
            "context": "A first-in-class NAE inhibitor, MLN4924, blocks lentiviral infection in myeloid cells by disrupting neddylation-dependent Vpx-mediated SAMHD1 degradation. MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells. SAMHD1 is required for MLN4924-mediated SIVmac inhibition. Our findings indicate the potential efficacy of inhibiting neddylation as an antiretroviral strategy and identify the readily available anticancer drug MLN4924 as a candidate agent for that purpose.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 213,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Eukaryotic DNA Replication Fork. This review focuses on the biogenesis and composition of the eukaryotic DNA replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork. Physical and genetic methodologies aimed at understanding these processes are discussed. The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork. DNA polymerases α and δ carry out the initiation of Okazaki fragment synthesis and its elongation and maturation, respectively. This review also discusses alternative proposals, including cellular processes during which alternative forks may be utilized, and new biochemical studies with purified proteins that are aimed at reconstituting leading and lagging strand DNA synthesis separately and as an integrated replication fork.",
            "question": "What cellular process are okazaki fragments associated with?",
            "answers": {
                "answer_start": 105,
                "text": "DNA replication"
            }
        },
        {
            "context": "Calpain cleavage regulates the protein stability of p73. The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 634,
                "text": "7"
            }
        },
        {
            "context": "Yeast recombination pathways triggered by topoisomerase II-mediated DNA breaks. Topoisomerase II is a ubiquitous enzyme that removes knots and tangles from the genetic material by generating transient double-strand DNA breaks. While the enzyme cannot perform its essential cellular functions without cleaving DNA, this scission activity is inherently dangerous to chromosomal integrity. In fact, etoposide and other clinically important anticancer drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. Cells rely heavily on recombination to repair double-strand DNA breaks, but the specific pathways used to repair topoisomerase II-generated DNA damage have not been defined. Therefore, Saccharomyces cerevisiae was used as a model system to delineate the recombination pathways that repair DNA breaks generated by topoisomerase II. Yeast cells that expressed wild-type or a drug-hypersensitive mutant topoisomerase II or overexpressed the wild-type enzyme were examined. Based on cytotoxicity and recombination induced by etoposide in different repair-deficient genetic backgrounds, double-strand DNA breaks generated by topoisomerase II appear to be repaired primarily by the single-strand invasion pathway of homologous recombination. Non-homologous end joining also was triggered by etoposide treatment, but this pathway was considerably less active than single-strand invasion and did not contribute significantly to cell survival in S.cerevisiae.",
            "question": "Which topoisomerase is essential in yeast?",
            "answers": {
                "answer_start": 80,
                "text": "Topoisomerase II"
            }
        },
        {
            "context": "A novel frameshift mutation in the McLeod syndrome gene in a Japanese family. We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome. A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis. The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK. This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408. We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 112,
                "text": "XK"
            }
        },
        {
            "context": "The epidemiology of infectious mononucleosis in Northern Scotland: a decreasing incidence and winter peak. BACKGROUND: Infection with Epstein-Barr virus (EBV) is almost ubiquitous in humans and generally occurs at two ages: infantile, which is usually asymptomatic and associated with poorer socioeconomic conditions, and adolescent, which causes infectious mononucleosis (IM) in ~25% cases. The determinants of whether the infection causes IM remain uncertain. We aimed to evaluate seasonality and temporal trends in IM. METHODS: Data from all Monospot tests, used as a marker for IM, were collected from the Grampian population over 16 years. RESULTS: Positive Monospot test results peaked at 17 years in females and 19 in males. Females had 16% more diagnoses, although 55% more tests. IM was ~38% more common in winter than summer. The annual rate of positive tests decreased progressively over the study period, from 174/100 000 (95% CI 171-178) in 1997 to 67/100 000 (95% CI 65-69) in 2012. CONCLUSIONS: IM appears to be decreasing in incidence, which may be caused by changing environmental influences on immune systems. One such factor may be exposure to sunlight.Words 168. FUNDING: The Medical Research Council and NHS Grampian-MS endowments.",
            "question": "Which virus can be diagnosed with the monospot test?",
            "answers": {
                "answer_start": 134,
                "text": "Epstein-Barr virus"
            }
        },
        {
            "context": "Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.",
            "question": "Do origins of replication close to yeast centromeres fire early or late?",
            "answers": {
                "answer_start": 669,
                "text": "early"
            }
        },
        {
            "context": "The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts. A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 154,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats. In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.",
            "question": "Which drug is benserazide usually co-administered with?",
            "answers": {
                "answer_start": 855,
                "text": "L-dopa"
            }
        },
        {
            "context": "Positive and negative selection in murine ultraconserved noncoding elements. There are many more selectively constrained noncoding than coding nucleotides in the mammalian genome, but most mammalian noncoding DNA is subject to weak selection, on average. One of the most striking discoveries to have emerged from comparisons among mammalian genomes is the hundreds of noncoding elements of more than 200 bp in length that show absolute conservation among mammalian orders. These elements represent the tip of the iceberg of a much larger class of conserved noncoding elements (CNEs). Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development. Here, we quantify negative and positive selection acting in murine CNEs by analyzing within-species nucleotide variation and between-species divergence of CNEs that we identified using a phylogenetically independent comparison. The distribution of fitness effects of new mutations in CNEs, inferred from within-species polymorphism, suggests that CNEs receive a higher number of strongly selected deleterious mutations and many fewer nearly neutral mutations than amino acid sites of protein-coding genes or regulatory elements close to genes. However, we also show that CNEs experience a far higher proportion of adaptive substitutions than any known category of genomic sites in murids. The absolute rate of adaptation of CNEs is similar to that of amino acid sites of proteins. This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.",
            "question": "Which is the process that Conserved noncoding elements mostly regulate?",
            "answers": {
                "answer_start": 1741,
                "text": "development"
            }
        },
        {
            "context": "A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion. We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.",
            "question": "The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?",
            "answers": {
                "answer_start": 167,
                "text": "Na(+)/Ca(2+) exchanger"
            }
        },
        {
            "context": "Formin Is Associated with Left-Right Asymmetry in the Pond Snail and the Frog. While components of the pathway that establishes left-right asymmetry have been identified in diverse animals, from vertebrates to flies, it is striking that the genes involved in the first symmetry-breaking step remain wholly unknown in the most obviously chiral animals, the gastropod snails. Previously, research on snails was used to show that left-right signaling of Nodal, downstream of symmetry breaking, may be an ancestral feature of the Bilateria [1 and 2]. Here, we report that a disabling mutation in one copy of a tandemly duplicated, diaphanous-related formin is perfectly associated with symmetry breaking in the pond snail. This is supported by the observation that an anti-formin drug treatment converts dextral snail embryos to a sinistral phenocopy, and in frogs, drug inhibition or overexpression by microinjection of formin has a chirality-randomizing effect in early (pre-cilia) embryos. Contrary to expectations based on existing models [3, 4 and 5], we discovered asymmetric gene expression in 2- and 4-cell snail embryos, preceding morphological asymmetry. As the formin-actin filament has been shown to be part of an asymmetry-breaking switch in vitro [6 and 7], together these results are consistent with the view that animals with diverse body plans may derive their asymmetries from the same intracellular chiral elements [8].",
            "question": "What is formin associated with in the snail?",
            "answers": {
                "answer_start": 26,
                "text": "Left-Right Asymmetry"
            }
        },
        {
            "context": "An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. Histone H3 lysine 4 (K4) methylation is a prevalent mark associated with transcription activation and is mainly catalyzed by the MLL/SET1 family histone methyltransferases. A common feature of the mammalian MLL/SET1 complexes is the presence of three core components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Unlike most other histone lysine methyltransferases, all four proteins are required for efficient H3 K4 methylation. Despite extensive efforts, mechanisms for how three core components regulate MLL/SET1 methyltransferase activity remain elusive. Here we show that a heterodimer of Ash2L and RbBP5 has intrinsic histone methyltransferase activity. This activity requires the highly conserved SPRY domain of Ash2L and a short peptide of RbBP5. We demonstrate that both Ash2L and the MLL1 SET domain are capable of binding to S-adenosyl-L- [methyl-(3)H] methionine in the MLL1 core complex. Mutations in the MLL1 SET domain that fail to support overall H3 K4 methylation also compromise SAM binding by Ash2L. Taken together, our results show that the Ash2L/RbBP5 heterodimer plays a critical role in the overall catalysis of MLL1 mediated H3 K4 methylation. The results we describe here provide mechanistic insights for unique regulation of the MLL1 methyltransferase activity. It suggests that both Ash2L/RbBP5 and the MLL1 SET domain make direct contacts with the substrates and contribute to the formation of a joint catalytic center. Given the shared core configuration among all MLL/SET1 family HMTs, it will be interesting to test whether the mechanism we describe here can be generalized to other MLL/SET1 family members in the future.",
            "question": "What is the characteristic domain of histone methyltransferases?",
            "answers": {
                "answer_start": 471,
                "text": "SET domain"
            }
        },
        {
            "context": "[Intracellular targets : current data on effectiveness and safety profile]. Protein kinase inhibitors represent a novel and promising approach to the treatment of rheumatoid arthritis (RA). By targeting intracellular signaling pathways of cytokine-mediated reactions, these substances are able to interfere with critical immune processes that underly the pathology of RA. With tofacitinib, the first Janus kinase (JAK) inhibitor has been approved in the USA, as well as in Switzerland and other countries. Several other substances are currently undergoing phase II or phase III trials.A crucial question that will shape the future of these new drugs is whether they are safe and in particular, whether they are safer than biological therapies. This article provides an overview on current data concerning the efficacy and safety of the most promising substances and discusses the potential future role of intracellular kinase inhibitors.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 377,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.",
            "question": "Andexanet Alfa is an antidote of which clotting factor inhibitors?",
            "answers": {
                "answer_start": 2002,
                "text": "Xa"
            }
        },
        {
            "context": "Acquired cerebral hemiatrophy: Dyke-Davidoff-Masson Syndrome - a case report. A rare syndrome, Dyke-Davidoff-Masson Syndrome (DDMS), with a diagnostic conundrum, and the way it was solved is presented. A 13-year-old boy presented with recurrent seizures for the past 10 years. He had been treated with anticonvulsant medication which was satisfactory at first but later the seizures recurred. Recently, the frequency of the seizures increased with preictal dizziness and postictal drowsiness. Physical examination revealed mild left hemiparesis and left deviated gait irregularity. He was mentally alert but had not achieved all the developmental milestones as compared to normal child of his age. CT and MRI scan of the head showed hemiatrophic cerebral parenchyma with prominent sulci and encephalomalacia. 24-hour intensive video EEG monitoring revealed suppression of alpha rhythm and local slow wave activity on the side of the atrophic hemisphere. PET-CT showed highly functional left cerebral hemisphere and less functional right cerebral hemisphere. The patient underwent functional hemispherectomy under neurophysiological monitoring and the nonfunctional brain tissues were resected while selectively preserving the functional areas detected by fMRI and PET-CT scan. During follow up, the patient was seizure free as well as without difficulties in performing his daily activities and communications. Functional hemispherectomy for DDMS patient has a good prognosis.",
            "question": "What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.",
            "answers": {
                "answer_start": 9,
                "text": "cerebral hemiatrophy"
            }
        },
        {
            "context": "[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. INTRODUCTION: Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. OBJECTIVES: Mutations were identified in the TYR gene as responsible for oculocutaneous albinism type 1 in five Colombian individuals, and a new ophthalmic system was tested that corrected visual defects and symptoms in a patient with oculocutaneous albinism. MATERIALS AND METHODS: Samples were taken from 5 individuals, four of whom belong to a single family, along with a fifth individual not related to the family. Five exons in the TYR gene were sequenced to search for the gene carriers in the family and in the non-related individual. In addition, clinical ophthalmological evaluation and implementation of an new oculo-visual system was undertaken. RESULTS: A G47D and 1379delTT mutation was identified in the family. The unrelated individual carried a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus and photophobia. CONCLUSIONS: This is the first study in Colombia where albinism mutations are reported. The methods developed will enable future molecular screening studies in Colombian populations.",
            "question": "Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?",
            "answers": {
                "answer_start": 411,
                "text": "tyrosinase"
            }
        },
        {
            "context": "Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.",
            "question": "Which protein is the main marker of Cajal bodies?",
            "answers": {
                "answer_start": 629,
                "text": "coilin"
            }
        },
        {
            "context": "Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.",
            "question": "What is the role of eteplirsen in DMD patients?",
            "answers": {
                "answer_start": 325,
                "text": "skipping of dystrophin exon 51"
            }
        },
        {
            "context": "Protrusio acetabuli in Marfan's syndrome. Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems. Revised criteria for the clinical diagnosis of Marfan's syndrome regard skeletal involvement as a major criterion if at least four of eight typical skeletal manifestations are present, one of which is protrusio acetabuli. Using Kulman's method to determine the presence of protrusio, we analysed the pelvic X-rays of 15 patients with Marfan's syndrome and 15 controls. Protrusio was present in 47% (7/15) of Marfan patients, compared with 7% (1/15) of controls (P = 0.035). Using the revised criteria, the presence of protrusio would have affected the final diagnosis of Marfan's syndrome in only one patient out of 15. Therefore, we recommend that a pelvic X-ray is reserved for those cases in which the presence of protrusio will alter the final diagnosis. With regard to the radiological assessment of protrusio, in our opinion this can be performed simply and reliably using the position of the acetabular line alone.",
            "question": "What tissue is commonly affected in Marfan's syndrome",
            "answers": {
                "answer_start": 97,
                "text": "connective tissue"
            }
        },
        {
            "context": "Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study. We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.",
            "question": "What is the synonym of the lubag disease?",
            "answers": {
                "answer_start": 248,
                "text": "X-linked dystonia-parkinsonism"
            }
        },
        {
            "context": "Allele-specific silencing of Alzheimer's disease genes: the amyloid precursor protein genes with Swedish or London mutations. Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.",
            "question": "Which disease the London mutation involved in?",
            "answers": {
                "answer_start": 242,
                "text": "AD"
            }
        },
        {
            "context": "A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. OBJECTIVE: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS: In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: At week 12, ACR20 response rates for patients receiving all tofacitinib dosages > 3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P < 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION: In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage > 3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 2053,
                "text": "tofacitinib"
            }
        },
        {
            "context": "Two-site interaction of nuclear factor of activated T cells with activated calcineurin. Transcription factors belonging to the nuclear factor of activated T cells (NFAT) family regulate the expression of cytokine genes and other inducible genes during the immune response. The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin. Here we show that the binding of calcineurin to NFAT is substantially increased when calcineurin is activated with calmodulin and calcium. FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of NFAT with activated calcineurin much more effectively than they inhibited the interaction with inactive calcineurin, suggesting that part of the interaction with activated calcineurin involved the enzyme active site. We have previously shown that NFAT is targeted to inactive calcineurin at a region distinct from the calcineurin active site (Aramburu, J., Garcia-Cozar, F. J., Raghavan, A., Okamura, H., Rao, A., and Hogan, P. G. (1998) Mol. Cell 1, 627-637); this region is also involved in NFAT binding to activated calcineurin, since binding is inhibited by an NFAT peptide spanning the calcineurin docking site on NFAT. The interacting surfaces are located on the catalytic domain of the calcineurin A chain and on an 86-amino acid fragment of the NFAT regulatory domain. NFAT binding to the calcineurin catalytic domain was inhibited by the calcineurin autoinhibitory domain and the RII substrate peptide, which bind in the calcineurin active site, as well as by the NFAT docking site peptide, which binds to a region of calcineurin distinct from the active site. We propose that, in resting cells, NFAT is targeted to a region of the calcineurin catalytic domain that does not overlap the calcineurin active site. Upon cell activation, displacement of the autoinhibitory domain by calmodulin binding allows NFAT to bind additionally to the calcineurin active site, thus positioning NFAT for immediate dephosphorylation at functional phosphoserine residues.",
            "question": "Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?",
            "answers": {
                "answer_start": 381,
                "text": "calcineurin"
            }
        },
        {
            "context": "Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.",
            "question": "Which disease is treated with ZMapp?",
            "answers": {
                "answer_start": 22,
                "text": "Ebola virus disease"
            }
        },
        {
            "context": "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 433,
                "text": "xa"
            }
        },
        {
            "context": "microRNAs: a new frontier in kallikrein research. microRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression. Rapidly accumulating evidence has revealed that miRNAs are associated with cancer. The human tissue kallikrein gene family is the largest contiguous family of proteases in the human genome, containing 15 genes. Many kallikreins have been reported as potential tumor markers. In this review, recent bioinformatics and experimental evidence is presented indicating that kallikreins are potential miRNA targets. The available experimental approaches to investigate these interactions and the potential diagnostic and therapeutic applications are also discussed. miRNAs represent a possible regulatory mechanism for controlling kallikrein expression at the post-transcriptional level. Many miRNAs were predicted to target kallikreins and a single miRNA can target more than one kallikrein. Recent evidence suggests that miRNAs can also exert 'quantitative' control of kallikreins by utilizing multiple targeting sites in the kallikrein mRNA. More research is needed to experimentally verify the in silico predictions and to investigate the possible role in tumor initiation and/or progression.",
            "question": "How many tissue kallikrein genes are present in the human genome?",
            "answers": {
                "answer_start": 358,
                "text": "15"
            }
        },
        {
            "context": "Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 319,
                "text": "7"
            }
        },
        {
            "context": "OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.",
            "question": "Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica",
            "answers": {
                "answer_start": 132,
                "text": "OikoBase"
            }
        },
        {
            "context": "Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. OBJECTIVE: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the context of autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), which are caused by activating germline mutations in the RET proto-oncogene. The aim of this study was to characterize the RET mutational spectrum in MEN2 families and apparently sporadic MTC (AS-MTC) cases originating from the central region of Portugal. SUBJECTS AND METHODS: We studied a total of 82 individuals (64 affected and 18 family members), comprising five MEN2 families (four MEN2A and one MEN2B), as well as 53 AS-MTC cases. RET germline mutations were screened using PCR-DNA sequencing, SSCP and RFLP. The haplotypes associated with recurrent mutations were determined by fragment analysis of microsatellite markers, and by RFLP, in the case of intragenic polymorphisms. RESULTS: Frequency of the Cys611Tyr (TGC-TAC) mutation was significantly increased in this region of Portugal, due to the fact that three apparently unrelated MEN2A/FMTC families, out of the five in which mutations were identified, harboured this specific mutation. Haplotype analysis revealed that a common haplotype was shared between two of these three families. We have also characterized a novel RET mutation, Arg886Trp, located in the tyrosine kinase domain, which was found in an AS-MTC case. CONCLUSIONS: There are regional specificities in the relative frequency of RET mutations, which are consistent with a cluster-like distribution of specific disease-causing mutations, as a result of the inheritance of a shared haplotype. These data, along with the finding of a novel RET mutation (Arg886Trp), have important implications towards facilitating and improving the molecular diagnosis of hereditary MTC on a regional basis.",
            "question": "What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?",
            "answers": {
                "answer_start": 539,
                "text": "RET"
            }
        },
        {
            "context": "First deep intronic mutation in the NOTCH3 gene in a family with late-onset CADASIL. CADASIL is the most prominent inherited form of vascular dementia. The main clinical features include migraine with aura, stroke, mood disturbances, and cognitive decline, with a mid-life (30s-60s) adult onset. Genetic testing is the gold standard for the diagnosis. CADASIL is caused mostly by missense mutations in the NOTCH3 gene, invariably involving a cysteine residue. Only a couple of splice site mutations have been reported. In a few pathologically defined patients, genetic mutations remain unidentified. We report a family with late-onset CADASIL phenotype carrying a novel intronic deletion in the NOTCH3 gene (c.341-26_24delAAC). Transcript analysis revealed a splicing alteration, with the complete intron 3 retention. The insertion was in-frame and encoded an extra 25 amino acids, including 1 cysteine. This is the first report of an aberrant splicing event of the NOTCH3 gene associated with a mutation far away from the canonical splice site. Our finding suggests that the assays used to evaluate splicing should be mandatory in the diagnostic setting of genetically undefined CADASIL cases.",
            "question": "Which amino acid residue appears mutated in most of the cases reported with  cadasil syndrome?",
            "answers": {
                "answer_start": 442,
                "text": "cysteine"
            }
        },
        {
            "context": "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. BACKGROUND: Plasma kallikrein plays a major role in the contact (kallikrein-kinin) cascade producing bradykinin. Bradykinin is a vasodilator, which increases vascular permeability, activates inflammation and produces pain. Plasma kallikrein is also crosslinked to the coagulation system and the complement cascade. OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. Ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor. It was identified through phage display technology. METHODS: The search terms 'ecallantide', 'DX-88' and 'hereditary angioedema' were entered into Pubmed/Medline, ClinicalTrials and Google. RESULTS/CONCLUSION: At present, the drug is being studied for two major indications. First, the results for the treatment of hereditary angioedema are promising. Second, a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008.",
            "question": "DX-88 is investigational name of which drug?",
            "answers": {
                "answer_start": 0,
                "text": "Ecallantide"
            }
        },
        {
            "context": "Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics. OBJECTIVE: A frequent complication of Clostridium difficile infection (CDI) is recurrent disease. The aim of this study was to determine whether early recurrence risk was higher after infection with ribotype 027 (outbreak strain) compared with infection with endemic strain types of C. difficile. METHODS: Consecutive patients diagnosed with CDI between May 2013 and March 2014 were included (outbreak strain, and non-outbreak strains). Patients who developed recurrent CDI within 30 days after completion of CDI treatment, were compared with patients without a recurrence. Medical charts were reviewed for demographic and clinical characteristics. General practitioners were contacted to complete data about the occurrence of recurrent CDI, and the use of medication after hospital discharge. RESULTS: In total, 135 patients were at risk for the development of recurrent CDI; 74 patients were infected by ribotype 027, and 61 patients by other ribotypes. Thirty-nine patients (29%) developed recurrent CDI within 30 days after completion of CDI treatment. In multivariable analysis, age > 70 years (HR 3.05, 95% CI 1.54-6.03), and a duration of CDI treatment > 11 days (HR 1.92, 95% CI 1.00-3.69) were clearly associated with recurrence; infection with ribotype 027 showed a HR of 1.72 (95% CI 0.88-3.33). CONCLUSION: During this outbreak of C. difficile in a tertiary care centre, age and a prolonged duration of CDI therapy (which is most likely a marker of underlying disease severity) were the main risk factors for recurrent CDI. This points to host factors as more important predictors for recurrent CDI than strain type or antibiotic use.",
            "question": "Which main ribotype of Clostridium difficile is responsible of the recent outbreak?",
            "answers": {
                "answer_start": 325,
                "text": "ribotype 027"
            }
        },
        {
            "context": "Identification and characterization of a selenoprotein family containing a diselenide bond in a redox motif. Selenocysteine (Sec, U) insertion into proteins is directed by translational recoding of specific UGA codons located upstream of a stem-loop structure known as Sec insertion sequence (SECIS) element. Selenoproteins with known functions are oxidoreductases containing a single redox-active Sec in their active sites. In this work, we identified a family of selenoproteins, designated SelL, containing two Sec separated by two other residues to form a UxxU motif. SelL proteins show an unusual occurrence, being present in diverse aquatic organisms, including fish, invertebrates, and marine bacteria. Both eukaryotic and bacterial SelL genes use single SECIS elements for insertion of two Sec. In eukaryotes, the SECIS is located in the 3' UTR, whereas the bacterial SelL SECIS is within a coding region and positioned at a distance that supports the insertion of either of the two Sec or both of these residues. SelL proteins possess a thioredoxin-like fold wherein the UxxU motif corresponds to the catalytic CxxC motif in thioredoxins, suggesting a redox function of SelL proteins. Distantly related SelL-like proteins were also identified in a variety of organisms that had either one or both Sec replaced with Cys. Danio rerio SelL, transiently expressed in mammalian cells, incorporated two Sec and localized to the cytosol. In these cells, it occurred in an oxidized form and was not reducible by DTT. In a bacterial expression system, we directly demonstrated the formation of a diselenide bond between the two Sec, establishing it as the first diselenide bond found in a natural protein.",
            "question": "What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?",
            "answers": {
                "answer_start": 293,
                "text": "SECIS"
            }
        },
        {
            "context": "JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic and destructive inflammatory synovitis. The multiple cytokines play pivotal roles in RA pathogenesis by inducing intracellular signaling, and members of the Janus kinase (JAK) family are essential for such signal transduction. An orally available JAK3 inhibitor, tofacitinib, has been applied for RA, with satisfactory effects and acceptable safety in multiple clinical examinations. From phase 2 dose-finding studies, tofacitinib 5 mg and 10 mg twice a day appear suitable for further evaluation. Subsequently, multiple phase 3 studies were carried out, and tofacitinib with or without methotrexate (MTX) is efficacious and has a manageable safety profile in active RA patients who are MTX naïve or show inadequate response to methotrexate (MTX-IR), disease-modifying antirheumatic drugs (DMARD)-IR, or tumor necrosis factor (TNF)-inhibitor-IR. The common adverse events were infections, such as nasopharyngitis; increases in cholesterol, transaminase, and creatinine; and decreases in neutrophil counts. Although the mode of action of tofacitinib remains unclear, we clarified that the inhibitory effects of tofacitinib could be mediated through suppression of interleukin (IL)-17 and interferon (IFN)-γ production and proliferation of CD4(+) T cells in the inflamed synovium. Taken together, an orally available kinase inhibitor tofacitinib targeting JAK-mediated signals would be expected to be a new option for RA treatment.",
            "question": "Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?",
            "answers": {
                "answer_start": 14,
                "text": "tofacitinib"
            }
        },
        {
            "context": "A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES).",
            "question": "Mutation of which gene is implicated in the Christianson syndrome?",
            "answers": {
                "answer_start": 57,
                "text": "SLC9A6"
            }
        },
        {
            "context": "BACE-1 inhibition prevents the γ-secretase inhibitor evoked Aβ rise in human neuroblastoma SH-SY5Y cells. BACKGROUND: Accumulation of amyloid β-peptide (Aβ) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aβ peptides. Preventing Aβ formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development. METHODS: Combining BACE-1 and γ-secretase inhibition on Aβ secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Aβ40 and Aβ42 levels were measured from SH-SY5Y cells stably transfected with APPwt or APPswe genes. A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase. RESULTS: LY450139 increased Aβ40 and Aβ42 secretion from SH-SY5Y APPwt cells at low concentrations (by 60% at 3 nM) followed by subsequent inhibition at higher concentrations (IC(50) 90 nM). Washout studies showed that the Aβ increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Aβ formation. By contrast, LY450139 inhibited Aβ formation from SH-SY5Y APPswe in a monophasic manner (IC(50) 18 nM). The BACE inhibitor per se inhibited Aβ secretion from both SH-SY5Y APPwt and SH-SY5Y APPswe cells with IC(50)s ranging between 7 - 18 nM and also prevented the increased Aβ secretion evoked by 3 nM LY450139. Combining the BACE inhibitor with higher inhibitory concentrations of LY450139 failed to demonstrate any clear additive or synergistic effects. CONCLUSION: BACE-1 inhibition attenuates the Aβ increase evoked by LY450139 while not providing any obvious synergistic effects on LY450139-mediated inhibition.",
            "question": "LY450139 is investigational name of which drug?",
            "answers": {
                "answer_start": 854,
                "text": "semagacestat"
            }
        },
        {
            "context": "XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1β-mediated diseases. Interleukin-1β (IL-1β) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1β are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1β-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists. To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. XOMA 052 has a 300 femtomolar binding affinity for human IL-1β and an in vitro potency in the low picomolar range. XOMA 052 binds to a unique IL-1β epitope where residues critical for binding have been identified. We have previously reported that XOMA 052 is efficacious in vivo in a diet-induced obesity mouse model thought to be driven by low levels of chronic inflammation. We report here that XOMA 052 also reduces acute inflammation in vivo, neutralizing the effect of exogenously administered human IL-1β and blocking peritonitis in a mouse model of acute gout. Based on its high potency, novel mechanism of action, long half-life, and high affinity, XOMA 052 provides a new strategy for the treatment of a number of inflammatory, autoimmune and metabolic diseases in which the role of IL-1β is central to pathogenesis.",
            "question": "Which molecule is targeted by the drug Gevokizumab?",
            "answers": {
                "answer_start": 764,
                "text": "IL-1β"
            }
        },
        {
            "context": "Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome. The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes.",
            "question": "Which mutated gene is associated with Waardenburg and Tietz syndromes?",
            "answers": {
                "answer_start": 36,
                "text": "Mitf"
            }
        },
        {
            "context": "Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design. The exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase α from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1.",
            "question": "Which stapled peptide has been designed to target Ctf4?",
            "answers": {
                "answer_start": 777,
                "text": "the stapled Sld5 peptide"
            }
        },
        {
            "context": "JTV519 (K201) reduces sarcoplasmic reticulum Ca²⁺ leak and improves diastolic function in vitro in murine and human non-failing myocardium. BACKGROUND AND PURPOSE: Ca²⁺ leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca²⁺ leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²⁺ leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH: SR Ca²⁺ leak was induced by ouabain in murine cardiomyocytes. [Ca²⁺]-transients, SR Ca²⁺ load and RyR2-mediated Ca²⁺ leak (sparks/waves) were quantified, with or without JTV519 (1 µmol·L⁻¹). Contribution of Ca²⁺ -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY RESULTS: Ouabain increased systolic and diastolic cytosolic [Ca²⁺](i) , SR [Ca²⁺], and SR Ca²⁺ leak (Ca²⁺ spark (SparkF) and Ca²⁺ wave frequency), independently of CaMKII and RyR-Ser(2814) phosphorylation. JTV519 decreased SparkF but also SR Ca²⁺ load. At matched SR [Ca²⁺], Ca²⁺ leak was significantly reduced by JTV519, but it had no effect on fractional Ca²⁺ release or Ca²⁺ wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS: JTV519 was effective in reducing SR Ca²⁺ leak by specifically regulating RyR2 opening at diastolic [Ca²⁺](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca²⁺ overload.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 384,
                "text": "benzothiazepine"
            }
        },
        {
            "context": "[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 500,
                "text": "CD38"
            }
        },
        {
            "context": "Two cap-binding proteins CBP20 and CBP80 are involved in processing primary MicroRNAs. MicroRNAs (miRNAs) are 21 nt RNAs that regulate many biological processes in plants by mediating translational inhibition or cleavage of target transcripts. Arabidopsis mutants defective in miRNA biogenesis have overlapping and highly pleiotropic phenotypes including serrated leaves and ABA hypersensitivity. Recent evidence indicates that miRNA genes are transcribed by RNA polymerase II (Pol II). Since Pol II transcripts are capped, we hypothesized that CBP (cap-binding protein) 20 and 80 may bind to capped primary miRNA (pri-miRNA) transcripts and play a role in their processing. Here, we show that cbp20 and cbp80 mutants have reduced miRNA levels and increased pri-miRNA levels. Co-immunoprecipitation experiments revealed that pri-miRNAs 159, 166, 168 and 172 could be associated with CBP20 and CBP80. We found that CBP20 and CBP80 are stabilized by ABA by a post-translational mechanism, and these proteins are needed for ABA induction of miR159 during seed germination. The lack of miR159 accumulation in ABA-treated seeds of cbp20/80 mutants leads to increased MYB33 and MYB101 transcript levels, and presumably higher levels of these positive regulators result in ABA hypersensitivity. Genetic and molecular analyses show that CBP20 and 80 have overlapping function in the same developmental pathway as SE and HYL1. Our results identify new components in miRNA biogenesis.",
            "question": "Which polymerase transcribes pri-miRNAs?",
            "answers": {
                "answer_start": 459,
                "text": "RNA polymerase II"
            }
        },
        {
            "context": "Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease. Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.",
            "question": "Which disease is treated with taliglucerase alfa?",
            "answers": {
                "answer_start": 271,
                "text": "Gaucher disease"
            }
        },
        {
            "context": "Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas. BACKGROUND: Facial nerve preservation surgery for large vestibular schwannomas is a novel strategy for maintaining normal nerve function by allowing residual tumor adherent to this nerve or root-entry zone. OBJECTIVE: To report, in a retrospective study, outcomes for large Koos grade 3 and 4 vestibular schwannomas. METHODS: After surgical treatment for vestibular schwannomas in 52 patients (2004-2013), outcomes included extent of resection, postoperative hearing, and facial nerve function. Extent of resection defined as gross total, near total, or subtotal were 7 (39%), 3 (17%), and 8 (44%) in 18 patients after retrosigmoid approaches, respectively, and 10 (29.5%), 9 (26.5%), and 15 (44%) for 34 patients after translabyrinthine approaches, respectively. RESULTS: Hearing was preserved in 1 (20%) of 5 gross total, 0 of 2 near-total, and 1 (33%) of 3 subtotal resections. Good long-term facial nerve function (House-Brackmann grades of I and II) was achieved in 16 of 17 gross total (94%), 11 of 12 near-total (92%), and 21 of 23 subtotal (91%) resections. Long-term tumor control was 100% for gross total, 92% for near-total, and 83% for subtotal resections. Postoperative radiation therapy was delivered to 9 subtotal resection patients and 1 near-total resection patient. Follow-up averaged 33 months. CONCLUSION: Our findings support facial nerve preservation surgery in becoming the new standard for acoustic neuroma treatment. Maximizing resection and close postoperative radiographic follow-up enable early identification of tumors that will progress to radiosurgical treatment. This sequential approach can lead to combined optimal facial nerve function and effective tumor control rates.",
            "question": "Which disease can be categorized using the Koos grading system?",
            "answers": {
                "answer_start": 57,
                "text": "vestibular schwannoma"
            }
        },
        {
            "context": "Investigational anticoagulants for hematological conditions: a new generation of therapies. INTRODUCTION: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options. AREAS COVERED: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV. EXPERT OPINION: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 626,
                "text": "xa"
            }
        },
        {
            "context": "Posttraumatic stress disorder in victims of the March 11 attacks in Madrid admitted to a hospital emergency room: 6-month follow-up. PURPOSE: To determine the change in prevalence of posttraumatic stress disorder (PTSD) symptoms in victims of the March 11 attacks and their relatives, 1 and 6 months after the attacks. SUBJECTS AND METHODS: Evaluation of PTSD symptoms using the Davidson Trauma Scale (DTS) and General Health Questionnaire (GHQ) in a sample of 56 patients admitted to an emergency room of a general hospital, and assessment of PTSD symptoms in relatives of the patients. RESULTS: At Month 1, 41.1% of patients (31.3% of males and 54.2% of females) presented with PTSD. At Month 6, this figure was 40.9% (30.4% of males and 52.4% of females). There was a significant improvement in perception of health among females between Month 1 and Month 6. Relatives presented similar DTS scores at baseline and at 6 months. DISCUSSION: We verified that rates of PTSD did not vary substantively between the two evaluations. PTSD symptoms positively correlated with psychological health involvement. This correlation points out that both PTSD symptoms and subjective general health involvement are part of the psychological response to trauma. CONCLUSION: The prevalence of PTSD symptoms was high and remained stable between Month 1 and Month 6, while subjective perception of health improved significantly.",
            "question": "Symptoms of which disorder are evaluated with the Davidson Trauma Scale?",
            "answers": {
                "answer_start": 355,
                "text": "PTSD"
            }
        },
        {
            "context": "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 183,
                "text": "Xa"
            }
        },
        {
            "context": "Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation D307H (CASQ2(D307H)) on Ca2+ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated approximately 4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2(WT)) or CASQ2(D307H). Expression of CASQ2(D307H) reduced the Ca2+ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks were reduced significantly in myocytes expressing CASQ2(D307H). Myocytes expressing CASQ2(D307H) also displayed drastic disturbances of rhythmic oscillations in [Ca2+]i and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca2+ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2(D307H) mutation impairs SR Ca2+ storing and release functions and destabilizes the Ca2+-induced Ca2+ release mechanism by reducing the effective Ca2+ buffering inside the SR and/or by altering the responsiveness of the Ca2+ release channel complex to luminal Ca2+. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.",
            "question": "Which is the main calcium binding protein of the sarcoplasmic reticulum?",
            "answers": {
                "answer_start": 137,
                "text": "CASQ"
            }
        },
        {
            "context": "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.",
            "question": "The drug JTV519 is derivative of which group of chemical compounds?",
            "answers": {
                "answer_start": 366,
                "text": "1,4-benzothiazepine"
            }
        },
        {
            "context": "[Alu repeats in the human genome]. Highly repetitive DNA sequences account for more than 50% of the human genome. The L1 and Alu families harbor the most common mammalian long (LINEs) and short (SINEs) interspersed elements. Alu elements are each a dimer of similar, but not identical, fragments of total size about 300 bp, and originate from the 7SL RNA gene. Each element contains a bipartite promoter for RNA polymerase III, a poly(A) tract located between the monomers, a 3'-terminal poly(A) tract, and numerous CpG islands, and is flanked by short direct repeats. Alu repeats comprise more than 10% of the human genome and are capable of retroposition. Possibly, these elements played an important part in genome evolution. Insertion of an Alu element into a functionally important genome region or other Alu-dependent alterations of gene functions cause various hereditary disorders and are probably associated with carcinogenesis. In total, 14 Alu families differing in diagnostic mutations are known. Some of these, which are present in the human genome, are polymorphic and relatively recently inserted into new loci. Alu copies transposed during ethnic divergence of the human population are useful markers for evolutionary genetic studies.",
            "question": "From which sequence does the Alu repeat originate from?",
            "answers": {
                "answer_start": 347,
                "text": "7SL RNA"
            }
        },
        {
            "context": "Microsatellite analysis in Turner syndrome: parental origin of X chromosomes and possible mechanism of formation of abnormal chromosomes. Turner syndrome is a chromosomal disorder in which all or part of one X chromosome is missing. The meiotic or mitotic origin of most cases remains unknown due to the difficulty in detecting hidden mosaicism and to the lack of meiotic segregation studies. We analyzed 15 Turner patients, 10 with a 45,X whereas the rest had a second cell line with abnormal X-chromosomes: a pseudodicentric, an isochromosome, one large and one small ring, and the last with a long arm deletion. Our aims were: to detect X cryptic mosaicism in patients with a 45,X constitution; to determine the parental origin of the abnormality; to infer the zygotic origin of the karyotype and to suggest the timing and mechanism of the error(s) leading to the formation of abnormal X chromosomes from maternal origin. Molecular investigation did not revealed heterozygosity for any microsatellite, excluding X mosaicism in the 45,X cases. Parental origin of the single X chromosome was maternal in 90% of these patients. Three of the structurally abnormal Xs were maternally derived whereas the other two were paternal. These results allowed us to corroborate breakpoints in these abnormal X chromosomes and suggest that the pseudodicentric chromosome originated from post-zygotic sister chromatid exchange, whereas the Xq deleted chromosome probably arose after a recombination event during maternal meiosis.",
            "question": "What chromosome is affected in Turner's syndrome?",
            "answers": {
                "answer_start": 208,
                "text": "X"
            }
        },
        {
            "context": "CancerSubtypes: an R/Bioconductor package for molecular cancer subtype identification, validation and visualization. Summary: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). Contact: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.",
            "question": "Which R/Bioconductor package has been developed for cancer subtype identification?",
            "answers": {
                "answer_start": 405,
                "text": "CancerSubtypes"
            }
        },
        {
            "context": "Heme and FLVCR-related transporter families SLC48 and SLC49. Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.",
            "question": "Which SLC family is FLVCR1 a member of?",
            "answers": {
                "answer_start": 265,
                "text": "SLC49"
            }
        },
        {
            "context": "The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells. BACKGROUND: Stromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. EXPERIMENTAL DESIGN: We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry. RESULTS: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases. CONCLUSIONS: MLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.",
            "question": "Which enzyme does MLN4924 inhibit?",
            "answers": {
                "answer_start": 459,
                "text": "Nedd8-activating enzyme"
            }
        },
        {
            "context": "Mortality in children with severe epilepsy: 10 years of follow-up. Epilepsy is the main neurological condition in children and adolescents. Unfortunately patients with medical refractory epilepsy are more susceptible for clinical complications and death. We report a prospectively evaluated cohort of children followed for approximately 10 years. Fifty-three of 1012 patients died. Forty-two patients died due to epilepsy or its clinical complications and the main causes of death were pneumonia (in 16 cases), sepsis (in 9 patients), status epilepticus (in 8 patients). In 11 patients cause of death was sudden unexpected death in epilepsy (SUDEP). Mental retardation was significantly more frequent in patients who did not die from SUDEP. SUDEP may be a significant condition associated with mortality in children and adolescents with epilepsy.",
            "question": "What condition is usually represented by the acronym SUDEP?",
            "answers": {
                "answer_start": 605,
                "text": "sudden unexpected death in epilepsy (SUDEP)"
            }
        },
        {
            "context": "Surgery for convexity meningioma: Simpson Grade I resection as the goal: clinical article. OBJECT: Recently the relevance of Simpson resection grade as a prognostic factor for recurrence of WHO Grade I meningiomas was challenged, contradicting many previous scientific reports and traditional neurosurgical teaching. The objective of this study was to determine whether the predictive value of Simpson resection grade is outdated or remains valid with respect to meningioma recurrence and overall survival. METHODS: All patients at least 16 years old who underwent primary craniotomies for convexity meningiomas at Oslo University-affiliated hospitals (Rikshospitalet and Ullevål University Hospitals) in the period between January 1, 1990, and January 27, 2011, were included. Overall survival and retreatment-free survival rates were correlated with patient- and surgery-specific factors. RESULTS: Three hundred ninety-one consecutive patients were included in the study. The median patient age was 60.1 years (range 19-92 years). The female-to-male ratio was 2.1:1. The WHO grades were Grade I in 353 (90.3%), Grade II in 22 (5.6%), and Grade III in 16 (4.1%). The follow-up rate was 100%. Median follow-up time was 7.1 years (range 0.0-20.9 years) and total observation time was 3147 patient-years. The 1-, 5-, and 10-year overall survival rates were 96%, 89%, and 78%, respectively. Age, sex, WHO grade, and Simpson grade were significantly associated with overall survival. The 1-, 5-, and 10-year retreatment-free survival rates were 99%, 94%, and 90%, respectively. Simpson resection grade and WHO grade were significantly associated with retreatment-free survival. The hazard ratios for retreatment after combined Simpson resection Grades II+III and IV+V were 4.9- and 13.2-times higher than after Simpson Grade I resection, respectively. CONCLUSIONS: Simpson Grade I resection should continue to be the goal for convexity meningiomas.",
            "question": "Simpson grading is used to describe resection of which brain tumor?",
            "answers": {
                "answer_start": 22,
                "text": "meningioma"
            }
        },
        {
            "context": "Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I. The classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown. We investigated whether cEDS affected the protein synthesis rate in skin and tendon, and whether this could be stimulated in tendon tissue with insulin-like growth factor-I (IGF-I). Five patients with cEDS and 10 healthy, matched controls (CTRL) were included. One patellar tendon of each participant was injected with 0.1 ml IGF-I (Increlex, Ipsen, 10 mg/ml) and the contralateral tendon with 0.1 ml isotonic saline as control. The injections were performed at both 24 and 6 h prior to tissue sampling. The fractional synthesis rate (FSR) of proteins in skin and tendon was measured with the stable isotope technique using a flood-primed continuous infusion over 6 h. After the infusion one skin biopsy and two tendon biopsies (one from each patellar tendon) were obtained. We found similar baseline FSR values in skin and tendon in the cEDS patients and controls [skin: 0.005 ± 0.002 (cEDS) and 0.007 ± 0.002 (CTRL); tendon: 0.008 ± 0.001 (cEDS) and 0.009 ± 0.002 (CTRL) %/h, mean ± SE]. IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0.007 ± 0.002, CTRL 0.001 ± 0.001%/h). In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.",
            "question": "What tissue is most affected in Ehlers-Danlos syndromes?",
            "answers": {
                "answer_start": 183,
                "text": "connective tissue"
            }
        },
        {
            "context": "Association of restless legs syndrome variants in Korean patients with restless legs syndrome. STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can be attributed to an epistasis. The study objectives were to evaluate whether the associations of RLS with all loci determined in previous GWAS for Caucasians can be replicated significantly for the Korean population and to elucidate whether an epistasis plays a role in the pathogenesis of RLS. DESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and sex-matched controls were genotyped for variants in the RLS loci. MEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and rs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) for rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for rs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of inheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 in PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the dominant model and 2.47 (P = 0.004) in the recessive model. There was no significant association between genotypes of all tested single nucleotide polymorphisms and the mean value of serum iron parameters. CONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of restless legs syndrome is more universal across populations than previously reported and more efforts should be focused on the role of epistasis in the genetic architecture of restless legs syndrome.",
            "question": "Willis-Ekbom disease is also known as?",
            "answers": {
                "answer_start": 255,
                "text": "restless legs syndrome"
            }
        },
        {
            "context": "[Krabbe disease (globoid cell leukodystrophy)]. Krabbe disease is an autosomal recessive inherited demyelinating disease, which is deficient in lysosomal enzyme, galactocerebrosidase. Pathophysiological characteristics of this disease are extreme demyelination in white matter and peripheral nerve, existence of globoid cells, absence of accumulation of main substrates, i.e. galactocerebrosidase in tissues and accumulation of psychosine. Molecular basis of this disease including isolation of a cDNA for human and murine galactocerebrosidase and cloning of genome of this gene are reviewed. The trial of gene therapy on twitcher, the mouse model of Krabbe disease, could break through on therapy on this progressive demyelinating disease.",
            "question": "Which enzyme is deficient in Krabbe disease?",
            "answers": {
                "answer_start": 162,
                "text": "galactocerebrosidase"
            }
        },
        {
            "context": "Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. This article discusses the infection control and public health measures taken whilst managing a case of laboratory-confirmed rabies, and the challenges faced in implementing these measures. Case management requires intensive multi-disciplinary co-ordination. The Milwaukee protocol, which to date has five reported human rabies survivors associated with its use, has been suggested as a potential management pathway for human rabies. Consensus among hospital and public health clinicians would aid future deployment of this approach in selected cases.",
            "question": "Milwaukee protocol was tested for treatment of which disease?",
            "answers": {
                "answer_start": 444,
                "text": "rabies"
            }
        },
        {
            "context": "Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.",
            "question": "Which clotting factor is inhibited by betrixaban?",
            "answers": {
                "answer_start": 584,
                "text": "xa"
            }
        },
        {
            "context": "XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression, and apoptosis. X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes' stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater. High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability.",
            "question": "What is the target of the drug Olaparib?",
            "answers": {
                "answer_start": 843,
                "text": "PARP"
            }
        },
        {
            "context": "Disruption of SMIM1 causes the Vel- blood type. Here, we report the biochemical and genetic basis of the Vel blood group antigen, which has been a vexing mystery for decades, especially as anti-Vel regularly causes severe haemolytic transfusion reactions. The protein carrying the Vel blood group antigen was biochemically purified from red blood cell membranes. Mass spectrometry-based de novo peptide sequencing identified this protein to be small integral membrane protein 1 (SMIM1), a previously uncharacterized single-pass membrane protein. Expression of SMIM1 cDNA in Vel- cultured cells generated anti-Vel cell surface reactivity, confirming that SMIM1 encoded the Vel blood group antigen. A cohort of 70 Vel- individuals was found to be uniformly homozygous for a 17 nucleotide deletion in the coding sequence of SMIM1. The genetic homogeneity of the Vel- blood type, likely having a common origin, facilitated the development of two highly specific DNA-based tests for rapid Vel genotyping, which can be easily integrated into blood group genotyping platforms. These results answer a 60-year-old riddle and provide tools of immediate assistance to all clinicians involved in the care of Vel- patients.",
            "question": "Which gene-defect causes the Vel-blood type?",
            "answers": {
                "answer_start": 770,
                "text": "a 17 nucleotide deletion"
            }
        },
        {
            "context": "Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.",
            "question": "Where can you find the annulus of Zinn?",
            "answers": {
                "answer_start": 1031,
                "text": "orbit"
            }
        },
        {
            "context": "A frameshift mutation in the LYST gene is responsible for the Aleutian color and the associated Chédiak-Higashi syndrome in American mink. One of the colors of mink is Aleutian (aa)-a specific gun-metal gray pigmentation of the fur-commonly used in combination with other color loci to generate popular colors such as Violet (aammpp) and Sapphire (aapp). The Aleutian color allele is a manifestation of mink Chédiak-Higashi syndrome (CHS), which has been described in humans and several other species. As with forms of CHS in other species, we report that the mink CHS is linked to the lysosomal trafficking regulator ( LYST ) gene. Furthermore, we have identified a base deletion (c.9468delC) in exon 40 of LYST, which causes a frameshift and virtually terminates the LYST product prematurely (p.Leu3156Phefs*37). We investigated the blood parameters of three wild-type mink and three CHS mink. No difference in the platelet number between the two groups was observed, but an accumulation of platelets between the groups appears different when collagen is used as a coagulant. Microscopic analysis of peripheral blood indicates giant inclusions in the neutrophils of the Aleutian mink types. Molecular findings at the LYST locus enable the development of genetic tests for analyzing the color selection in American mink.",
            "question": "Which mutated gene causes the Chédiak–Higashi Syndrome?",
            "answers": {
                "answer_start": 29,
                "text": "LYST gene"
            }
        },
        {
            "context": "Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency. Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency.",
            "question": "Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?",
            "answers": {
                "answer_start": 49,
                "text": "DNMT1"
            }
        },
        {
            "context": "First detection of Nosema ceranae, a microsporidian parasite of European honey bees (Apis mellifera), in Canada and central USA. Nosema ceranae is an emerging microsporidian parasite of European honey bees, Apis mellifera, but its distribution is not well known. Six Nosema-positive samples (determined from light microscopy of spores) of adult worker bees from Canada (two each from Nova Scotia, New Brunswick, and Prince Edward Island) and two from USA (Minnesota) were tested to determine Nosema species using previously-developed PCR primers of the 16S rRNA gene. We detected for the first time N. ceranae in Canada and central USA. One haplotype of N. ceranae was identified; its virulence may differ from that of other haplotypes.",
            "question": "What is the genus for the common European honey bee?",
            "answers": {
                "answer_start": 85,
                "text": "Apis"
            }
        },
        {
            "context": "Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport. Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts. Our understanding of the function of phospholamban stems primarily from studies in genetically altered mouse models. To evaluate the significance of this protein in larger mammalian species, which exhibit Ca cycling properties similar to humans, we overexpressed phospholamban in adult rabbit cardiomyocytes. Adenoviral-mediated gene transfer, at high multiplicities of infection, resulted in an insignificant 1.22-fold overexpression of phospholamban. There were no effects on twitch Ca-transient amplitude or decay under basal or isoproterenol-stimulated conditions. Furthermore, the SR Ca load and Na/Ca exchanger function were not altered. These apparent differences between phospholamban overexpression in rabbit compared with previous findings in the mouse may be due to a significantly higher (1.5-fold) endogenous phospholamban-to-sarco(endo)plasmic reticulum Ca-ATPase (SERCA) 2a ratio and potential functional saturation of SERCA2a by phospholamban in rabbit cardiomyocytes. The findings suggest that important species-dependent differences in phospholamban regulation of SERCA2a occur. In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve.",
            "question": "Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?",
            "answers": {
                "answer_start": 112,
                "text": "Phospholamban"
            }
        },
        {
            "context": "Restless leg syndrome manifested by iron deficiency from chronic hemoptysis in cystic fibrosis. Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be a continuum of a neurological sleep disorder associated with abnormal iron metabolism or deficiency. I describe a case of RLS and PLMD in a cystic fibrosis patient with iron deficiency from chronic hemoptysis. This is the first case that reports RLS and PLMD manifesting from iron deficiency caused by chronic hemoptysis in advanced cystic fibrosis lung disease.",
            "question": "Which deficiency is the cause of restless leg syndrome?",
            "answers": {
                "answer_start": 36,
                "text": "iron"
            }
        },
        {
            "context": "Resolving the daratumumab interference with blood compatibility testing. BACKGROUND: Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS: DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS: Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION: DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.",
            "question": "Which molecule is targeted by Daratumumab?",
            "answers": {
                "answer_start": 1516,
                "text": "CD38"
            }
        },
        {
            "context": "The anti-apoptotic protein HAX-1 is a regulator of cardiac function. The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as a regulator of contractility and calcium cycling in the heart. HAX-1 overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium kinetics and mechanics. Conversely, downregulation of HAX-1 enhanced calcium cycling and contractility. The inhibitory effects of HAX-1 were abolished upon phosphorylation of phospholamban, which plays a fundamental role in controlling basal contractility and constitutes a key downstream effector of the beta-adrenergic signaling cascade. Mechanistically, HAX-1 promoted formation of phospholamban monomers, the active/inhibitory units of the calcium pump. Indeed, ablation of PLN rescued HAX-1 inhibition of contractility in vivo. Thus, HAX-1 represents a regulatory mechanism in cardiac calcium cycling and its responses to sympathetic stimulation, implicating its importance in calcium homeostasis and cell survival.",
            "question": "Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?",
            "answers": {
                "answer_start": 101,
                "text": "(HAX-1)"
            }
        },
        {
            "context": "Differential effects of diverse p53 isoforms on TAp73 transcriptional activity and apoptosis. The p53 activities are due, at least in part, to its ability to form oligomers that bind to specific DNA sequences and activate transcription. Since some mutant p53 proteins and ΔNp73 isoforms form heterocomplexes with TAp73, we asked whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73. Moreover, it has already been found that some isoforms form complex with wtp53 and some of them inhibit p53 tumor-suppressor functions. Therefore, we studied the complex formation and co-immunoprecipitation assays show that all six p53 isoforms examined can form complexes with TAp73β, whereas only Δ133p53α/β/γ isoforms form complex with TAp73α. All p53 isoforms counteract TAp73β transactivation function but with different efficiency and in a promoter-dependent manner. Furthermore, apoptotic activity of TAp73β was augmented by coexpression of p53β, whereas Δ133p53α and β inhibit its apoptotic activity most efficiently. We have determined the half-life of different p53 isoforms: p53γ isoform has the shortest half-life, whereas Δ133p53γ has the longest half-life. Inhibitory interactions of two proteins in complex often lead to their stabilization. However, only three isoforms (Δ133p53α, Δ133p53β and Δ40p53α) stabilize TAp73β. We are convinced that defining the interactions between p53/p73 would give a new insight into how the p53 isoforms modulate the p73 functions in tumorigenesis.",
            "question": "How many TAp73 isoforms have been identified in humans?",
            "answers": {
                "answer_start": 316,
                "text": "7"
            }
        },
        {
            "context": "methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.",
            "question": "Which R package is used for the analysis of genome-wide DNA methylation profiles?",
            "answers": {
                "answer_start": 272,
                "text": "methylKit"
            }
        },
        {
            "context": "The chorea of McLeod syndrome. Among the movement disorders associated with acanthocytosis, McLeod syndrome (McKusick 314850) is the one that is best characterized on the molecular level. Its defining feature is low reactivity of Kell erythrocyte antigens. This is due to absence of membrane protein KX that forms a complex with the Kell protein. KX is coded for by the XK gene on the X-chromosome. We present six males (aged 29 to 60 years), with proven XK mutations, to discuss the chorea associated with McLeod syndrome. The movement disorder commonly develops in the fifth decade and is progressive. It affects the limbs, the trunk and the face. In addition to facial grimacing, involuntary vocalization can be present. In early stages there may only be some restlessness or slight involuntary distal movements of ankles and fingers. Lip-biting and facial tics seem more common in autosomal recessive choreoacanthocytosis linked to chromosome 9. This, together with the absence of dysphagia in McLeod syndrome, may help in differential diagnosis. Recent findings suggest a role for the endothelin system of the striatum in the pathogenesis of McLeod syndrome.",
            "question": "Mutation of which gene is associated with McLeod syndrome?",
            "answers": {
                "answer_start": 455,
                "text": "XK"
            }
        }
    ]
}